The role of dynamic hyperinflation in asthma

Asthma is a heterogeneous condition with many clinical and inflammatory
subtypes/phenotypes. Late-onset asthma is less prevalent as compared to
early-onset asthma and patients with this type of asthma frequently present
with atypical symptoms and fixed airflow limitation instead of reversible
bronchoconstriction. Due to the lower prevalence and atypical presentation,
patients with late onset asthma are at risk of being misdiagnosed as chronic
obstructive pulmonary disease (COPD), even in the absence of a significant
smoking history, and treated accordingly, with only bronchodilating and no
anti-inflammatory medication. Yet patients with this late-onset asthma subtype
are at risk of faster decline in lung function and are prone to frequent and
even life-threatening exacerbations.
There is growing evidence that ongoing eosinophilic inflammation in the small
airways plays an important role. This inflammation may lead to dynamic
hyperinflation, a phenomenon that might underlie the atypical COPD-like
symptoms and increased risk of exacerbations. These atypical symptoms might not
be detected by standard asthma control questionnaires but more so by
questionnaires used in COPD.
In the present project we hypothesize that systemic eosinophilic inflammation
in airway disease (asthma/COPD/asthma-COPD-overlap-syndrome (ACOS)) is
associated with small airway inflammation manifesting in dynamic hyperinflation
and specific symptoms, which can be reduced by systemic anti-inflammatory
treatment.

Primary objective:
To investigate the effect of supplementation of a single intramuscular dose of
80 mg triamcinolone on the level of MPT-induced dynamic hyperinflation, in
adult asthma patients with demonstrated dynamic hyperinflation. (Part 1)

Secondary objectives:
Part 2: To investigate the relationship between metronome-paced tachypnea (MPT)
induced dynamic hyperinflation and respiratory symptoms and limitations in
daily activities as assessed in different questionnaires.
Part 3: To investigate the relationship between MPT induced dynamic
hyperinflation and eosinophilic inflammation in peripheral blood.
Part 4: To evaluate the agreement between level of dynamic hyperinflation
induced by metronome-paced tachypnea (MPT) versus cardiopulmonary exercise
testing (CPET).
Part 5: To evaluate the difference between levels of MPT-induced dynamic
hyperinflation pre vs post bronchodilation in relationship to symptoms, blood
eosinophils and triamcinolone-induced changes in dynamic hyperinflation.
Part 6: To investigate whether specific immunophenotipic characteristics are
associated with (small) airway inflammation and dynamic hyperinflation.

Prospective randomised, double-blind, placebo-controlled intervention study.

One group receives a single dose of triamcinolone acetonide injection (80mg)
intramuscular. The other group receives a placebo.

The burden associated with this study includes 3 hospital visits, during which
several measurements will be done. At visit 1 several questionnaires will be
completed and blood test and lung function tests (spirometry, exhaled NO,
metronome-paced tachypneu (MPT)) will be performed. Eligible patients will
continue to visit 2, at which a cycle exercise test will be performed and study
medication will be given intramuscular. At the final visit all assessments
performed at visit 1 will be repeated.
The risk and discomfort of these procedures are small. Intramuscular
triamcinolone has proven to be safe and is registered for and regularly used in
asthma. Possible adverse effects (1-10%) listed for regular use of i.m.
triamcinolone include headache, infection and cataract. Data on side effects of
a single injection are not available. As possible local adverse effects are
listed: injection side reaction, pain following intramuscular injection,
sterile abces, (sub)cutaneous atrophy, hyper- or hypopigmentation and Charcot
like arthropathy.
The results of this study may be important for asthmatic patients, as it may
help to understand the relationship between systemic eosinophilic inflammation,
dynamic hyperinflation and symptoms. If indeed small airway inflammation and
subsequent dynamic hyperinflation underlies the atypical pattern of symptoms
and increased risk of exacerbations, it is important to identify these patients
in time and to treat them adequately.
We think the potential gained insights outweigh the risks and discomfort of
this study.