Sputum cytokines associated with raised FeNO after anti-IL5
biologic therapy in severe asthma.
To the Editor,
Biomarkers such as circulating absolute eosinophil count, % of
eosinophils in sputum, and fraction of exhaled nitric oxide (FeNO) are
predictors of response to anti-inflammatory therapy for asthma. Failure
to normalize FeNO with high doses of corticosteroids are likely to be
related to cytokines and chemokines such as IL-5, IL-4, IL-13, eotaxin
and TARC derived from eosinophils and other Th2 cells, and alarmins such
as TSLP and IL-33 from sources such as the airway epithelium(1). All
Anti-IL5 biologics suppress eosinophils in sputum. However benralizumab
(anti-IL5RMab) has greater effect in the severe prednisone-dependent
patients than mepolizumab/reslizumab (anti-IL5 neutralizing Mab)(2,3).
While raised eosinophil count is a predictor of clinical response to
anti-IL5 biologics, raised FeNO is often not(4). However, they reduce
FeNO to variable levels(4,5) suggesting that FeNO is partly regulated by
cytokines derived from eosinophils in the airway(1). The cytokines in
sputum associated with raised FeNO in prednisone-dependent severe
asthmatics treated with effective anti-eosinophil drugs are not known.
In this retrospective observational study, we measured cytokines in
sputum using an automated ELISA reader (EllaTM,
Protein Simple, R&D Systems, BioTechne, Minneapolis) at baseline and
after 4 months of treatment with either benralizumab or
mepolizumab/reslizumab and compared the levels of cytokines in those
whose FeNO remained high after treatment. Raised FeNO was defined by
FeNO >40ppb and an increase of at least 16ppb from
pre-treatment value. The study was approved by Hamilton Integrated
Research Ethics Board (#11227, 5037), and all patients gave written
informed consent. The cytokines assayed were IL-5, IL-4 and IL-13 (Th2
inflammation) and IL-1β, IL-6, IL-10, IL-12p70, IL-15 IL-17A, IL-18,
IL-33, IFNγ and TNFα (Th1/Th17 inflammation, Table e3). Details of
baseline demographics, methods and statistics are shown in the online
supplement.
Paired measurements were made in 30 patients who received benralizumab,
and 10 each who received mepolizumab/reslizumab. Overall, as previously
reported(5), FeNO levels were not significantly reduced by anti-IL5
treatment (median FeNO pre-treatment 29 [5-156] vs FeNO post
treatment 37 [6-280]; p=0.25; Figure e1). This change in FeNO did
not correlate with a reduction of sputum eosinophils (r=-0.24; p=0.16).
Among 15 patients, FeNO remained raised after treatment (Table 1). On
average, IL-4 and IL-13 were the only cytokines significantly higher in
the sputum of these patients compared to those in whom the FeNO values
normalized (Figure 1, Figure e2). Within this group, there were patients
with raised IL-4 (31%) and IL-13 (15%) and those with normal
IL-4/IL-13. A small proportion of those with normal IL4/13 had raised
levels of IL-18 or IL-1β (20%). Residual eosinophilic airway
inflammation was significantly more present in patients with raised FeNO
(30.8% vs 8.1%; P=0.04; Table e2). Patients with raised FeNO remained
to have poor asthma control with an ACQ>1.5, however this
did not significantly differ from those with a normalized FeNO (ACQ
1.7±0.9 vs 1.4±1.1; P=0.36; Table 1).
This study, despite its limitation of retrospective design and small
numbers, provide novel information on the cytokine profile in the
airways of severe prednisone-dependent eosinophilic asthma patients
whose FeNO remain high after anti-IL5 treatment. This is a common
clinically encountered situation. Our observations suggest that
IL-4/IL-13 are the cytokines most associated with this phenomenon. This
may be due to the airway eosinophilia being uncontrolled or due to a
non-eosinophilic source of these cytokines. However, there could be
non-IL-4/IL-13 related increase in FeNO that may be due to inflammasome
activation and through non-Th2 cytokine pathways that may raise the
possibility of airway infections or autoimmune activation(6). This has
important clinical implication. These patients may not show adequate
response to switching to anti-IL4R Mab if their asthma remains
uncontrolled. This needs to be evaluated prospectively.
References:
- Couillard S, Shrimanker R, Chaudhuri R, et al. Fractional Exhaled
Nitric Oxide Nonsuppression Identifies Corticosteroid-Resistant Type 2
Signaling in Severe Asthma. Am J Respir Crit Care Med 2021; 204:
731-734.
- Mukherjee M, Forero DF, Tran S, Boulay ME, et al. Suboptimal treatment
response to anti-IL-5 monoclonal antibodies in severe eosinophilic
asthmatics with airway autoimmune phenomena. Eur Respir J 2020 Oct
8;56(4):2000117. doi: 10.1183/13993003.00117-2020.
- Mukherjee M, Bhalla A, Venegas-Garrido C, et al. Benralizumab
attenuates blood and airway eosinophilia in severe asthmatics with
inadequate response to anti-IL-5 neutralizing antibodies
[abstract]. Eur Respir J 2022; 60 (suppl 66): 3994; DOI:
10.1183/13993003.
- Hearn AP, Kavanagh J, d’Ancona G, et al. The relationship between Feno
and effectiveness of mepolizumab and benralizumab in severe
eosinophilic asthma. J Allergy Clin Immunol Pract 2021; 9:
2093-2096.e1.
- Nair P, Kjarsgaard M, Armstrong S, Efthimiadis A, O’Byrne PM,
Hargreave FE. Nitric oxide in exhaled breath is poorly correlated to
sputum eosinophils in patients with prednisone-dependent asthma. J
Allergy Clin Immunol 2010; 126: 404-6.
- Donnelly LE, Barnes PJ. Expression and regulation of inducible nitric
oxide synthase from human primary airway epithelial cells. Am J Respir
Cell Mol Biol 2002; 26: 144-51.
Authors
Pieter-Paul Hekking 1,2, Kayla Zhang1, Carmen Paz Venegas Garrido 1,
Raquel Lopez-Rodriguez 1,3, Melanie Kjarsgaard1, Manali Mukherjee 1, Parameswaran
Nair 1
1. Division of Respirology, Department of Medicine, St. Joseph’s
Healthcare Hamilton, McMaster University, Hamilton, Ontario, Canada.
2. Department of Respiratory Diseases, STZ Centre of Excellence for
Asthma & COPD, Franciscus Gasthuis & Vlietland Hospital, Rotterdam,
the Netherlands.
3. Department of Allergy, Lucus Augusti Hospital, Lugo, Spain
Correspondence
Dr Parameswaran Nair
Firestone Institute for Respiratory Health
St Joseph’s Healthcare Hamilton
50 Charlton Avenue East
Hamilton, Ontario, L8N4A6, Canada
Tel: 905-522-1155 x 35044
Fax: 905-521-6183
E-mail:
parames@mcmaster.ca