Treatment approaches: personalising therapy using biomarkers
The first serious attempt to personalise therapy was the INFANT study,
using peripheral blood eosinophil count and aeroallergen sensitization,
both readily available in the clinic [49]. 300 children age between
12 and 59 months prescribed step two treatment were recruited from 18
sites in the USA. They received in a blinded, three-way crossover trial
in random order either daily ICS, daily montelukast or as needed ICS and
short acting β-2 agonist. Each treatment period was 4 months, with the
first two weeks of data in each treatment arm being discarded in lieu of
a washout period which was thought to be unethical. The primary endpoint
was a composite outcome of asthma control days and time to attack
requiring oral corticosteroids. They prespecified that aeroallergen
sensitization, gender and wheeze attacks would predict a differential
treatment response; the use of blood eosinophil count was apost-hoc analysis. Sixty of 300 improved spontaneously, and
unsurprisingly there was no differential response to treatment; whatever
they received they did well. 170 children showed a differential
response, and in this group as a whole, regular ICS was the best option,
and montelukast the least good. When they divided the group by
aeroallergen sensitization, the non-sensitized patients (n=130) did
equally well (or badly) irrespective of treatment, whereas those
allergen sensitized (n=100) did best in the regular ICS arm. They then
carried out a post-hoc analysis, dividing the groups at the
semi-arbitrary cut point of a blood eosinophil count of 300 cells/μλ.
Below this level, the treatment results were the same in all three arms
(n=82). Those with a count of 300 and above (n=71) were the group that
did best on regular ICS. Those who were both aeroallergen sensitized and
with a blood eosinophil count of at least 300 (n=64) were the group who
did best when prescribed regular ICS; in all others, treatment effects
were the same.
This study has opened the door to personalising treatment using two
simple biomarkers, but a note of caution must be sounded. The blood
eosinophil analyses were post-hoc , and thus hypothesis generating
and requiring confirmation in a second study. The stability of blood
eosinophil count was not measured; at least in school age children with
asthma, sputum inflammatory biomarkers are not stable [50]. The
cut-off level of blood eosinophils needs thought; 300 cells/μλ is the
upper limit of normal for adults and used as an indicator for Type 2
biologics, [51] but the upper limit of normal in children is much
higher [52]. Furthermore, elevated blood eosinophil count may be
caused by eczema or other atopic disease, or parasitic infections. There
are limited paediatric data showing bronchoalveolar lavage and
peripheral blood eosinophil counts correlate [48] but probably the
safest interpretation is that if blood eosinophil count is normal,
airway eosinophilia is unlikely; if high, then one possible explanation
is that the treatable trait of airway eosinophilia may be present.
The use of biomarkers was further explored in a meta-analysis [53]
of three previously reported randomised controlled trials in 1074
children age 12-71 months (Table 6) [27. 35, 40]. Blood eosinophil
count and aeroallergen sensitisation were determined at the start of the
trial. The investigators determined the predictive value of different
blood eosinophil counts from > 150 to 350 cells/μλ.
Unsurprisingly, patients with eczema had higher blood eosinophil counts.
The risk of an exacerbation increased with increasing blood eosinophil
count, but the predictive value of a blood eosinophil count was low.
Prediction was improved if allergen sensitization was added to the
model, such that at any level of eosinophil count, allergen
sensitization was present. In children prescribed ICS, the predictive
effect of the two biomarkers was not clinically significant. Perhaps it
is unsurprising that these three studies did not give clearcut answers;
the treatments were randomised, not clinically prescribed, and this may
well have affected the findings.
Future work, in addition to validating the original INFANT observations,
will include optimising the eosinophil cut-off, including in areas of
high parasite burden, and exploring whether the addition of exhaled
nitric oxide (FeNO), as in adults [54], will improve risk assessment
and personalising medicine. At the present time, it seems reasonable at
least in secondary care to measure both biomarkers and use them to guide
whether ICS are indicated – specifically, if neither blood eosinophilia
nor aeroallergen sensitisation is present, it is probably right to
withhold ICS.
Whatever the biomarker status, if an N-of-1 trial of ICS is
contemplated, a three step protocol is advocated, to prevent transient
symptoms being interpreted as chronic. The steps are:
- Commence ICS through an age-appropriate spacer; dose is arbitrary, but
I would use a relatively high dose, beclomethasone 200 mcg twice daily
on the basis that if the child does not respond, then a steroid
sensitive airway disease is unlikely. The family is told that the
treatment will be reviewed and discontinued after six weeks (again, an
arbitrary time period). Ideally adherence should be monitored
electronically
- Review the child at six weeks. If there has been no response, then the
treatable trait of airway eosinophilia is not present, and alternative
diagnoses and management strategies should be sought. If the child is
symptomatically improved, it is not clear whether this was
spontaneous, or treatment related. This is resolved by a period off
treatment.
- Review again after 6-8 weeks. If the child is asymptomatic, no further
action is needed. If symptoms have recurred, then ICS are re-started
and titrated down to the lowest dose needed to control symptoms