Long-term
prognosis after low-dose peanut challenge for patients with history of
anaphylaxis
Nobuko Akamatsu, MD, PhD1,2, Ken-ichi Nagakura, MD,
PhD1, Sakura Sato, MD3, Noriyuki
Yanagida, MD, PhD1,3,*, Motohiro Ebisawa, MD,
PhD3
1Department of Pediatrics, National Hospital
Organization, Sagamihara National Hospital, Kanagawa, Japan
2Department of Pediatrics and Adolescent Medicine,
Tokyo Medical University Hospital, Tokyo, Japan
3Clinical Research Center for Allergy and
Rheumatology, National Hospital Organization, Sagamihara National
Hospital, Kanagawa, Japan
Running title: Prognosis after low-dose peanut challenge
*Corresponding author: Noriyuki Yanagida, MD,
PhD
Department of Pediatrics, National Hospital Organization, Sagamihara
National Hospital,
18-1, Sakuradai, Minami-ku, Sagamihara, Kanagawa 252-0392, Japan
E-mail: yana@foodallergy.jp
Word count: 1190
Number of figures: 2 Number of tables: 0
Conflict
of interest: Motohiro Ebisawa and Sakura Sato have received speaker
honoraria from Viatris. All other authors declare that they have no
conflicts of interest.
Financial support: This paper has not received any financial
support.
Keywords : low-dose oral food challenge, peanut, food allergy,
low-dose-tolerant, tolerant, pediatric, anaphylaxis
To the Editor,
Peanuts cause severe allergic reactions, and only 20% of
peanut-allergic patients acquire tolerance.1 Peanut
oral food challenge (OFC) has a high risk of severe symptoms such as
anaphylaxis, and OFC is avoided in children with an immediate history,
especially with a history of anaphylaxis.1Peanut-allergic patients and their guardians have a lower quality of
life because of worry that anaphylaxis may occur at any
time.2 Low-dose OFC may be useful to manage children
with a history of anaphylaxis,3 but it has not been
used to evaluate prognosis. This study investigated long-term prognosis
after low-dose peanut OFC for patients with a history of immediate
reactions, including anaphylaxis.
We retrospectively analyzed participants with a history of immediate
symptoms due to peanut ingestion, who received baseline low-dose OFC
with 133 mg of peanut protein from August 2013–August 2017 at
Sagamihara National Hospital (Figure 1), and evaluated two-year
tolerance acquisition.
We defined tolerance as passing an OFC with
795
mg protein (medium-dose OFC) and ingesting more than 795 mg protein
without symptoms at home; consuming this dose enables cessation of
strict avoidance in daily life. We defined baseline low-dose OFC
negative patients as the low-dose-tolerant group and positive patients
as the low-dose-reactive group. The low-dose-tolerant group was
instructed to consume 133 mg at home twice a week. Then, based on
guardians’ preference, patients received a medium-dose OFC every 6
months or gradually increased peanut ingestion to 795 mg at home under a
physician’s direction. The low-dose-reactive group completely avoided
peanuts and received low-dose OFC every 6 months. When the
low-dose-reactive group passed low-dose OFC, they received medium-dose
OFC (Supplementary Figure 1).
Anaphylaxis was defined according to the World Allergy Organization
Guidelines.4 OFC protocol is described in the
supplementary information.5 The percentage of patients
who acquired tolerance within two years was estimated using Kaplan-Meier
curves. The co-factors for tolerance acquisition were analyzed using Cox
regression analysis. Multivariate analysis was performed on the results
of low-dose OFC, total IgE, peanut-specific IgE (Pn-sIgE), and history
of peanut-related anaphylaxis. SPSS (version 27.0; SPSS Inc., Chicago,
IL) was used for all analyses; p <0.05 was considered
statistically significant. The Ethics Committee of The Sagamihara
National Hospital (2016-015) approved the study according to the
Helsinki Declaration. Written informed consent was obtained from all
patients’ guardians.
Fifty-three patients (median age, 7.1 years) were enrolled; 43% had a
history of anaphylaxis. The median Pn-sIgE level was 20.7 (interquartile
range 7.0–57.5) kUA/L. The median Ara h
2-specific IgE level was 10.4 (4.98–28.3)
kUA/L. The median thresholds of past immediate
symptoms were 26.6 mg (13.3–133) (Supplementary Table 1).
Twenty-one patients (40%) passed the low-dose OFC and were defined as
the low-dose-tolerant group, and 32 (60%) failed and were defined as
the low-dose-reactive group (Supplementary Table 1); 35% of patients
with a history of anaphylaxis passed the low-dose OFC. During low-dose
OFC, oral mucosal symptoms were most common (72%), then
gastrointestinal (63%) and respiratory symptoms (63%). Three patients
required intramuscular adrenaline (Supplementary Table 2). When the
low-dose-tolerant patients ingested low-dose peanuts at home, six (29%)
had mild reactions like oral and throat discomfort; most reactions
resolved naturally and did not require medical attention.
In the low-dose-tolerant group, 13 patients (62%) acquired tolerance
within 2 years, including five patients with a history of anaphylaxis,
whereas in the low-dose-reactive group, one patient (3%), with no
history of anaphylaxis, acquired tolerance (p <0.001)
(Figure 2). In the low-dose-reactive group, 6% of patients passed
low-dose OFC within two years.
The predictive factors of failure to acquire tolerance have been
positive reactions to low-dose OFC (crude hazard ratios of total IgE,
Pn-sIgE: 0.37 [95% confidence interval 0.15–0.94, p =0.04),
and log (Pn-sIgE) 2.23 [1.01–4.92], p =0.048) (Supplementary
Table 3). In 23 patients with a
history of anaphylaxis, five (22%) acquired tolerance. In 30 patients
with no history of anaphylaxis, nine (30%) acquired tolerance. History
of anaphylaxis did not significantly affect tolerance acquisition
(Supplementary Figure 2).
This is the first report showing that
low-dose OFC can be undergone relatively safely with tolerance
acquisition in some peanut-allergic patients, including patients with a
history of anaphylaxis. Patients with a history of anaphylaxis have a
lower quality of life because of worry that anaphylaxis may occur at any
time.6 Therefore, these results are significant
because if patients realize that low-dose peanuts can be ingested,
complete avoidance becomes unnecessary, and tolerance acquisition could
be assessed. The low-dose-reactive group was less likely to develop
tolerance and required careful follow-up to prevent accidental
ingestion.
Previous studies of long-term prognosis after peanut OFC excluded
patients with a history of anaphylaxis,1 therefore,
their tolerance acquisition based on the results of OFC was unknown. In
our current study, more than half of patients in low-dose-tolerant
groups acquired tolerance within two years, even those with a history of
anaphylaxis. Furthermore, one-fifth of patients with a history of
anaphylaxis tolerated peanuts, and there was no significant difference
between patients with and without a history of anaphylaxis in acquiring
tolerance. Therefore, passing low-dose OFC could be considered to assess
tolerance acquisition, regardless of the history of anaphylaxis.
It has been reported that peanut OFC is high risk because it often
causes anaphylaxis and other serious symptoms.1 In the
previous studies of peanut OFC, subjects have no history of anaphylaxis
or as few as 10%, while this study had 40%, but the occurrence of
anaphylaxis in OFC was comparable.1,7 Furthermore,
there is a report of a group of subjects, 83% of whom had a history of
anaphylaxis, and all patients reacted with anaphylaxis in
OFC.8 It has been reported that the incidence of
anaphylaxis with OFC was higher with progression up to the total OFC
ingested.7 Therefore this study suggests that low-dose
OFC is relatively safe in patients with a history of anaphylaxis.
Recently, some trials of low-dose oral immunotherapy showed that
ingesting low-dose peanuts (133-300 mg) could induce immunological
changes and allow the intake of larger amounts.9Similarly, daily ingestion of low-dose wheat is effective in increasing
consumption dose and preventing accidental symptoms, even in patients
with a history of anaphylaxis.10 Therefore, twice
weekly ingestion of 133 mg in the low-dose-tolerant group may yield oral
tolerance. In addition, few serious reactions were observed in the
low-dose-tolerant group during the subsequent at-home dose escalation in
this study.
This study has several limitations. First, 33 subjects were excluded
because their two-year course could not be tracked. Although the
excluded and included patients’ backgrounds were similar (Supplementary
Table 4), predictors of tolerance acquisition, such as anaphylaxis may
be different with more subjects. Second, there was a lack of information
on several points. Although at-home intake methods were unified, the
frequency of home peanut intake and adherence was unknown. Additionally,
we couldn’t confirm thresholds of past immediate symptoms in 25% of
subjects. However, the median thresholds were 26.6 mg in 75% of
subjects who were able to assess the threshold. Therefore, we assume
that thresholds in the remaining children were similar.
For peanut-allergic patients with a history of anaphylaxis, low-dose OFC
is relatively safe and effective in the assessment of tolerance
acquisition. Low-dose OFC results may effectively stratify
peanut-allergic patients with anaphylaxis history with good and poor
tolerance acquisition to select optimal management plans.
Nobuko Akamatsu, MD, PhD1,2, Ken-ichi Nagakura, MD,
PhD1, Sakura Sato, MD3, Noriyuki
Yanagida, MD, PhD1,3, Motohiro Ebisawa, MD,
PhD3,
1Department of Pediatrics, National Hospital
Organization, Sagamihara National Hospital, Kanagawa, Japan
2Department of Pediatrics and Adolescent Medicine,
Tokyo Medical University Hospital, Tokyo, Japan
3Clinical Research Center for Allergy and
Rheumatology, Sagamihara National Hospital, Kanagawa, Japan