Abstract
Rationale
The past 25 years have seen huge progress in understanding of the pathobiology of type-2 (T2) asthma, identification of measurable biomarkers, and the emergence of novel monoclonal antibody treatments. Although present in a minority of patients with severe asthma, very little is known about the mechanisms underlying T2-low asthma, making it a significant unmet need in asthma research.
Objectives
The objective of this study was to explore the differences between study exacerbators and nonexacerbators, to describe physiological changes at exacerbation in those who are T2HIGH and T2LOW at the time of exacerbation, and to evaluate the stability of inflammatory phenotypes when stable and at exacerbation.
Methods
Exacerbation assessment was a prespecified secondary analysis of data from a 48-week, multicenter, randomized controlled clinical study comparing the use of biomarkers and symptoms to adjust steroid treatment in a T2-low severe asthma–enriched cohort. Participants were phenotyped as T2LOW (fractional exhaled nitric oxide ⩽ 20 ppb and blood eosinophil count ⩽ 150 cells/µl) or T2HIGH (fractional exhaled nitric oxide > 20 or blood eosinophil count > 150) at study enrollment and at each exacerbation. Here, we report the findings of the exacerbation analyses, including comparison of exacerbators and nonexacerbators, the physiological changes at exacerbation in those who had evidence of T2 biology at exacerbation versus those that did not, and the stability of inflammatory phenotypes when stable and at exacerbation.
Measurements and Main Results
Of the 301 participants, 60.8% (183) had one or more self-reported exacerbations (total of 390). Exacerbators were more likely to be female, have a higher body mass index, and have more exacerbations requiring oral corticosteroid and unscheduled primary care attendances for exacerbations. At enrollment, 23.6% (71) were T2LOW and 76.4% (230) T2HIGH. The T2LOW group had more asthma primary care attendances, were more likely to have a previous admission to HDU (high dependency unit)/ICU and to be receiving maintenance oral corticosteroids. At exacerbation, the T2LOW events were indistinguishable from T2HIGH exacerbations in terms of lung function (mean fall in T2LOW FEV1, 200 [400] ml vs. T2HIGH 200 [300] ml; P = 0.93) and symptom increase (ACQ5: T2LOW, 1.4 [0.8] vs. T2HIGH, 1.3 [0.8]; P = 0.72), with no increase in T2 biomarkers from stable to exacerbation state in the T2LOW exacerbations. The inflammatory phenotype within individual patients was dynamic; inflammatory phenotype at study entry did not have a significant association with exacerbation phenotype.
Conclusions
Asthma exacerbations demonstrating a T2LOW phenotype were physiologically and symptomatically similar to T2HIGH exacerbations. T2LOW asthma was an unstable phenotype, suggesting that exacerbation phenotyping should occur at the time of exacerbation. The clinically significant exacerbations in participants without evidence of T2 biology at the time of exacerbation highlight the unmet and pressing need to further understand the mechanisms at play in non-T2 asthma.
Clinical trial registered with www.clinicaltrials.gov (NCT02717689).
Keywords: severe asthma, T2-low, exacerbation
At a Glance Commentary
Scientific Knowledge on the Subject
Understanding the clinical presentation, physiological changes, and underlying inflammatory processes in non–type-2 (T2) exacerbations in severe asthma is a critically important and currently an unmet research need as supported by the absence of any published prospective observational data describing T2-low exacerbations in severe asthma.
What This Study Adds to the Field
These data show that asthma exacerbations without evidence of T2 biology were physiologically and symptomatically similar to T2-high exacerbations. The T2 phenotype was not stable, suggesting that exacerbation phenotyping should occur at the time of exacerbation. The clinically significant exacerbations in participants without evidence of T2 biology at the time of exacerbation highlights the unmet and pressing need to further understand the mechanisms at play in non-T2 asthma.
Patients with inadequately controlled severe asthma despite optimized controller therapies shoulder much of the disability, economic burden and healthcare consumption attributed to asthma (1–5). Exacerbation events that result from type-2 (T2) cytokine-driven eosinophilic inflammation are an important aspect of poor asthma control, and T2 biomarkers (peripheral blood eosinophils [PBE] and fractional exhaled nitric oxide [FeNO]) serve well as predictors of exacerbation risk (6–9). Despite the involvement of cytokine-driven eosinophilic inflammation in exacerbations, patients with well-suppressed T2 biology, including those receiving T2-suppressing biological agents, continue to experience exacerbations (9–14).
A proportion of patients in severe asthma clinics are characterized as having noneosinophilic, “T2 low” asthma, a phenotype often associated with smoking, obesity, and recurrent or persistent bacterial infection. Recent studies suggest that in many cases, patients with apparent T2 low severe asthma, expressing with low disease biomarkers (FeNO and PBE), also have underlying T2 biology suppressed by corticosteroids administered in response to their poor symptom control (15–17). Ongoing corticosteroid suppression serves to confound our understanding of disease in this patient group (18–20).
A recent trial comparing biomarker versus symptom-based treatment titration in patients with severe asthma enrolled a population of patients with a FeNO of <45 ppb to enrich for a cohort that included a substantial T2-low population (21). A prespecified secondary endpoint was analysis of asthma exacerbations. Here we report the findings of the exacerbation analysis in this T2-low enriched severe asthma cohort, including comparison of study exacerbators and nonexacerbators, the physiological changes at exacerbation in those who had evidence of T2 biology at exacerbation versus those that did not, and the stability of inflammatory phenotypes when stable and at exacerbation.
Methods
Study Design
This was a 48-week, multicenter, randomized controlled clinical study in severe asthma, where the primary objective was to compare a treatment algorithm led by composite T2 biomarkers (FeNO, blood eosinophils, and serum periostin) with a symptom-/risk-based algorithm to optimize the maintenance dose of corticosteroids (see Supplementary Appendix in the online supplement for details on the patient inclusion and exclusion criteria) (15). Comparison of exacerbation rates between the treatment algorithms was an important prespecified secondary outcome.
Participants were recruited from 12 specialist severe asthma centers in the United Kingdom between January 8, 2016, and July 12, 2018 (see the online supplement), with the last study visit on June 18, 2019. Full inclusion and exclusion criteria are presented in the online supplement, but of note, all enrolled participants had severe asthma (Global Initiative for Asthma steps 4 and 5) (2), were aged 18–80 years old, and were enrolled in a nonselective manner. Inclusion criteria included a documented history of ⩾12% change in FEV1 within the last 24 months, or a positive methacholine or mannitol challenge, and no “rescue” oral corticosteroids (OCS) for an exacerbation in the 4 weeks before enrollment. The study aimed to enrich for a T2 biomarker low population within the cohort, so patients only proceeded to study enrollment if they had a FeNO of <45 ppb at the screening visit.
All participants had one scheduled study visit at study entry, and all other study visits were unscheduled exacerbation study visits. All participants were asked to contact their study center for clinical assessment (unscheduled exacerbation study visit) when their asthma control deteriorated to a degree where they would usually seek medical advice or activate their personalized asthma action plan. During these unscheduled visits, detailed clinical evaluation, medication review, and spirometry were performed, asthma control questionnaire-7 (ACQ-7) completed, and FeNO, peripheral blood eosinophils (PBE), and serum C-reactive protein (CRP) measured. A urine sample and a spontaneous sputum sample for differential cell counting and biobanking of the supernatant were collected where feasible. An exacerbation was defined as “severe asthma symptoms worsening outside of a patient’s normal daily variation”, and after assessment, a clinical decision was provided by the clinical team on the need to prescribe oral OCS and/or antibiotic therapy. Where participants were unable to attend the clinical center for this unscheduled study visit, exacerbation information was collected at the subsequent scheduled study visit, which occurred every 8 weeks from the time of enrollment until study completion at 48 weeks.
The inflammatory phenotype was attributed contemporaneously at each study visit (at baseline and at each exacerbation), using peripheral biomarkers of T2 inflammation, namely FeNO and PBE. Biomarker cut-points similar to those described by the Global Initiative for Asthma guidelines were used to describe phenotypes; a FeNO of ⩽20 ppb and PBE of ⩽0.15 × 109/L was termed “T2LOW” and FeNO of >20 ppb or PBE of >0.15 × 109/L termed “T2HIGH” to indicate the presence of detectable T2 biology (2).
As this was an observational analysis, all outcome measures were treated as exploratory.
The study protocol and primary study outcome have been previously published (15, 21). Before participant recruitment, the protocol was approved by the Office for Research Ethics Northern Ireland (NI0158), local National Health Service Research and Development approval obtained for each site (NHS R&D), and the study registered on www.clinicaltrials.gov (NCT02717689). All participants provided informed, written consent.
Procedures
Spirometry was conducted according to the American Thoracic Society/European Respiratory Society guidelines, with Global Lung Function 2012 equations used to calculate FEV1 and FVC predictive values (22). NIOX Vero devices (Circassia) were used for FeNO measurement. Spontaneous sputum samples were collected and processed in line with a standard operating procedure applied across all centers; RNA was extracted and underwent analysis after PCR using LightCycler 480 II instrumentation (Roche Molecular Diagnostics) to test for respiratory viruses including influenza A/B, respiratory syncytial virus A/B, rhinovirus, metapneumovirus, adenovirus, parainfluenza 1–4, and coronavirus.
Bacterial load within the DNA extracted from sputum plugs was measured by quantitative PCR (qPCR), using ThermoFisher Quantstudio 5, on the basis of abundance of 16S ribosomal subunit encoding genes and pathogen-specific genes including Moraxella catarrhalis, Haemophilus influenzae, and Streptococcus pneumonia (23). We used a specific bacteria threshold of ⩾106 genome copies/ml on sputum qPCR as significant as this threshold of detection had a 98% concordance with bacteria detection on routine culture and was associated with an increased percentage sputum neutrophils in chronic obstructive pulmonary disease exacerbations (24).
Statistical Analysis
As this was a prespecified secondary analysis of existing data, no sample size calculation was conducted. Depending on distribution, descriptive statistics are presented as means (SD), medians (interquartile range [IQR]) or counts (%). Univariate analyses were conducted using ttests, chi-square tests, and Mann-Whitney U as appropriate. To ensure that bias was not introduced as a consequence of repeated exacerbations in an individual participant, each participant’s first exacerbation was used when comparing inflammatory phenotypes in the cohort.
The stability of the exacerbation phenotype across multiple exacerbations in an individual patient was assessed using McNemar’s test and the Kappa statistic. Data for assessed exacerbations were collected prospectively during exacerbations and there were few missing data, therefore, all analyses under a complete-case framework. Analyses were conducted using STATA 16 (StataCorp).
Results
Demographics and baseline clinical descriptors for the study cohort are presented in Table E1 in the online supplement. This cohort were generally middle aged (mean [SD], 55.7 [13.1] years), with a female preponderance (64.5%) and high body mass indexes (31.6 [7.2] kg/m2). During the 12-month period before enrollment, patients reported a median (IQR) of 2 (1–4) exacerbations; one-fifth had a history of ICU admission and their symptom burden and quality of life impairment were high, respectively judged by ACQ-7 and AQLQ (Asthma Quality of Life Questionnaire) patient-reported outcomes.
Clinical and Biomarker Characteristics of Exacerbating Patients
In all, 301 study participants reported a total of 390 exacerbation events, with 60.8% (183) experiencing at least one exacerbation (Figure 1 and Table E1). Baseline characteristics of those who exacerbated and those who did not are shown in Table 1. When compared with nonexacerbators, patients who exacerbated during the study were more likely to be female (70.5% vs. 55.1%), have a higher body mass index (33.1 kg/m2 vs. 29.4 kg/m2 on enrollment) and had more frequent exacerbations requiring OCS and unscheduled primary care attendances for exacerbations in the year before the study (Table 1). Those who exacerbated were more likely to be receiving maintenance OCS and had a lower sputum eosinophil count at study entry, although other T2 biomarkers (PBE, FeNO, or serum periostin) were not different. There was no difference between the exacerbators and nonexacerbators in the proportion of patients who reduced (24.4% vs. 29.3%), maintained (39.6% vs. 38.4%), or increased (36.0% vs. 32.3%) their steroid dose (OCS/ICS) during the study (P = 0.66).
Figure 1.
Cohort flow diagram of all exacerbations during the study. A “first exacerbation” was the initial exacerbation assessed as a clinical study visit for any individual patient.
Table 1.
Table of Baseline Characteristics of Study Exacerbators versus Nonexacerbators (N = 301)
| No Exacerbations (n = 118) | ⩾1 Exacerbation (n = 183) | P Value | ||
|---|---|---|---|---|
| Number of Exacerbations | ||||
| 0 | 118 (100%) | 0 (0.0%) | — | |
| 1 | — | 77 (42.1%) | — | |
| 2 | — | 47 (25.7%) | — | |
| 3 | — | 33 (18.0%) | — | |
| 4 | — | 15 (8.2%) | — | |
| 5 | — | 6 (3.3%) | — | |
| 6 | — | 5 (2.7%) | — | |
| Age at study enrollment, yr | N = 301 | 56.5 (13.1) | 55.2 (13.2) | 0.41 |
| Sex | N = 301 | 0.0064 | ||
| Female | 65 (55.1%) | 129 (70.5%) | ||
| Male | 53 (44.9%) | 54 (29.5%) | ||
| BMI, kg/m2 | N = 300 | 29.4 (5.4) | 33.1 (7.8) | <0.0001 |
| Smoking status | N = 301 | |||
| Never smoked | 83 (70.3%) | 141 (77.0%) | 0.19 | |
| Ex-smoker | 35 (29.7%) | 42 (23.0%) | ||
| Atopic disease | N = 300 | 81 (68.6%) | 126 (69.2%) | 0.91 |
| Hospital admissions for asthma in last year | N = 301 | 0.0 (0.0–0.0) | 0.0 (0.0–0.0) | 0.087 |
| ED visits in last year | N = 301 | 0.0 (0.0–0.0) | 0.0 (0.0–0.0) | 0.23 |
| GP visits for asthma in the last year | N = 301 | 0.0 (0.0–2.0) | 1.0 (0.0–4.0) | <0.0001 |
| Rescue courses of oral steroids in the last year | N = 301 | 1.0 (0.0–3.0) | 3.0 (1.0–4.0) | <0.0001 |
| Prior admission for asthma to HDU/ICU | N = 301 | 19 (16.1%) | 45 (24.6%) | 0.079 |
| Number of prior admissions for asthma to HDU/ICU | N = 63 | 1.0 (1.0–1.0) | 1.0 (1.0–3.0) | 0.027 |
| Ever been ventilated | N = 63 | 6 (31.6%) | 25 (56.8%) | 0.066 |
| ACQ-7 score | N = 301 | 1.7 (1.1) | 2.1 (1.1) | 0.0043 |
| AQLQ total score | N = 291 | 5.1 (1.3) | 4.8 (1.4) | 0.039 |
| FEV1, L | N = 301 | 2.4 (0.7) | 2.0 (0.7) | 0.0002 |
| % predicted FEV1 | N = 301 | 80.1 (18.8) | 72.5 (19.0) | 0.0008 |
| FVC, L | N = 301 | 3.6 (0.9) | 3.1 (0.8) | <0.0001 |
| % predicted FVC | N = 301 | 96.1 (16.9) | 87.9 (16.1) | <0.0001 |
| FEV1/FVC | N = 301 | 0.66 (0.11) | 0.65 (0.12) | 0.83 |
| PEFR, L/min | N = 298 | 403.8 (135.7) | 358.4 (119.6) | 0.0026 |
| Sputum eosinophils, % | N = 123 | 2.3 (1.0–8.0) | 1.0 (0.3–8.0) | 0.043 |
| Sputum neutrophils, % | N = 123 | 64.8 (35.5–79.3) | 58.3 (31.0–78.0) | 0.67 |
| FeNO, ppb | N = 301 | 22 (13–30) | 19 (13–28) | 0.17 |
| Blood eosinophils, 109/L | N = 301 | 0.20 (0.12–0.35) | 0.21 (0.10–0.33) | 0.39 |
| Periostin, ng/ml | N = 298 | 55.2 (16.7) | 51.4 (15.8) | 0.052 |
| OCS user | N = 301 | 35 (29.7%) | 76 (41.5%) | 0.037 |
| OCS dose | N = 111 | 10 (6–10) | 10 (5–10) | 0.71 |
| ICS dose (BDP) | N = 301 | 2,207 (681) | 2,256 (739) | 0.56 |
| T2 status at study enrollment | N = 301 | 0.29 | ||
| T2LOW | 24 (20.3%) | 47 (25.7%) | ||
| T2BIOLOGY | 94 (79.7%) | 136 (74.3%) | ||
Definition of abbreviations: ACQ-7 = Asthma Control Questionnaire-7; AQLQ = Asthma Quality of Life Questionnaire; BDP = beclometasone diproprionate equivalent; BMI = body mass index; ED = emergency department; FeNO = fractional exhaled nitric oxide; GP = general practitioner; HDU = high dependency unit; ICS = inhaled corticosteroid; OCS = oral corticosteroid; PEFR = peak expiratory flow rate; T2 = type 2.
Descriptive statistics are shown as mean (SD), median (interquartile range), or number (%) as appropriate.
When phenotyping at study enrollment, 23.6% (71) of participants met the criteria for T2LOW and 76.4% (230) had evidence of T2 biology (T2HIGH) (Table E2). The T2HIGH group had more obstructive lung function, higher sputum eosinophil count, higher periostin concentrations, and a higher incidence of nasal polyposis. The T2LOW group had more primary care attendances for asthma and were more likely to have had an ICU or HDU admission for asthma. There was no difference in symptom burden (ACQ-7: 2.1 vs. 1.9) or impact on quality-of-life (AQL: 4.7 vs. 5.0) between the T2LOW and T2HIGH cohorts. A higher proportion of the T2LOW cohort were receiving maintenance OCS (34 [47.9%] vs. 77 [33.5%]; P = 0.03) at a higher dose (10 mg [10–12 mg] vs. 8 mg [5–10 mg]; P = 0.04) than the T2HIGH cohort and were significantly more likely to be advised to downtitrate their corticosteroids (CS) usage as per the biomarker treatment strategy within the study.
A total of 118 exacerbation events (118 of 390, 30%) in 80 patients were assessed by study clinicians during unscheduled study visits (Figure 1). There was no evidence that the unassessed exacerbations differed in severity from those that were assessed, with a similar proportion of patients admitted to hospital during the event (8 of 118 [6.8%] vs. 23 of 272 [8.5%]; P > 0.5). As has been described in previous exacerbation studies (20), patients with unassessed exacerbations who followed their personalized asthma action plan or had nonspecialist assessment were more likely to receive rescue OCS than those treated by asthma specialists during an unscheduled study visit (265 of 272 [97.4%] vs. 84 of 118 [71.2%], respectively; P < 0.0001) or antibiotics (145 of 272 [53.3%] vs. 45 of 118 [38.1%], respectively; P = 0.0059). In patients assessed by asthma specialists, those who did not receive OCS had a lower FeNO than those who received OCS (15 ppb [10–23 ppb] vs. 28 ppb [14–45 ppb], respectively; P = 0.001). Thirty-four patients did not receive OCS during an unscheduled study visit, and of these, only four (11.8%) went on to have systemic CS from another source (general practitioners) within the following 7 days to address persistent or worsening symptoms (treatment failure).
Clinical and Biomarker Characteristics during Exacerbations
At first assessed exacerbation for each patient, 27% (19/71) exacerbations were phenotyped as T2LOW and 73% (52/71) of exacerbations as T2HIGH (Table 2). The exacerbations in both groups looked clinically similar with comparable increase in symptoms, fall in FEV1 (mean, ∼200 ml), decline in FVC, FEV1/FVC, and peak flow from study entry. The T2HIGH cohort had a greater increase in FeNO and PBE from study entry to time of exacerbation than the T2LOW cohort, who had no associated increase in any T2 biomarkers from baseline, despite the similar physiological changes and symptom increase.
Table 2.
Characteristics of T2LOW versus T2HIGH Exacerbations at First Assessed Exacerbation (n = 71)
| T2LOW (n = 19) | T2BIOLOGY (n = 52) | P Value | ||
|---|---|---|---|---|
| Characteristics at study entry | ||||
| Age at study enrollment, y | N = 71 | 56.3 (12.8) | 52.9 (14.0) | 0.35 |
| Sex | ||||
| Female | N = 71 | 15 (78.9%) | 33 (63.5%) | 0.22 |
| Male | 4 (21.1%) | 19 (36.5%) | ||
| BMI, kg/m2 | N = 70 | 35.8 (10.2) | 33.5 (6.7) | 0.27 |
| Atopic disease | N = 71 | 15 (78.9%) | 36 (69.2%) | 0.42 |
| Rescue courses of oral steroids in the last year | N = 71 | 3.0 (2.0 to 3.0) | 2.5 (2.0 to 4.0) | 0.46 |
| Prior admission for asthma to HDU/ICU | N = 71 | 4 (21.1%) | 14 (26.9%) | 0.61 |
| Number of prior admissions for asthma to HDU/ICU | N = 18 | 1.0 (1.0 to 1.0) | 1.0 (1.0 to 2.0) | 0.24 |
| At exacerbation | ||||
| FEV1, L | N = 70 | 1.7 (0.7) | 1.8 (0.8) | 0.64 |
| Difference from baseline in FEV1, L | N = 70 | −0.2 (0.4) | −0.2 (0.3) | 0.93 |
| % predicted FEV1 | N = 70 | 64.0 (24.1) | 61.4 (17.6) | 0.63 |
| Difference from baseline in % predicted FEV1 | N = 70 | −8.5 (12.8) | −8.3 (11.4) | 0.96 |
| FVC, L | N = 70 | 1.7 (0.7) | 1.8 (0.8) | 0.64 |
| Difference from baseline in FVC, L | N = 70 | −0.4 (0.7) | −0.3 (0.4) | 0.55 |
| % predicted FVC | N = 70 | 81.9 (20.1) | 78.0 (14.4) | 0.37 |
| Difference from baseline in % predicted FVC | N = 70 | −11.6 (22.7) | −8.1 (11.4) | 0.40 |
| FEV1/FVC | N = 69 | 0.61 (0.15) | 0.63 (0.11) | 0.60 |
| Difference from baseline in FEV1/FVC | N = 69 | −0.01 (0.07) | −0.02 (0.06) | 0.45 |
| PEFR, L/min | N = 64 | 301.9 (109.5) | 305.7 (109.6) | 0.90 |
| Difference from baseline in PEFR, L/min | N = 63 | −47.9 (52.7) | −46.6 (56.1) | 0.93 |
| Sputum eosinophils, %* | N = 26 | 0.0 (0.0 to 1.5) | 3.3 (1.3 to 15.8) | 0.018 |
| Difference from baseline sputum eosinophils, % | N = 21 | −0.3 (−2.0 to 0.0) | 2.9 (−3.8 to 10.3) | 0.14 |
| Sputum neutrophils, %* | N = 26 | 56.2 (25.7 to 73.2) | 53.3 (30.7 to 78.8) | 0.85 |
| Difference from baseline in sputum neutrophils, % | N = 21 | −5.6 (−37.3 to 4.2) | −5.1 (−13.8 to 11.0) | 0.65 |
| FeNO, ppb | N = 71 | 11 (9 to 14) | 32 (22 to 44) | <0.0001 |
| Difference from baseline in FeNO, ppb | N = 71 | −3 (−11 to 0) | 9 (−2 to 20) | 0.0005 |
| Blood eosinophils, 109/L | N = 71 | 0.04 (0.02 to 0.10) | 0.21 (0.12 to 0.41) | <0.0001 |
| Difference from baseline in blood eosinophils, 109/L | N = 71 | −0.15 (−0.19 to −0.01) | −0.00 (−0.11 to 0.16) | 0.0028 |
| Periostin, ng/ml | N = 70 | 47.2 (14.1) | 53.7 (19.5) | 0.19 |
| Difference from baseline in periostin, ng/mL | N = 69 | −1.0 (6.8) | 1.2 (18.6) | 0.62 |
| ACQ-7 score | N = 69 | 3.4 (1.1) | 3.7 (0.9) | 0.24 |
| Difference from baseline in ACQ-7 score | N = 69 | 1.4 (0.8) | 1.3 (0.8) | 0.72 |
| Temperature, C | N = 69 | 37.0 (36.6 to 37.4) | 36.7 (36.3 to 36.9) | 0.028 |
| Difference from baseline in temperature, C | N = 68 | 0.3 (−0.1 to 0.7) | 0.1 (−0.1 to 0.4) | 0.072 |
| CRP, mg/L | N = 55 | 4.8 (2.0 to 9.3) | 7.7 (5.0 to 11.0) | 0.31 |
| Any virus, PCR | N = 24 | 8 (88.9%) | 6 (40.0%) | 0.019 |
| Any bacteria, Spec qPCR | N = 23 | 4 (50.0%) | 6 (40.0%) | 0.65 |
| Any bacteria or virus, Spec qPCR | N = 23 | 8 (100.0%) | 10 (66.7%) | 0.065 |
| Oral/i.v. CS | N = 71 | 12 (63.2%) | 40 (76.9%) | 0.25 |
| ABX | N = 71 | 12 (63.2%) | 21 (40.4%) | 0.089 |
| Oral/i.v. CS and ABX | N = 71 | 10 (52.6%) | 19 (36.5%) | 0.22 |
Definition of abbreviations: ABX = antibiotics; ACQ-7 = asthma Control Questionnaire-7; BMI = body mass index; CRP = C-reactive protein; CS = corticosteroid; FeNO = fractional exhaled nitric oxide; HDU = high dependency unit; i.v. = intravenous; PEFR = peak expiratory flow rate; qPCR = quantitative PCR; Spec = specific bacteria threshold of ⩾106 genome copies/ml on quantitative PCR; T2 = type 2.
Descriptive statistics are shown as mean (SD), median (interquartile range), or number (%) as appropriate.
Sputum differential cell count at first exacerbation (n = 26), 9 of 26 were T2LOW, and 17 of 26 were T2HIGH.
Of the first assessed exacerbation episodes for each patient, 26 of 71 (33%) produced spontaneous sputum and had a cell differential: 7 of 26 (27%) had a sputum eosinophil count of <2% and neutrophil count of ⩾65%; 6 of 26 (23%) had a sputum eosinophil count of <2% and neutrophil count of <65%; 4 of 26 (15%) had a sputum eosinophil count of ⩾2% and neutrophil count of ⩾65%; and 9 of 26 (35%) had a sputum eosinophil count of ⩾2% and neutrophil count of <65%. Sputum eosinophils were higher in the T2HIGHgroup, with the T2HIGH group showing a median 2.9% (−3.8% to 10.3%) increase in sputum eosinophils from the stable to exacerbation state. The T2LOW group had a greater number of sputum samples positive for virus at exacerbation, and all of the T2LOW cohort had a virus or bacteria detected on qPCR above threshold; however, there was no concomitant elevation of the sputum neutrophil count or serum CRP (described in Table 2). The was no significant difference between the T2LOW and T2HIGH cohorts with regards to systemic CS or antibiotics prescribed by the asthma team.
Within the cohort who were T2LOW at study entry, those who went on to exacerbate had a higher number of primary care attendances for asthma before study entry, more OCS rescue courses in the previous year, and higher baseline ACQ-7 score than those who did not exacerbate (Table 3). Comparing T2 status at baseline (when stable) and exacerbation, 45 of 75 (60%) patients had T2 biology detectable at baseline and exacerbation. T2 biology was also evident during exacerbation in 11 of 17 (65%) who were T2LOW at study entry. The observed change in exacerbation phenotype may be related to changes in corticosteroid exposure, as five of seven who were T2LOW at baseline and subsequently reduced the dose of CS demonstrated a T2HIGH phenotype at exacerbation (see Table E3). However, further analysis showed the inflammatory phenotype at study entry was not associated significantly with the phenotype at exacerbation (P = 0.84; kappa = 0.12) (Table 4). Inflammatory phenotype at first exacerbation was not associated significantly with the phenotype at secondary exacerbation (p=1.00, kappa=0.19), Table 5).
Table 3.
T2LOW Cohort at Study Entry: Factors Associated with Those Who Proceeded to Exacerbation and Those Who Did Not
| No Exacerbation (N = 24) | ⩾1 exacerbation during Study (N = 47) | P Value | ||
|---|---|---|---|---|
| Age at inclusion, yr | N = 71 | 56.5 (12.5) | 50.7 (12.5) | 0.06 |
| Sex | ||||
| Female | N = 71 | 16 (66.7%) | 32 (68.1%) | 0.90 |
| Male | 8 (33.3%) | 15 (31.9%) | ||
| BMI, kg/m2 | N = 71 | 30.7 (6.4) | 32.4 (6.3) | 0.29 |
| Atopic disease | N = 71 | 17 (70.8%) | 34 (72.3%) | 0.89 |
| Hospital admissions for asthma in last year | N = 71 | 0.0 (0.0–0.0) | 0.0 (0.0–1.0) | 0.06 |
| A&E visits in last year | N = 71 | 0.0 (0.0–0.0) | 0.0 (0.0–1.0) | 0.16 |
| GP visits for asthma in the last year | N = 71 | 0.5 (0.0–4.0) | 3.0 (1.0–4.0) | 0.050 |
| Rescue courses of oral steroids in the last year | N = 71 | 2.0 (0.0–3.5) | 3.0 (2.0–5.0) | 0.012 |
| Prior admission for asthma to HDU or ICU | N = 71 | 4 (16.7%) | 19 (40.4%) | 0.043 |
| Number of prior admissions for asthma to HDU or ICU | N = 22 | 1.0 (1.0–2.0) | 1.0 (1.0–4.0) | 0.71 |
| Ever been ventilated | N = 22 | 1 (25.0%) | 9 (50.0%) | 0.36 |
| ACQ-7 score | N = 71 | 1.7 (0.8) | 2.4 (1.1) | 0.010 |
| AQLQ total score | N = 69 | 5.0 (1.1) | 4.5 (1.3) | 0.14 |
| FEV1, L | N = 71 | 2.3 (0.7) | 2.2 (0.8) | 0.47 |
| % predicted FEV1 | N = 71 | 82.7 (19.6) | 74.8 (20.5) | 0.12 |
| FVC, L | N = 71 | 3.4 (0.9) | 3.2 (0.8) | 0.25 |
| % predicted FVC | N = 71 | 94.3 (17.4) | 86.7 (15.1) | 0.06 |
| FEV1/FVC | N = 71 | 0.69 (0.11) | 0.69 (0.14) | 0.81 |
| PEFR, L/min | N = 70 | 387.8 (136.7) | 380.2 (132.3) | 0.82 |
| Sputum eosinophils, % | N = 24 | 1.0 (0.0–2.8) | 0.3 (0.0–0.8) | 0.35 |
| Sputum neutrophils, % | N = 24 | 60.8 (43.0–83.0) | 72.0 (53.4–87.8) | 0.55 |
| FeNO, ppb | N = 71 | 13 (10–17) | 12 (9–16) | 0.71 |
| Blood eosinophils, 109/L | N = 71 | 0.08 (0.05–0.11) | 0.08 (0.03–0.12) | 0.73 |
| Periostin, ng/mL | N = 70 | 49.1 (14.6) | 44.1 (11.7) | 0.12 |
| OCS user | N = 71 | 8 (33.3%) | 26 (55.3%) | 0.08 |
| OCS dose | N = 34 | 10 (8–13) | 10 (10–12) | 0.63 |
| ICS dose (BDP) | N = 71 | 2208 (655) | 2221 (726) | 0.94 |
| CS study change | ||||
| Reduce | N = 56 | 13 (65.0%) | 20 (55.6%) | 0.24 |
| Maintain | 6 (30.0%) | 8 (22.2%) | ||
| Increase | 1 (5.0%) | 8 (22.2%) | ||
Definition of abbreviations: A&E = accident and emergency; ACQ-7 = Asthma Control Questionnaire-7; AQL = Asthma Quality of Life Questionnaire; BDP = beclometasone dipropionate equivalent; BMI = body mass index; CS = corticosteroid; FeNO = fractional exhaled nitric oxide; GP = general practitioner; HDU = high dependency unit; ICS = inhaled corticosteroid; OCS = oral corticosteroid; PEFR = peak expiratory flow rate; T2 = type 2.
Descriptive statistics are shown as mean (SD), median (interquartile range), or number (%) as appropriate.
Table 4.
Stability of Inflammatory Phenotype from Baseline Study Entry to First Assessed Exacerbation
| First Exacerbation |
|||
|---|---|---|---|
| Baseline | T2LOW | T2HIGH | Total |
| T2LOW | 6 | 11 | 17 |
| T2HIGH | 13 | 45 | 58 |
| Total | 19 | 56 | 75 |
Definition of abbreviation: T2 = type 2.
McNemars (P value) = 0.84; Kappa = 0.12. Descriptive statistics are shown as mean (SD), median (interquartile range), or number (%) as appropriate.
Table 5.
Stability of Inflammatory Phenotype from First to Second Assessed Exacerbation
| Second Exacerbation |
|||
|---|---|---|---|
| First Exacerbation | T2LOW | T2HIGH | Total |
| T2LOW | 2 | 3 | 5 |
| T2HIGH | 4 | 16 | 20 |
| Total | 6 | 19 | 25 |
Definition of abbreviation: T2 = type 2.
McNemars (P value) = 1.00; Kappa = 0.19. Descriptive statistics are shown as mean (SD), median (interquartile range), or number (%) as appropriate.
Discussion
The advent of biologic therapies targeting the T2-cytokine axis has reduced the frequency of asthma exacerbations in patients with severe asthma with an underlying T2-driven eosinophilic phenotype (9–12). Under these conditions, T2 biomarkers (FeNO and PBE) have been shown to perform well both as prognostic biomarkers for exacerbation events (as shown in placebo arms of clinical trials) and as predictors of good therapeutic responses to T2 biologic therapies. The RASP (Refractory Asthma Stratification Programme)-UK study population for the present analysis was purposefully enriched for patients with severe asthma expressing a T2 biomarker low phenotype, within a clinical setting where residual exacerbation events represent an unmet medical need, as the mechanisms are poorly understood. In this cohort, T2-biomarkers (FeNO, PBE and serum periostin) at randomization were not prognostic for the frequency of exacerbation events, an observation consistent with mechanisms other than type-2 inflammation being responsible. Baseline sputum eosinophil counts were significantly lower in patients who went on to have an exacerbation, but as this biomarker was only obtained in approximately one-third of patients at baseline (which is a common limitation when using sputum as source of a biomarkers), we cannot exclude some selection bias for sputum eosinophil counts in this subgroup. However, the biomarker measurement data appear to confirm recruitment of an exacerbation prone T2 biomarker low noneosinophilic population as planned for the study.
In the present study, poor asthma symptom control, female sex, obesity, restrictive lung function, and multiple unscheduled prior healthcare visits for exacerbation events in the prior year to study emerged as clinical factors associated with patients experiencing exacerbations. Poor asthma control and prior exacerbation history has consistently been associated with exacerbation risk and specifically in heavily treated severe asthma populations (25, 26).
The association between higher symptom burden and higher exacerbation rate was also seen in the MEX (mepolizumab exacerbation) study, which examined exacerbation phenotype in patients with severe eosinophilic asthma established on mepolizumab (20). This association between higher symptom burden and higher prebiologic exacerbation rates was also seen in those patients who went on to exacerbate while being treated with mepolizumab, suggesting that these factors are important for future risk despite significant background treatment. There may be a smaller window for symptom deterioration in these highly symptomatic patients with severe asthma, before their self-identifying asthma deterioration, as they more easily cross a threshold, whereby they revert to their personal action plan and seek medical intervention.
The interaction among female sex, obesity, and severe asthma needs further analysis but importantly the obese female phenotype has been described previously in severe asthma cohorts, and this group is often T2 biomarker low with a high symptom burden despite high-dose ICS and systemic CS (15, 17, 26, 27). These data extend our knowledge for this high–symptom burden clinical group, identifying them (both retrospectively and prospectively) as being particularly exacerbation prone. Defining the relationship between these clinical parameters and risk of exacerbation is key to understanding the underlying mechanism.
Those patients who self-treated according to their asthma plan or were seen in primary care almost always received systemic CS (97.4%), whereas those assessed by treating clinicians with broader access to clinical assessments, specifically FeNO measurement (as blood eosinophil data would not be available at the time of consultation) were less likely to receive these (70%). The similarity in rates of hospitalization for assessed and unassessed exacerbations suggests that the exacerbation severity in both groups was similar. However, interpretation of the present data is limited by the absence of markers of exacerbation severity in patients not attending clinical assessments, such as symptom diary and peak flow measurements. Although the study did not mandate that FeNO be used to decide on prescription of systemic CS, mean FeNO was significantly lower in those not receiving OCS, and it is possible that this easily measured biomarker was being used to determine the perceived requirement for OCS during exacerbations. Importantly, there was a low observed incidence of treatment failure (defined as requirement for OCS or hospital admission in the 7 days after clinical assessment) when OCS were not prescribed after study clinical assessment. This fits with the findings of a recent study with mepolizumab (and assumed PBE suppression) in which FeNO measurement emerged as a useful means of discriminating between eosinophilic and noneosinophilic events, with the latter more likely to be infection driven (20). An important clinical consideration is the nature of all exacerbation events and specifically whether treatment with OCS is an appropriate treatment in T2 biomarker low events. Describing the clinical and demographic features associated with the T2 biomarker low frequent exacerbator phenotype will allow these patients to be better identified, and given the potential harm caused by regular systemic CS exposure, we believe that the routine use of systemic CS for all exacerbation events in severe asthma requires further study and that clinical assessment and biomarker measurement may be helpful in making more targeted treatment choices. This hypothesis, and specifically the use of FeNO to guide therapeutic use of OCS during exacerbation needs to be formally tested via controlled clinical trials.
We were particularly interested in the T2LOW phenotype in this cohort and wished to identify clinical and demographic features associated with exacerbation events. Importantly, the T2LOW events had a similar increase in symptoms and fall in lung function to those in the T2HIGHpopulation, suggesting that the T2LOW events are clinically significant, albeit indistinguishable on the basis of symptoms or lung function. In contrast, measurement of T2 biomarkers showed greater increases in FeNO and PBE from baseline values at the time of exacerbation. In contrast, the T2LOW cohort showed no increase in any T2 biomarker expression, despite similar physiological changes and symptom increase.
A limitation of the current study was the use of spontaneous rather than induced sputum measures, meaning that only a third of patients produced a spontaneous sputum sample at exacerbation. Peripheral biomarkers (PBE and FeNO) were used primarily to determine T2 status; however, as anticipated, the T2LOW cohort as defined by FeNO and PBE were noneosinophilic on sputum cytology, whereas the T2-Biology cohort had sputum eosinophilia, consistent with the use of composite T2 biomarker profiling with FeNO and PBE as a surrogate of eosinophilic airways inflammation (8, 28). Exacerbations with sputum data demonstrated a mixed inflammatory profile, with evidence of eosinophilic, neutrophilic, and mixed eosinophilic–neutrophilic inflammation on sputum differential cell count, in keeping with previous reports of exacerbation analysis in patients with mild to moderate asthma (13, 14). However, this contrasts with observations from the MEX study, which explored exacerbation events on mepolizumab and where it was noted that eosinophilic and noneosinophilic events were predominantly mutually exclusive (20). This difference may reflect the greater PBE suppression with mepolizumab, allowing for clearer differentiation of the inflammatory phenotype. It is not yet clear whether the neutrophilic, infection-driven exacerbations seen in patients treated with mepolizumab reflect natural infections, immunosuppression due to biologics-induced reduction in airway eosinophils, or a broader suppression of the T2-cytokine axis and antiinfective pathways from high-dose inhaled corticosteroids (ICS).
The T2LOW group had a greater number of sputum samples positive for virus at exacerbation, and all of the T2LOW cohort had a virus or bacteria detected on qPCR above threshold, although they did not have a concomitant elevated sputum neutrophil count or CRP. The proportion of exacerbations with bacteria identified was similar between both groups at exacerbation; however, the number of sputum samples available at exacerbation are a limiting factor for drawing conclusions on the role of infectious agents being drivers of T2LOW exacerbations. The dynamic nature of inflammatory phenotype seen between the different study visits (from stable to exacerbation, and from one exacerbation to the next in the same individual) is in keeping with descriptions in the literature (20, 29).
The need to elicit the pathways underlying these T2LOW exacerbations is a prerequisite to establishing effective treatments and minimizing the unwanted side effects of treatments that are known to have limited effectiveness (i.e. the use of OCS in T2LOW exacerbations and asthma management more generally). Within the T2LOW cohort, exacerbation risk during the study was related to higher primary care asthma attendances and rescue systemic CS courses in the previous year, and a higher ACQ-7 score, suggesting that these parameters are consistently associated with exacerbation risk in all patients with severe asthma.
The present study demonstrated how asthma exacerbations in patients expressing the T2LOW phenotype are similar physiologically and symptomatically and occur as frequently as those with underlying T2 biology. T2LOW asthma emerged as an unstable phenotype that needs to be assessed at the time of exacerbation. These data highlight our limited understanding of the underlying pathology and lack of effective, evidence-based management strategies for asthma in the absence of T2 biology, as well as the need for further mechanistic and clinical studies.
Acknowledgments
Acknowledgment
This study was part of the Medical Research Council UK Refractory Asthma Stratification Programme, and program support was obtained from Hoffman la Roche-Genentech (periostin assay and sample biobanking and Circassia (FeNO measurements – reduced pricing for machines and test kits) for in-kind support within that Consortium. The authors thank the members of the Trial Steering Committee for all their support and assistance with study delivery: Professor Martyn Partridge (chair), Professor Mike Morgan, Professor Anne Millar, Mr. Mark Stafford-Watson (patient representative – during his tenure on the Trial Steering Committee, Mark sadly passed away and the authors gratefully acknowledge his significant contribution to this program and his involvement in other research projects), and Ms. Gabriella Cooper. The authors thank Niche Science & Technology Ltd. for assistance with study delivery and all the patients who volunteered for the study and clinical and research teams at all the participating clinical and academic centers. They also thank Sofia Mosesova, Chris Patterson, and Nicola Gallagher for statistical advice during study setup and analysis. They thank Amgen Inc. (Thousand Oaks, California, USA), Astra Zeneca (London, UK), Jannsen Research & Development LLC (London, UK), and Vitalograph Inc. (Ennis, Ireland) for supporting the RASP-UK Consortium.
Footnotes
Supported by the Medical Research Council (grant MR/M016579/1).
Author Contributions: All authors contributed to the conception and design of the trial and delivery of the clinical trial. P.J.M., J.B., and L.G.H. interpreted the data and wrote the manuscript in collaboration with all coauthors. J.B. performed the statistical analysis. All authors read and approved the final manuscript. The corresponding author had final responsibility for reviewing and submitting the manuscript for publication.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.
Originally Published in Press as DOI: 10.1164/rccm.202201-0129OC on May 12, 2022
Author disclosures are available with the text of this article at www.atsjournals.org.
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