A Thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy (PhD), 2017 / Asthma is the most prevalent chronic respiratory disease worldwide, with South Africa having
the fourth highest asthma mortality rate in the world (1.5 per 100,000 people) and the fifth
highest asthma mortality among five to thirty-five year old asthmatics (18.5 per 100,000
asthmatics). Current guidelines recommend that the achievement of ‘asthma control’ may still
be plagued with persistent airway inflammation despite normalisation of spirometric
parameters and control of asthmatic symptoms. This may result in structural damage with
airway remodelling, fibrosis and progressive loss of lung capacity over time. Assessment of
inflammation,‘Inflammometry’ is now increasingly used to titrate therapeutic interventions and
achieve better asthma control. The current study aims to identify simple, objective, non
invasive and reproducible biomarkers for airway inflammation; that would allow
documentation of the presence or absence of airway inflammation in individual asthmatic
patients. The availability of such tests may allow titration of therapeutic interventions to an
outcome parameter that is a true reflection of the state of inflammation of the airways.
This was a prospective, single centre, cross-sectional study of patients with confirmed asthma
attending a dedicated specialist asthma clinic at the Charlotte Maxeke Johannesburg Academic
Hospital Asthma Clinic. Patients attending the clinic were identified from patient records and
those who met the inclusion and exclusion criteria, were selected for the study.
The level of asthma control of each patient was determined using the Asthma Control
Questionnaire (ACQ). Patients undertook the Asthma Control Test (ACT), had an independent
assessment of their asthma control as well as performed lung function tests in a dedicated lung
function laboratory. Blood and exhaled breath samples from patients were analysed for
inflammatory biomarkers. Optimisation experiments were performed to establish a protocol for
the measurement of serum leukotrienes in the asthmatic patient. For the statistical analyses,
patients were characterised into asthma control groups as defined by the ACQ.
The current study found that the ACQ and the ACT, as well as the ACQ and an independent
physician’s assessment of the level of asthma control were in synchrony. Baseline FEF 25-75
levels, expressed as percentage of predicted, were low in the totally controlled, well-controlled
and uncontrolled groups of asthmatic patients with medians of 35.7%, 27.3% and 17.3%
respectively. The FEF 25-75 values in the three groups demonstrated an absolute post
bronchodilator reversibility of 32%, 27% and 31% respectively. These findings confirmed the presence of bronchial airway hyper-reactivity (BAH), and suggest probable remodelling in the
small airways. Impulse oscillometry (IOS) had a greater value in differentiating small airway
resistance in the controlled when compared to the uncontrolled adult asthmatic patient.
Biomarker assessments found that CRP, IL-2 and RANTES were significantly higher in the
uncontrolled group when compared with the controlled group of asthmatic patients (p = 0.03,
p = 0.02 and p = 0.03 respectively). Of the three serum leukotrienes measured (i.e. LTB4, LTC4
and LTE4), LTE4 levels were significantly higher in the totally controlled group compared to
the uncontrolled and well-controlled groups (p = 0.007 and p = 0.006 respectively). Therefore,
an elevated LTE4 coupled to a suppressed level of RANTES in the same patient may identify
a different asthma phenotype. This could provide opportunities for identifying asthma
phenotypes and using biomarkers in assessing asthma control.
The study also found that TGFβ1 and TGFβ2 levels were significantly higher in patients using
high-dose inhaled corticosteroids (ICS) (dose category as defined by the Global Initiative for
Asthma (GINA)), compared to those patients not using high-dose ICS (p = 0.01 and p = 0.001 respectively). By comparison, TGFβ1 and TGFβ2 levels were significantly lower in the patients
using moderate-dose ICS (dose category as defined by GINA), compared to those not using
moderate-doses of ICS (p = 0.02 and p = 0.001 respectively). These findings suggest that airway inflammation is modulated by the upregulation of Treg cells as TGFβ is produced by Treg cells.
It is also possible that Treg cells under the influence of elevated IL-2 levels inhibited the expression of the other Th1 as well as Th2 cytokines measured. Therefore, an elevated TGFβ
level coupled with an elevated IL-2 level in the same patient may also identify a different
asthma phenotype. Collectively, biomarker assessments may prove useful in assessing asthma
control. Such assessments may require individualisation for different asthma endotypes and
phenotypes, possibly even using biomarker profiling using multiple biomarkers for future
patient care considering the heterogeneity of inflammation in asthma. / XL2019
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/27347 |
| Date | January 2017 |
| Creators | Kalla, Ismail Sikander |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | Online resource (254 leaves), application/pdf |
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