Blood eosinophil numbers are of limited use to guide biologics:
asthma is an airway disease!
Manali Mukherjee and Parameswaran Nair
There is no dispute that eosinophils are associated with asthma, and
that their numbers in circulation may increase with asthma symptoms
and severity. There is also no dispute that there are number of
processes, in addition to IL-5, that may contribute to the recruitment
of these cells out of the bone marrow into target organs.
- However, their numbers in circulation are not specific to asthma.
Other allergic conditions such as rhinitis, sinusitis, and food
allergies, and most importantly, atopic dermatitis could determine the
eosinophil numbers even when asthma is mild.
- Circulating eosinophils traffic to the airway and spill over into the
lumen, release their cationic proteins and other contents including
DNA, and these contribute to airflow obstruction. When eosinophils are
confined to the circulation, however raised their numbers may be (for
example, as in hypereosinophilic syndromes), they cause minimal asthma
symptoms (9). Of course, circulating eosinophil numbers may reflect
the numbers that may eventually track into the lumen, but in general,
they are not activated. This correlation between blood and airway
(sputum) eosinophil numbers are poor in the very severe patients who
are on oral glucocorticosteroids (OCS) (10), with higher blood
eosinophil counts
(>600>>500>400>300/µL)
being associated with higher sputum eosinophil counts. Further, given
their diurnal fluctuation, lack of specificity for asthma, and
generally non-activated state, circulating eosinophil number may
simply be an indicator of Th2 biology, rather than the eosinophil
being the effector cell.
- Therefore, it is not surprising that asthmatic patients with raised
blood eosinophil counts respond well to anti-Th2 biologics (11). The
annualized relative reduction in exacerbations (AAER) is greater (up
to 70%) in those with higher blood eosinophil counts, particularly
over 500 or 600/µL, as these are the patients who are likely to have
sputum eosinophilia as well. The response in the most severe
OCS-dependent patients are less, and this partly dependent on the
dose, route of administration, and mechanisms of action of the
biologics (12).
- While accepting that raised baseline blood eosinophil counts (of
>400/µL) may be helpful to predict response to an
anti-Th2 biologic (albeit up to 70% AAER), the have limited role to
monitor response to treatment. As we recently reported in 250 patients
with baseline blood eosinophilia who were treated with either
mepolizumab or reslizumab for at least 4 months (13), there was an
overall suboptimal response in 43%. An absolute blood eosinophil
count of 530/µL at baseline (that had 70% sensitivity and 90%
specificity to predict ≥3% sputum eosinophils) best predicted a
clinical response. Of the 129 patients in whom paired blood and sputum
eosinophils were available after at least 4 months of treatment, there
were 65 sub-optimal responders. 78% of them had sputum eosinophils
≥3%. Blood eosinophils were ≥400/µL in only 7 patients(figure 2). This discordance is likely due to in-situ
eosinophilopoiesis resulting from inadequate neutralization of airway
IL-5 largely from ILC2 cells. Sputum eosinophil counts are
reproducible and reliable. Reports that they have poor measurement
properties are relate to poor processing techniques, specifically
related to poor dispersal, and not properly selecting out the squamous
cells. The method is simple and should be easy to set up in any
tertiary centre that looks after patients with severe asthma.
- Blood eosinophil count may be mis-leading also to monitor
anti-IL4/IL-13 therapies. While associated with clinical improvement,
dupilumab treatment is associated with an increase in circulating
blood eosinophil count in almost all patients (putative mechanisms
include preventing egress of eosinophils from circulation into tissues
by blocking VCAM, endothelial miRNA1 etc).
- In summary, while circulating blood eosinophil count of ≥400/µL may be
helpful to identify a Th2 immune biology to initiate therapy with an
anti-Th2 Mab, it has very limited value to monitor response. Normal
blood eosinophil counts on anti-IL5 mabs may be associated with poor
asthma control and sputum eosinophilia. Conversely, raised blood
eosinophil counts on anti-IL4R mab may be associated with good asthma
control.