CORRESPONDENCE

this strategy can improve cardiopulmonary and diaphragm function
and enhance patient-centered clinical outcomes. 䊏
Author disclosures are available with the text of this letter at
www.atsjournals.org.
Correspondence and requests for reprints should be addressed to
Ewan C. Goligher, M.D., Ph.D., Toronto General Hospital, 585 University
Avenue, 9-MaRS-9024, Toronto, ON M5G 2N2, Canada.
Email: ewan.goligher@uhn.ca.
References
1. Goligher EC, Fan E, Herridge MS, Murray A, Vorona S, Brace D, et al.
Evolution of diaphragm thickness during mechanical ventilation:
impact of inspiratory effort. Am J Respir Crit Care Med 2015;192:
1080–1088.
2. Froese AB, Bryan AC. Effects of anesthesia and paralysis on
diaphragmatic mechanics in man. Anesthesiology 1974;41:242–255.
3. Masmoudi H, Persichini R, Cecchini J, Delemazure J, Dres M, Mayaux J,
et al. Corrective effect of diaphragm pacing on the decrease in cardiac
output induced by positive pressure mechanical ventilation in
anesthetized sheep. Respir Physiol Neurobiol 2017;236:23–28.
4. Dianti J, Fard S, Wong J, Chan TCY, Del Sorbo L, Fan E, et al. Strategies
for lung- and diaphragm-protective ventilation in acute hypoxemic
respiratory failure: a physiological trial. Crit Care 2022;26:259.
5. Etienne H, Morris IS, Hermans G, Heunks L, Goligher EC, Jaber S, et al.
Diaphragm neurostimulation assisted ventilation in critically ill patients.
Am J Respir Crit Care Med 2023;207:1275–1282.
6. Morris IS, Dres M, Goligher EC. Phrenic nerve stimulation to protect the
diaphragm, lung, and brain during mechanical ventilation. Intensive Care
Med 2022;48:1299–1301.
To the Editor:
Targeting the IL-4 receptor signaling pathway with dupilumab
improves asthma outcomes (1). The clinical benefits of IL-4 receptor
antagonism are likely due to the reduction in characteristic features
of IL-13 (and IL-4) signaling, which include mucus production
and airway remodeling (2). Direct assessment of airway mucus and
remodeling using quantitative computed tomography (CT), and
their functional consequence on ventilation visualized by magnetic
resonance imaging (MRI), can be leveraged to provide mechanistic
insight into the clinical benefits of IL-4 receptor antagonism.
Therefore, in a randomized, placebo-controlled trial of adults with
moderate to severe asthma, we examined the effects of dupilumab on
airway mucus and remodeling assessed on CT and their functional
consequence on ventilation assessed on 129Xe MRI as exploratory
outcomes. Some of the results have been previously reported in the
form of an abstract (3).
Methods
We completed a single-center, randomized, double-blind, placebo-
controlled trial (ClinicalTrials.gov identifier NCT 03884842) in
25 adults with uncontrolled moderate to severe asthma and type 2
Table 1. Baseline Demographics and Clinical Characteristics
Dupilumab Placebo
(n = 13) (n = 11)

Copyright © 2023 by the American Thoracic Society

Age, yr 48 (16) 60 (8)
Female sex 8 (62%) 4 (36%)
BMI, kg/m2 29 (5) 31 (4)
Former smoker 3 (23%) 6 (54%)
ACQ-5 score 2.0 (1.1) 3.0 (1.2)
AQLQ score 5.0 (1.2) 3.8 (1.2)
Effects of Dupilumab on Mucus Plugging and Spirometry
Ventilation Defects in Patients with Moderate-to- Pre-BD FEV1, L 1.79 (0.76) 1.94 (0.70)
Severe Asthma: A Randomized, Double-Blind, Pre-BD FEV1, %pred 55 (21) 62 (20)
Placebo-Controlled Trial Post-BD FEV1, L 2.17 (0.83) 2.36 (0.63)
Post-BD FEV1, %pred 68 (22) 77 (21)
Sarah Svenningsen1,2,3, Melanie Kjarsgaard1,3, Ehsan Haider2,4, BD reversibility 19 (12–32) 22 (12–40)
Carmen Venegas1,3, Norman Konyer2, Yonni Friedlander1,2, of FEV1, %
Neha Nasir5, Colm Boylan2,4, Miranda Kirby5, and Post-BD FEV1/FVC, % 63 (45–74) 66 (62–68)
Parameswaran Nair1,3 Inflammatory biomarkers
1
FENO, ppb 39 (24–55) 56 (32–86)
Firestone Institute for Respiratory Health and 2Imaging Research Center, Sputum eosinophils, % 3.5 (0.5–14.8) 2.5 (1.5–11.8)*
St. Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada;
3
Blood eosinophils, 0.6 (0.2–0.9)† 0.5 (0.3–0.8)
Department of Medicine and 4Department of Radiology, McMaster 3109 cells/L
University, Hamilton, Ontario, Canada; and 5Department of Physics, Asthma medications
Toronto Metropolitan University, Toronto, Ontario, Canada ICS dose, μg/d 1,000 (500–1,000) 1,000 (750–1,500)
OCS dependent 3 (23%) 3 (27%)
OCS dose, mg/d 0.0 (0.0–1.25) 0.0 (0.0–5.0)

Definition of abbreviations: ACQ-5 = Asthma Control Questionnaire–5;

Supported by the Canada Research Chairs program and a Tier 2
Canada Research Chair (S.S.) and the Frederick E. Hargreave Teva
Innovation Chair in Airways Disease (P.N.). This was an investigator-
initiated study funded by Sanofi and Regeneron.
Clinical trial registered with www.clinicaltrials.gov (NCT 03884842).
Originally Published in Press as DOI: 10.1164/rccm.202306-1102LE
on August 21, 2023
AQLQ = Asthma Quality of Life Questionnaire; BD = bronchodilator;
BMI = body mass index; FENO = fraction of exhaled nitric oxide;
ICS = inhaled corticosteroid by fluticasone propionate equivalent;
OCS = oral corticosteroid by prednisone equivalent.
Data are expressed as mean (SD), n (%), or median (interquartile
range).
*n = 10 as differential cell count could not be performed for one
patient.
†
n = 12 as venous access could not be achieved for one patient at
baseline.

Correspondence 995
 CORRESPONDENCE

Figure 1. Change in quantitative computed tomography (CT) and 129Xe ventilation magnetic resonance imaging (MRI) biomarkers between
baseline (Week 0) and the end of treatment (Week 16) in patients who received dupilumab and placebo. (A–C) Individual (A) CT mucus score,
(B) CT wall area percentage, and (C) 129Xe MRI ventilation defect percentage (VDP) measured at baseline (Week 0) and at the end of treatment
(Week 16) in the dupilumab and placebo groups. Paired Week 0 and Week 16 individual patient values are presented for each group, and
bars represent mean or median values. (D) 129Xe ventilation MRI (cyan) and CT coronal slices acquired at baseline (Week 0) and the end of
treatment (Week 16) for a 40-year-old man who received dupilumab. CT mucus score (from 18 to 11) and MRI ventilation (VDP from 13% to 3%)
were improved but not normalized by dupilumab. Yellow crosshairs identify a mucus plug in the apical segment of the right upper lobe and a
distal ventilation defect (arrow) at baseline that were resolved after dupilumab administration. CI = confidence interval.

inflammation who were randomized (1:1) to dupilumab (600-mg
loading dose followed by 300-mg subcutaneous injections) or placebo
every 2 weeks for 16 weeks. We intended to evaluate the provocative
concentration of methacholine resulting in a 20% decrease in FEV1 as
the primary outcome; however, most patients had FEV1 , 65%
predicted, and the challenge could not be performed. In this
report we focus on prospectively defined exploratory chest CT and
129
Xe ventilation MRI outcomes. At baseline (Week 0) and the end
of treatment (Week 16), full-inspiration and full-expiration chest
CT scans (4) were acquired using a 64-slice LightSpeed VCT system
(GE HealthCare), and hyperpolarized 129Xe ventilation MRI (5) was
performed using a Discovery MR750 3T system (GE HealthCare).
Additional assessments reported here included spirometry,
respiratory oscillometry (6), and the Asthma Control
Questionnaire–5 (ACQ-5). The protocol was approved by the
Hamilton Integrated Research Ethics Board, and all patients provided
written informed consent. The funder of the study had no role in
study design; in the collection, analysis, and interpretation of data;
in the writing of the manuscript; or in the decision to submit the
manuscript for publication.
CT and 129Xe ventilation MRI outcomes were the change from
Week 0 to Week 16 in postbronchodilator CT mucus score, CT gas
trapping, CT wall area percentage (WA%), CT lumen area (LA), and
MRI ventilation defect percentage (VDP). The CT mucus score was
determined using a bronchopulmonary segment scoring system
(7, 8). CT gas trapping was quantified at residual volume as the low-
attenuation area of the lung below 2856 Hounsfield units. CT WA%
and LA were quantified at TLC as the average segmental airway
measurements from five standardized paths using VIDA|vision
(VIDA Diagnostics Inc.) (9). 129Xe MRI VDP was generated as the
ventilation defect volume normalized to the thoracic cavity volume
(10). Respiratory oscillometry was performed using the tremoflo
C-100 (Thorasys), and change from Week 0 to Week 16 in respiratory
system resistance (Rrs) and reactance (Xrs) at 5 Hz (Rrs5Hz and
Xrs5Hz), Rrs at 19 Hz (Rrs19Hz), the frequency dependence of Rrs
(Rrs5–19 Hz), and the integrated area of low-frequency reactance (AX)
were reported.
Between-group differences in treatment changes were evaluated
using unpaired t tests or Mann-Whitney tests, and the difference in
mean or median change with the confidence interval (CI) is shown.
Analyses were performed using Prism 9.2.0 (GraphPad).
Results
Thirteen patients who received dupilumab and 11 who received
placebo were included in the efficacy analysis. The treatment groups
were well balanced with respect to baseline demographics and clinical

996 American Journal of Respiratory and Critical Care Medicine Volume 208 Number 9 | November 1 2023
CORRESPONDENCE
characteristics, although the placebo group reported worse asthma
control (higher ACQ-5 scores) and quality of life (lower Asthma
Quality of Life Questionnaire scores) (Table 1).
Figure 1 summarizes the effect of dupilumab in comparison with
placebo on airway structure and function assessed on CT and 129Xe
MRI. Improvements in the mucus score (24 [95% CI, 27 to 21];
P = 0.018; Figure 1A), WA% (22.0% [95% CI, 23.5% to 20.4%];
P = 0.016; Figure 1B), gas trapping (26.5% [95% CI, 211.6% to
21.3%]; P = 0.016), and VDP (25.0% [95% CI, 29.8% to 20.2%];
P = 0.041; Figure 1C) were all greater with dupilumab than with
placebo. The change in LA was not different between treatment
groups (2.1 mm2 [95% CI, 20.6 to 4.8 mm2]; P = 0.12), although it
increased after dupilumab administration (1.6 mm2 [95% CI, 0.1 to
3.1 mm2]; P = 0.040). Figure 1D shows ventilation MRI and CT
coronal slices for a patient with regional improvements in ventilation
and mucus plugging after dupilumab administration. Improvements
in oscillometry measurements of Rrs5Hz (20.98 cm H2O
s/L [95%
CI, 21.76 to 20.20 cm H2O
s/L]; P = 0.016), Rrs5–19 Hz (20.63 cm
H2O
s/L [95% CI, 21.18 to 20.08 cm H2O
s/L]; P = 0.027), Xrs5Hz
(1.14 cm H2O
s/L [95% CI, 0.30 to 1.97 cm H2O
s/L]; P = 0.013),
and AX (214.3 cm H2O/L [95% CI, 224.1 to 24.4 cm H2O/L];
P = 0.0066) were greater with dupilumab than with placebo.
Improvements in FEV1 (0.34 L [95% CI, 0.07 to 0.61 L]; P = 0.016)
and ACQ-5 score (20.8 [95% CI, 21.4 to 0.0]; P = 0.042) were also
greater with dupilumab.
Considering patients treated with dupilumab, baseline mucus
score was correlated with the change in VDP (r = 20.68; P = 0.011),
Rrs5Hz (r = 20.65; P = 0.023), Xrs5Hz (r = 0.60; P = 0.038), AX
(r = 20.62; P = 0.033), and FEV1 (r = 0.75; P = 0.003). The change in
VDP was correlated with the change in mucus score (r = 0.61;
P = 0.027) and gas trapping (r = 0.70; P = 0.023).
Discussion
We demonstrated, in a placebo-controlled, randomized clinical trial,
that dupilumab reduces CT biomarkers of airway mucus, remodeling,
and gas trapping and consequently improves ventilation assessed by
MRI and metrics of small airway function assessed by oscillometry
in patients with moderate to severe asthma.
The reductions in mucus plugging and segmental WA% with
dupilumab are consistent with the mechanism of action of the drug
and IL-13 biology. These observations suggest that dupilumab
modifies large airway patency over a relatively short period of time.
The functional consequence of this on improved airflow was
confirmed by improved ventilation quantified using 129Xe MRI.
Although improved ventilation observed on MRI may reflect reduced
large and/or small airway obstruction, reduced CT gas trapping and
improved Rrs5–19 Hz, Xrs5Hz, and AX indicate that dupilumab also
improves small airway function (11). For patients treated with
dupilumab, higher mucus burden at baseline was associated with
greater improvements in lung function (VDP, Rrs5Hz, Xrs5Hz, AX,
and FEV1). We also observed that a greater reduction in mucus
plugging after dupilumab administration was associated with
a greater improvement in ventilation. These relationships are
important, as they implicate mucus plugging as a relevant mechanism
by which dupilumab improves lung function. Similar mechanistic
relationships were not observed for WA% or LA; however, they
should not be negated given the small size of our trial. The small
sample size is a limitation of our trial, and this likely contributed to
Correspondence
randomization of patients reporting worse asthma control and quality
of life to the placebo arm. P values and between-group effects should
be interpreted accordingly.
Despite the aforementioned benefits of IL-4 receptor
blockade on airway structure and function, residual ventilation
defects and mucus plugs persisted in 6 of 13 (46%) patients.
The residual burden of ventilation defects and mucus plugs may
be related to the short intervention period, and it is possible that
further resolution may be observed after a longer treatment
course. Alternatively, they may be explained by non–IL-4/IL-
13–driven pathologies. Future mechanistic studies are required to
evaluate this. 䊏
Author disclosures are available with the text of this letter at
www.atsjournals.org.
Correspondence and requests for reprints should be addressed to
Parameswaran Nair, M.D., Ph.D., McMaster University, Firestone Institute
for Respiratory Health, St. Joseph’s Healthcare Hamilton, 50 Charlton
Avenue East, Hamilton, ON L8N 4A6, Canada. Email: parames@
mcmaster.ca.
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Copyright © 2023 by the American Thoracic Society
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