Discussion
In the light of the high prevalence of asthma worldwide, particularly
given the substantial absolute numbers of patients with severe or
“difficult-to-treat” asthma, there is considerable value in
identifying new targets that can be utilized as biomarkers, or as
targets for novel therapy, thereby facilitating precision medicine. In
this study, we determined whether systemic levels of the Type 17
cytokines IL-26 and IL-17A are altered in allergen-sensitized children,
with and without asthma, compared with non-sensitized children. Indeed,
we observed that systemic protein concentrations of both IL-26 and
IL-17A are altered in a similar manner; the serum concentrations of both
these cytokines are enhanced in children sensitized to dog allergen as
compared to non-sensitized children. Based on prior studies
demonstrating that systemic concentrations of IL-26 are enhanced in
adults with asthma as compared to adults without asthma5, 22, 23, we were not surprised to discover that both
systemic IL-26 and IL-17A concentrations were likewise enhanced in
children sensitized to dog-allergen who also had asthma. However, we
were surprised to discover that systemic IL-26 and IL-17A concentrations
did not markedly differ between sensitized children with and without
asthma. Moreover, systemic IL-26 and IL-17A concentrations amongst
allergen-sensitized children were not clearly different with respect to
other allergic manifestations, namely eczema, allergic rhinitis, or a
history of one or more food allergies. In this respect, the presence of
elevated IL-26 and/or IL-17A concentrations in our cohort was not
distinctly associated with asthma or specific allergic disease, but
rather emerge as general biomarkers of an inflammation that has
traditionally been regarded as mediated by Type 2 cytokines. Along with
this, we observed a statistically significant positive correlation
between systemic IL-26 and IL-17A concentrations, regardless of whether
the analysis included all allergen-sensitized subjects or if it was
restricted to only those with asthma. Of note, in the control group of
non-sensitized children, there was a small number of subjects with
self-reported eczema that did not appear to be associated with elevated
levels of either IL-26 or IL-17A, but it is difficult to make clinically
meaningful conclusions from this due to the small sample size.
Although we found that enhanced IL-26 concentrations are not restricted
to children with asthma in our study material, we sought to determine
whether IL-26 concentrations may correlate with disease severity amongst
allergen-sensitized children with asthma. Previous studies have reported
that increasing local IL-26 concentrations correlate with worsening
disease severity in adults with asthma 5, 24. However,
Salhi and colleagues did not observe a specific correlation between
systemic IL-26 concentration and markers of disease severity in adults
with asthma 22. In our study material, we observed
that, amongst children with asthma, increasing systemic IL-26 levels
correlate with increasing ACT scores. That is to say: We found that
increased systemic IL-26 values were associated with improved control of
symptoms. However, we detected no statistically significant correlation
between systemic IL-26 concentrations and AQLQ scores, nor was there any
statistically significant correlation between systemic IL-26 and lung
function according to spirometry (FEV1,
FEV1/FVC%) in the current study material. It should be
noted however, that the range of spirometry values in the
allergen-sensitized study group, while clearly different than the
non-sensitized control group, was quite modest and reflects primarily
mild-to-moderate asthma. This limited range of disease severity,
combined with limited statistical power due to the moderate size of the
current material, may explain why we did not detect correlations between
systemic IL-26 concentrations and certain clinical assessments.
As these observations were somewhat mixed and were discordant with the
previous studies comparing local IL-26 and markers of asthma severity,
we wondered whether systemic IL-26 concentrations may correlate with
other surrogate markers of asthma severity in a manner similar to that
of ACT scores. To this end, we compared systemic IL-26 to daily inhaled
corticosteroid doses in the patients with asthma. We observed that
increasing systemic IL-26 values correlated with decreasing inhaled
corticosteroid doses, which supports the notion that systemic IL-26
concentrations correlate with improved overall symptom control.
Moreover, patients that received one or more course of oral
corticosteroids for asthma exacerbations in the year preceding study
enrolment had significantly lower systemic IL-26 levels compared to the
patients with asthma who had not received oral corticosteroids. As
patients could not have evidence of an active asthma exacerbation at the
time of enrolment, this difference was not due to direct inhibition of
systemic IL-26 production by systemic glucocorticoids, a phenomenon
which has been described in vitro 18. If
replicable, these findings would suggest that elevated systemic IL-26
concentrations predict milder disease severity in allergen-sensitized
children, in contrast with observations of local IL-26 production in the
airways. Furthermore, they raise the question of whether these
observations indicate that the cellular sources of IL-26 have been
recruited into the airways in severe asthma, or whether elevated
systemic IL-26 levels per se may confer a protective effect
against the development of severe asthma in allergen-sensitized
children.
There are some limitations of this retrospective analysis of previously
collected study materials. First, the primary focus for patient
recruitment was to establish a cohort of allergen-sensitized children,
with or without other clinical allergic manifestations. While a majority
of these children also had clinically documented asthma, the cohort was
not originally designed with this in mind, which could suggest that
there are certain differences between our study population and those in
similar studies. Second, while the majority of allergen-sensitized
children in our study had asthma, most participants had only mild to
moderate disease as reflected in spirometry values, ACT and AQLQ scores.
This limited range of severity was also reflected by the fact that there
were few asthma exacerbations in the 12 months leading up to study
enrolment, whereas other studies have focused more on subjects with
clinically severe asthma. Nevertheless, it is interesting that so many
of the asthmatic subjects in our study had significantly elevated levels
of IL-26 and/or IL-17A, cytokines which are typically associated with
more severe and often steroid-resistant asthma. This raises the question
of whether the cytokine elevations we observed are merely due to general
allergic inflammation in our allergen-sensitized group, or if those
children with elevated systemic IL-26 and/or IL-17A concentrations may
be predisposed to developing the more severe Type 1/Type 17 asthma
endotype over time. A third limitation of this study is a lack of
concurrent airway sampling for analysis, either via sputum or BAL, that
would have allowed a concurrent assessment of local and systemic
cytokine concentrations, and finally, a lack of concurrent
microbiological data. Given that both IL-26 and IL-17A expression can be
affected by microbial pathogens 19, 30, 31, it would
be ideal to have a thorough microbiological analysis performed in future
studies, to rule out dysbiosis per se as a confounding factor.
In summary, our findings demonstrate that the systemic levels of both
IL-26 and IL-17A are altered in children with sensitization to dog
allergen regardless of clinical allergic symptoms to dog dander,
suggesting that both cytokines are involved in allergen sensitization.
While elevations of these cytokines are not directly linked to the
presence or absence of asthma, increasing systemic IL-26 concentrations
are associated with multiple surrogate markers of improved asthma
symptom control. Indeed, these observations are compatible with the
cellular sources being recruited into the airways in severe asthma,
which supports the notion that this kinocidin bears potential both as a
biomarker and therapeutic target. Given the clinical relevance of the
current observations, our study provides a rationale for larger,
prospective studies on the pathogenic role of these Type 17 cytokines,
simultaneously examining systemic as well as local cytokine
concentrations in asthma, ideally combined with an ex vivoevaluation of key cellular and molecular mechanisms.