DISCUSSION
We established that coldU in children has a lower resolution rate than
CSU. Further, among children with coldU, 17.3% of patients experienced
coldA, predominantly cases with elevated eosinophils.
Similar to prior studies, we found that pediatric coldU has no sex
predilection12,13, unlike in adults where females make
up the majority of cases6,14. The median age of onset
of symptoms in our population (9.5 years) was consistent with other
reports in children (7-8.5 years)7,12,13.
We found that approximately half of patients had concomitant CU of other
types, predominantly CSU, and a minority had cholinergic urticaria. A
large retrospective study of coldU in children reported that only 14.2%
and 3.6% of participants had concomitant CSU and cholinergic urticaria,
respectively12. The elevated proportion of patients
with concomitant CSU (42.3%) and cholinergic urticaria (9.6%) in our
study may be because patients were assessed for concomitant types of CU
at study entry. In line with our results, a study of both adults and
children study reported that 8% of patients with cold urticaria had
co-existent cholinergic urticaria15.
Other studies suggest that co-existing atopic conditions may be more
common. Yee et al. report that among children with coldU, 59.5% had
concomitant allergic rhinitis, 46.8% had asthma, and 33.4% had food
allergies12. However, the prevalence of atopic
dermatitis among children with coldU was slightly lower than in the
present study (24.6% versus 30.8%)12. These
differences may reflect geographic or ethnic differences between the
studied populations16,17.
Relative to CSU, we found an increased proportion of coldU patients with
IgE/Th2 mediated diseases (i.e., asthma and atopic dermatitis)
and elevated total IgE. Consistent with these findings, the majority of
CSU cases are associated with an autoimmune etiology consisting of
auto-IgG or auto-IgE antibodies18,19, whereas coldU is
predominantly an IgE mediated disease3. A Th2/IgE
etiology underlying coldU indicates the potential therapeutic utility of
IgE (i.e., omalizumab) and Th2 (i.e., dupilumab)
inhibitors. Omalizumab efficacy in treating coldU refractory to
antihistamines has been established in adults20, but
not yet in children. A case report has documented the resolution of
coldU and concomitant atopic dermatitis in an adult taking
dupilumab21, and a clinical trial is underway to
determine its efficacy in adult coldU (NCT04681729). Dupilumab is
already licenced for the treatment of atopic dermatitis in children;
therefore, it may be a treatment option in children with both atopic
dermatitis and coldU. Further studies are necessary to elucidate the
role of IgE and the Th2 response in coldU.
Children in our cohort were predominantly managed with sgAHs, of which
56.8% of patients had well-controlled symptoms. Concomitant CSU was
associated with poorly controlled disease on sgAHs. No clinical trials
have assessed the efficacy of sgAHs in pediatric
coldU22. However, several studies have found that
sgAHs significantly diminish symptoms and decrease the minimum
temperature at which symptoms develop in adults22-26.
Further studies are required to establish the efficacy of sgAHs in the
treatment of pediatric coldU, and to determine the usefulness of
concomitant CSU as a predictor of sgAH response.
In this study, 17.3% of children had a history of coldA. This is in
line with a recent meta-analysis conducted by our team that determined
that the prevalence of anaphylaxis among cases of adult and pediatric
coldU was 21.5% (95%CI: 15.8%, 28.5%;
I2=69%)4. Further, we identified
that elevated blood eosinophils were associated with coldA. These
results suggest that blood eosinophils may be used identify patients at
risk for coldA, which can inform epinephrine autoinjector prescription
and counselling of patients to avoid common triggers of coldA. A recent
case report recorded the successful treatment of coldU and concomitant
CSU with reslizumab, an anti-IL-5 monoclonal antibody, which
downregulates eosinophil activation and recruitment27.
However, little is known on the role of eosinophils in the pathogenesis
of coldU/coldA.
The resolution of coldU in our cohort was fewer than 5 per 100
patient-years, almost half the resolution rate of
CSU10. The resolution rate observed was similar to
other studies that included both pediatric and adult patients
(17.9-26.6% of patients resolved in five years)6,28.
Because of insufficient sample size, we were unable to assess factors
associated with disease resolution.
Our study has some potential limitations. This study had a relatively
small sample size thereby limiting the power of subgroup analyses of
participants with coldA and disease resolution. Our study was conducted
at a tertiary urticaria referral center, which likely evaluates more
severe cases of coldU that are refractory to antihistamines/involve
anaphylaxis. However, we also recruited children from clinics outside
the hospital and, hence, we believe that this study maintains external
validity. Additionally, the wait time to see a specialist at our center
is approximately four to eight months; therefore, our results may
underestimate disease resolution because more self-limited cases were
not recruited. Although we assessed all children with the UCT, it has
not been validated for children under 12 years of age. However, the UCT
is reported to have high validity and reliability in
adults29 and preliminary work by our group supports
its validity in children. Finally, we were unable to obtain follow-up
data on four (7.7%) of patients and certain lab values were not
available in approximately a quarter of patients. However, given that
data was available for most patients we do not expect these missing
values to bias our results.
Taken together, our findings demonstrated a low resolution rate of
pediatric coldU versus CSU. Elevated eosinophils were associated with
anaphylaxis, which occurred in approximately one sixth of patients.
Future multicentre studies are necessary to determine factors associated
with coldU resolution.