To the Editor
Asthma is characterized by
recurrent airflow limitation with airway hyperresponsiveness (AHR) due
to chronic inflammation.1 Various types of cells,
cytokines, chemokines and mediators are involved in the pathogenesis of
asthma.2 The mechanisms underlying AHR have attracted
considerable attention in recent decades. AHR reportedly did not develop
in several asthma models, e.g., mice lacking certain cell types—such
as mast cells or eosinophils—or not expressing certain genes, such as
for type 2 cytokines or FcεRI. However, T2 inflammation itself is also
impaired in some of these genetically-engineered mice. In addition,
these models do not completely recapitulate human asthma. Therefore, the
specific molecular pathway(s) regulating human AHR remains
unknown.3
In humans, mechanisms of AHR have been partially identified in ex
vivo models using lung, trachea, or bronchi,4,5 but
the in vivo mechanisms remain unclear. Recently, biologics have
been approved for steroid-refractory asthma and provide strong evidence
of roles for certain molecular pathways in the pathogenesis of
asthma.6,7 For example, an anti-IgE monoclonal
antibody (omalizumab) did not alleviate AHR even after the symptoms were
significantly reduced.8 However, no studies have
investigated AHR after treatment with anti-IL-5, anti-IL-5R, or
anti-IL-4Rα antibodies.
Here, we describe our experience using dupilumab, an anti-IL-4Rα
antibody, to treat a 12-year-old boy with refractory atopic asthma.
An 8-year-old boy who had suffered from bronchial asthma since he was 3
years old was admitted to a tertiary-care hospital, Yawatahama City
General Hospital, due to a severe asthma exacerbation in May 2016.
Following discharge, he visited the allergy unit of the hospital. He was
treated with an oral leukotriene receptor antagonist, a β2 agonist and
slow-release theophylline (SRT), as well as with inhaled high-dose
corticosteroid and a long-acting β2 agonist. However, his asthma
symptoms did not fully resolve. In Spring of 2019, he developed
pertussis, with repeated chronic coughing and wheezing episodes, and his
respiratory function subsequently worsened. He became unable to exercise
normally at school due to exercise-induced bronchoconstriction. In
September 2019, he was subcutaneously injected with 600 mg of dupilumab,
followed by 300 mg every 2 weeks.
AHR, respiratory function, serum total and specific IgE levels, and
peripheral eosinophil counts were evaluated before and at 4 and 6 months
after starting dupilumab. AHR was assessed by the standard acetylcholine
inhalation test (AcIT) in accordance with the guideline of the Japanese
Society of Allergology. That is, he inhaled acetylcholine chloride
solutions diluted with saline from low to high concentrations (0, 39,
78, 156, 313, 625, 1250, 2500, 5000, 10000, 20000 µg/mL) for two
minutes, followed by a pulmonary function test; this was repeated until
there was a 20% decline in his forced expiratory volume in one second
(FEV1). The last concentration of inhaled solution was
defined as the threshold of the AcIT, and the cut-off concentration
between asthma patients and normal subjects was 10000 µg/ml. All
medications except SRT were stopped 48 hours before the AcIT, and SRT
was stopped 18 hours before the AcIT.
His subjective symptoms gradually improved during the first 4 months of
dupilumab treatment. Surprisingly, his AHR induced by acetylcholine
inhalation completely disappeared at that point, and that status
continued for two months. SRT and other oral and inhaled bronchodilators
were discontinued 7 months after dupilumab was started. Since then, he
has experienced no asthma symptoms, such as cough, wheeze or dyspnea,
even after daily exercise, although his respiratory function has not yet
fully recovered.
Table 1 shows the following data that were determined before and at 4
and 6 months after starting dupilumab: respiratory function data, serum
theophylline level, AcIT threshold concentration, serum total IgE level,Dermatophagoides pteronyssinus -specific IgE level, and peripheral
eosinophil count. After starting dupilumab, the AcIT threshold
concentration increased dramatically, from 313 to over 20000 µg/mL, and
the total and specific IgE levels decreased, but the peripheral
eosinophil count decreased only by half.
We administered dupilumab, an anti-IL-4Rα antibody, to a 12-year-old boy
with severe atopic asthma, and his asthmatic symptoms disappeared, with
drastic improvement of AHR. His total and specific IgE levels decreased
markedly, but his peripheral eosinophil count decreased only by half. On
the other hand, an earlier study found that omalizumab, an anti-IgE
biologic, improved the clinical symptoms and decreased the peripheral
eosinophil count, but AHR remained unchanged.8 Taken
together, those findings imply that blockade of IL-4 and IL-13 is
involved in the causation of AHR.
IL-4 and IL-13, but not IL-5 or IL-17A, were reported to induce
hyperresponsiveness to histamine by enhancing expression of histamine
H1 receptor and cysteinyl leukotriene receptor 1 in
isolated human small airway tissue.5 On the other
hand, dupilumab treatment abrogated those effects of IL-4 and
IL-13.5 The clinical course of our case is in good
agreement with those earlier findings.
This report has a limitation, since it reports a single case.
Nevertheless, we believe that this is the first study showing that
dupilumab therapy directly improved AHR in an atopic asthma patient. In
the present patient, the peripheral eosinophil count after dupilumab
treatment decreased only by half. That is presumably because IL-5, the
critical cytokine for eosinophil development, activation and survival,
was not inhibited by dupilumab. The dupilumab treatment also reduced his
asthma symptoms and improved his quality of life, although his
respiratory function, especially the maximal mid-expiratory flow, was
not normalized, presumably due to the presence of airway remodeling. We
expect that his respiratory function will improve later, and further
observation and assessment are thus needed.
In conclusion, IL-4R signaling is likely involved in development of AHR
in atopic asthma patients.