To the Editor,

Anti-T2 biological therapy is recommended as an add-on treatment for severe eosinophilic asthma [1]. Several randomized clinical trials have demonstrated the efficacy of anti-T2 therapy in reducing acute exacerbations and daily doses of oral steroids, while also indicating some improvements in forced expiratory volume in 1 s (FEV1) [2,3,4]. The improvements in FEV1 do not seem to correspond properly with the marked clinical response to biological therapy, suggesting that measures of large airway obstruction like the FEV1 might be a poor tool and that measures of other lung function abnormalities like small airway dysfunction (SAD) might better reflect the clinical response. Indeed, SAD is a hallmark of asthma that is associated with disease severity and poor symptom control [5]. Moreover, SAD is associated with frequent exacerbations [6, 7] and has a negative impact on daily physical activity [8]. We aimed to investigate if measures of SAD in patients with severe eosinophilic asthma might better correlate or even be helpful in predicting clinical response to biological therapy, thereby potentially describing a distinct phenotype within this severe asthma population.

In this study, we analyzed data of patients who were previously recruited in the prospective longitudinal All Age Asthma Cohort (ALLIANCE), a national cohort of pediatric and adult patients with asthma in Germany, initiated by the German Centre for Lung Research (DZL). The study was approved by the local ethics committee at the medical school Luebeck (Az.21–215) and is registered at clinicaltrials.gov (adult arm: NCT02419274) [9]. Since 2014, the adult arm of the ALLIANCE cohort recruits patients with mild to severe asthma and healthy controls. Patients had to be in specialist care for more than three months, and criteria of “difficult to control” asthma were addressed according to current guidelines [10]. Study visits take place in 12 months intervals. Patients had to have stable disease without acute exacerbations or respiratory tract infections within four weeks prior to study visits.

The selection criteria for this study were adult patients with severe eosinophilic asthma in whom a treatment with anti-T2 biological agent has been initiated while already being recruited into the observational ALLIANCE study and in whom at least one complete follow-up visit was available. Indication, prescription and administration of the biological therapy were not part of the study but rather were done by their respiratory physicians.

On each study visit, we assessed asthma control by asthma control test (ACT) as well as number of severe exacerbations 12 months prior to the study visit, defined as a burst of systemic corticosteroids for ≥ 3 days [10]. We performed a spirometry, body plethysmography and impulse oscillometry (Masterscreen Body and IOS, Vyaire Medical, Germany) according to guidelines [11,12,13]. IOS is a feasible diagnostic tool that measures increased resistance in peripheral airways at tidal breathing, even in subjects with normal spirometry [14]. We studied the small airway function using both spirometry measures (FEF25–75) and IOS measures (frequency dependence of resistance, FDR (R5Hz-R20Hz, kPa/l/s)). Percent predicted FDR values (FDR %pred.) were calculated according to recently provided prediction equations by the German KORA cohort [15]. We also included measures of air trapping like the residual volume (RV) and RV to total lung capacity ratio (RV/TLC) as indirect markers for SAD. We studied peripheral blood eosinophils and fractional exhaled nitric oxide (FeNo) as surrogates for eosinophilic airway inflammation [16, 17]. Based on their clinical response, patients were classified into responders and partial-/non-responders: Responders (n = 13) had at least a 50% reduction of severe exacerbations averaged over the last 12 months or ≥ 50% reduction in oral steroid doses [2, 18] and additionally, an increase in the ACT score by at least 3 points as this is the minimal clinically important difference (MCID) [19]. Partial-/Non-responders had less than 50% reduction in both severe exacerbations and in oral steroid doses and the ACT increase was beneath the MCID, or they even experienced worsening of symptoms (i.e. increase in severe exacerbations and a decrease in the ACT score) upon tapering systemic steroids. We evaluated the capacity of baseline FDR in predicting clinical treatment response by creating a Receiver Operator Characteristic (ROC). To evaluate FDR measures as potential markers for clinical response, we carried out comparative linear regressions between the change in FDR and other lung function measures with the change in severe exacerbations and in the ACT score.

Twenty patients with severe eosinophilic asthma under a treatment with anti-T2 agents (mepolizumab, n = 18; benralizumab, n = 1; dupilumab, n = 1) were included, (mean age, 59 ± 9 years; 60% female; mean body mass index (BMI), 27.6 ± 5.4 kg/m2). All patients were on inhaled corticosteroids (ICS; mean inhaled fluticasone equivalent 818 ± 403 µg) and long-acting β2 adrenoceptor agonists (LABA). 55% were treated with long-acting muscarinic receptor antagonists (LAMAs) and 80% were on maintenance oral corticosteroids (OCS, mean daily prednisolone dose 6.4 ± 4.9 mg) prior to starting with biological therapies. Mean predicted FEV1 at baseline was 76 ± 21%, mean FEF25-75 1.1 ± 0.73 (l/s), mean predicted RV 148 ± 25%, mean RV/TLC 47 ± 8%, mean FDR 0.21 ± 0.18 kPa/L/s, mean FDR%pred. 224% ± 140%, mean absolute blood eosinophils 570 ± 389/µl, mean FeNO 60 ± 33 ppb. Mean ACT score was 15.5 ± 5.4 points and patients experienced 5 ± 3 severe exacerbations 12 months prior to initiating the biological therapy. Between responders and partial-/non-responder, there were no significant differences in the baseline values of all clinical variables except for FDR%pred, which was significantly higher in responders (Table 1). Area under the curve (AUC) for FDR%pred. was better than for FeNO, blood eosinophils, and FEV1 (Table 2). At a cut off of 191% for FDR%, we observed a sensitivity of 75%, specificity of 71% and AUC of 79% [59–99%] (CI: 0.95, p = 0.035). The best AUC was achieved by combining FDR%pred. with blood eosinophils count. At cut off values for FDR of 216%pred, and blood eosinophils of 365/μL, the ROC curve showed a sensitivity of 75%, specificity of 87%, and AUC of 85% [67–100%], (CI = 0.95, p = 0.01) (Fig. 1).

Table 1 Clinical characteristics of Responders and Partial-/Non-Responders at baseline and under treatment with Anti-T2 biological therapy
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Table 2 Area under the curve (AUC) of clinical predictors
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Fig. 1
figure 1

Receiver Operator Characteristic (ROC) curve: x axis (1-specifecity), y-axis sensitivity, each curve represents the predictability of each clinical marker (in different colors). AUC values and p-values for the separate variables are detailed in Table 2. A combination of FDR%pred. with absolute blood eosinophil counts demonstrated the best predictive capacity (AUC = 0.85, p-value = 0.01, CI95 = 0.67–1.00)

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Within response groups, responders to anti-T2 biological therapies experienced significant improvements in all clinical markers (i.e. lung function, inflammatory biomarkers) in contrast to partial/non-responders that did not demonstrate any statistically significant changes; details are given in (Table 1).

Linear regressions indicated better associations between improvements in FDR and ACT score than with FEV1 and ACT score as well as better associations between improvements in FDR and reduction of exacerbations than with FEV1 (Fig. 2). The other included lung function measures (FEF25–75, RV and RV/TLC) were not superior to FEV1 when correlated to improvements in exacerbations or ACT with R2 values around 0.20.

Fig. 2
figure 2

comparative linear regressions: between small airway dysfunction (FDR, KPa/L/s) and airflow limitation (FEV1, ml) in correlation to ACT score (points) and reduction in exacerbations (%). All values represent the difference (delta) between baseline and under therapy. A: linear regression between (delta ACT) scores on the x-axis, and the change in FDR (delta R5-20), y-axis: R2 = 0.42, DF = 18, p = 0.001. B: linear regression between (delta ACT) scores on the x-axis and the change in FEV1 (delta FEV1), y-axis: R2 = 0.25, DF = 18, p = 0.013. C: linear regression between (delta exacerbations) on the x-axis and the change in FDR (delta FEV1), y-axis: R2 = 0.41, DF = 18, p = 0.001. D: linear regression between (delta exacerbations) on the x-axis and the change in FEV1 (delta R5-20), y-axis: R2 = 0.20, DF = 18, p = 0.025

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The main finding of our study is that SAD improves substantially under anti-T2 biological therapy in patients with severe eosinophilic asthma. Furthermore, pre-treatment IOS measures of SAD demonstrated to be meaningful predictors of clinical response, thereby indicating that severe SAD might describe a distinct phenotype with therapeutic implications among patients with severe eosinophilic asthma. Our results are consistent with the findings of previous studies which indicated that measures of SAD like FEF25-75, lung clearance index, regional ventilation inhomogeneity in acinar and conducting airways improve significantly under biological therapy [20, 21]. Oscillometric measures of SAD seem to be feasible tools in selecting appropriate patients qualifying for anti-T2 biological therapy beyond the rather crude measurement of baseline blood eosinophils count that is frequently influenced by a multitude of factors, e.g. dose of inhaled or oral steroids [22], diurnal variations [23] and atopic comorbidities [24]. Our observations on the improvements in SAD might be explained by the findings that in severe asthmatics, small airway function is significantly altered with type-2 inflammation (T cells and activated eosinophils infiltration) compared to large airways [25, 26]. In our study, partial or non-responders experienced a 58% mean reduction of circulating blood eosinophils (p > 0.05), indicating the pharmacological effect of the biological therapy without marked improvements in clinical symptoms. These results are consistent with the finding of Kelly et al., which showed that despite the clear reduction in circulating and airway eosinophilia under mepolizumab, it does not suppress other eosinophil activation markers which might explain the clinical deterioration in some subjects [27].

The main limitations of this study are its observational nature and the small number of the included subjects. Further, additional measures of small airway function like inert gas distribution could have supported our findings. Therefore, clinical trials involving larger cohorts and multimodular assessment of small airway function are needed to confirm our observation. Finally, two patients had a treatment with either dupilumab or benralizumab which do not share the exact same pharmacological mechanism compared with mepolizumab.

Our data support that SAD is potentially linked to asthma control as SAD improves substantially under anti-T2 biological therapy in therapy responders. Measures of small airway function like the FDR might be useful in selecting appropriate patients qualifying for anti-T2 biological therapy in addition to blood eosinophil count and might also serve as markers to assess clinical treatment response in patients with newly initiated biological therapy.