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2. food allergies

Review
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Recent advances in the
diagnosis and therapy of
peanut allergy
Expert Rev. Clin. Immunol. 9(6), 551–560 (2013)
Saira Z Sheikh*1 and
A Wesley Burks2
Division of Rheumatology, Allergy and
Immunology, Department of Medicine
and Thurston Arthritis Research
Center, University of North Carolina at
Chapel Hill, Chapel Hill NC, CB 7280,
3300 Thurston Building, Chapel Hill,
NC 27599-7280, USA
2
Department of Pediatrics, University of
North Carolina at Chapel Hill, Chapel
Hill NC 260 MacNider Hall, CB 7220,
Chapel Hill, NC 27599-7220, USA
*Author for correspondence:
Tel.: +1 866 827 2862
Fax: +1 919 966 1739
[email protected]
1
www.expert-reviews.com
Peanut allergy is a life-threatening, IgE-mediated allergic disease. In developed countries, the
prevalence rate of peanut allergy in school-aged children is reported to be in excess of 1% and
continues to rise, representing a major public health concern. Peanut allergy is diagnosed on
the basis of a relevant clinical history combined with results of skin-prick testing and/or peanutspecific IgE levels. A double-blind placebo-controlled oral food challenge is the gold standard
for diagnosis. Currently, there is no approved treatment or disease-modifying therapy for peanut
allergy. This review discusses recent advances in molecular diagnostic techniques for peanut
allergy and highlights advances in peanut allergy therapeutics, discussing allergen-specific and
allergen-nonspecific treatments that are currently in Phase I/II clinical trials.
Keywords: allergen-nonspecific • allergen-specific • allergy • component resolved • diagnosis • diagnostics
• IgE-mediated • immunotherapy • peanut • treatment
Peanut allergy is a life-threatening, IgE-mediated
allergic disease. The prevalence of peanut allergy
in school-aged children in ­developed countries
is estimated to be in excess of 1% and c­ ontinues
to increase [1–12] . Compared with other food
allergies, peanut allergy is less likely to be outgrown and is estimated to resolve for only 20%
of children by school age [13,14] . All peanutallergic individuals are counseled about strict
dietary avoidance and given self-injectable epinephrine. Despite constant parent and patient
vigilance, accidental ingestions of peanut are
common and are estimated to be 15–40%
annually [15–18] . These accidental ingestions in
peanut-allergic individuals may result in severe
and fatal reactions [19–21] . The first step in taking care of peanut-allergic patients is arriving at
an accurate diagnosis, which is critical in order
to identify patients at risk of having an allergic reaction. Unfortunately, current diagnostic
tests have limitations such as the fact that they
are unable to predict the severity of an allergic
reaction and that positive tests to tolerated foods
can be seen [22] .
There has been much discussion and debate
about risk factors for development of peanut
allergy. The majority of peanut-allergic children
react on their first known exposure to peanut
[23,24] ; however, the route by which sensitization
10.1586/ECI.13.33
occurs is unclear. Several ­studies have focused
on the role of maternal c­ onsumption of allergen
during pregnancy or lactation; however, interventional studies have failed to demonstrate any
benefit of dietary e­ limination [25,26] . It has been
hypothesized that peanut sensitization may occur
as a ­c onsequence of ­environmental ­e xposure
through cutaneous or inhalational routes rather
than from maternal or infant allergen [23] . While
peanut allergy appears to have strong heritability, its genetic basis is unknown [27] . Given that
loss-of-function mutations within the filaggrin
gene are associated with atopic diseases such as
atopic dermatitis, it is felt that filaggrin may also
be a candidate gene in the etiology of peanut
allergy [27,28] . In the past few years, much effort
has been dedicated to the development of more
sensitive and accurate diagnostic tools for the
diagnosis of peanut allergy and this review discusses some of those advances (Box 1) . There is a
strong recognition of the unmet need to develop
effective treatments for peanut allergy, and much
progress has been made in the development of
novel therapies, which are showing promise.
While there is currently no approved treatment
available for peanut allergy beyond allergen
avoidance, it is probable that the current work
in the field will soon lead to the development of
a ­disease-modifying therapy for peanut allergy.
© 2013 Expert Reviews Ltd
ISSN 1744-666X
551
Review
Sheikh & Burks
Box 1. Overview of advances in peanut allergy
diagnostics and novel therapeutic approaches.
Diagnostics
• Component-resolved diagnostics
• Protein microarrays
• IgE epitope mapping
Therapeutics
• Allergen-specific approaches
– Oral immunotherapy
– Sublingual immunotherapy
– Epicutaneous therapy
– Immunotherapy with modified recombinant food proteins
• Allergen-nonspecific approaches
– Anti-IgE monoclonal antibodies
– Chinese herbal medicine (FAHF-2)
FAHF-2: Food Allergy Herbal Formula 2.
Diagnosis of peanut allergy
Current methods of diagnosis
The diagnosis of peanut allergy is typically made on the basis of
clinical history combined with evidence of peanut-specific IgE,
established by skin-prick testing and/or in vitro testing measuring serum peanut-specific IgE antibodies. While these are good
diagnostic tools, they have a number of limitations including
the fact that they are unable to predict the severity of an allergic reaction and that positive test results to tolerated foods can
be seen (indicating sensitization but not clinical allergy) [22] .
Sampson and colleagues have reported 95% predictive decision points of peanut-specific IgE (which can predict clinical
reactivity to peanut with greater than 95% certainty). These
suggest that with a peanut-specific IgE <2 kU/l (measured in
the ImmunoCAP®-FEIA system [Thermo Fisher Scientific, MA,
USA), a subject has an approximately 50% chance to pass an
open food challenge [10,29] . However, none of these diagnostic
tools have been able to achieve sufficiently high predictive values
to allow any one test to serve as an accurate modality for the
diagnosis of peanut allergy. For patients without a clear clinical
history or laboratory evidence that points towards peanut allergy,
a physician-supervised food challenge is necessary to help arrive
at a definitive diagnosis [30] . A double-blind placebo-controlled
oral food challenge (DBPCFC) remains the gold standard for
diagnosing peanut allergy. While these are routinely conducted
in the research setting, open or single-blind food challenges
are appropriate for the routine clinical setting. Currently, such
challenges are seldom performed in the clinic due to time and
the labor-intensive nature of the procedures as well as the perceived risk for severe allergic reactions. While a DBPCFC is the
gold standard for diagnosis of peanut allergy, it is important to
recognize that it cannot be used to predict the severity of future
allergic reactions, nor does it provide prognostic information
regarding development of anaphylaxis. Current focus is on developing techniques to improve the diagnosis of peanut allergy and
identifying tools that provide better ­prognostic information.
552
Advances in peanut allergy diagnostics
Allergen component-resolved diagnostics has become the focus of
attention, because it offers the potential to become a more accurate
diagnostic tool than those already established. Instead of crude
allergen extracts, this method utilizes purified allergen proteins,
which are produced from natural allergen sources or by recombinant expression of allergen-encoding cDNA [22] . Several studies
have suggested that component-resolved diagnostics could improve
the specificity of peanut-allergy testing. Koppelman et al. showed
that Ara h 2 was the most important allergen in predicting clinical reactivity to peanut as 26 out of 32 peanut-allergic subjects
in their cohort recognized it [31] . Nicolaou et al. demonstrated
that Ara h 2 was the most important predictor of clinical peanut
allergy, showing that Ara h 2-specific IgE levels >0.35 kU/l resulted
in 100% sensitivity and 96.1% specificity in identifying subjects
with peanut allergy, correctly identifying 97.5% of peanut-allergic
subjects in their cohort [32] . Other studies also show that compared
with whole peanut-specific IgE levels that are currently used for
in vitro testing, Ara h 2-specific IgE levels provide higher accuracy
in diagnosing peanut allergy [33,34] . Currently the best method for
diagnosis in an individual patient is the peanut-specific IgE; as
other studies are completed, it will be interesting to see whether
component testing replaces the crude allergen testing.
Several studies have shown that the pattern of binding to peanut
proteins may vary according to the geographic location [35–39] .
Other studies suggest that component testing can help in assessing
the severity of an allergic reaction. Binding to Ara h 8, without
binding to Ara h 1–3, has been shown to be associated with no
reaction or mild reactions [40,41] . In addition, individuals who have
isolated Ara h 8 sensitization typically have lower peanut-specific
IgE and are sensitized to birch pollen [39–41] . Using either purified
or recombinant peanut proteins, Peeters et al. [42] , Palmer et al. [43]
and Astier et al. [44] have published studies indicating increased
potency of Ara h 2 [39] . However, it is important to point out
that studies have not yet specifically correlated clinical severity
with Ara h 2 IgE [39] . Hence, at this time, Ara h 2 cannot be used
to predict the severity of a clinical reaction in p
­ eanut-allergic
individuals.
Protein microarrays permit the simultaneous assessment of
specific IgE to different peanut protein components. This technique requires small amounts of sera, which is an important
consideration in children and may be a cost-efficient approach
because it delivers results for multiple components simultaneously
[32,45] . Microarray technology can potentially provide additional
information, such as assessment of relative IgE antibody affinity [45,46] and the parallel determination of different antibody
isotypes [45,47] .
IgE-binding epitopes have recently been recognized as important factors in driving allergic reactions to peanut [32,45] . Partially
digested and absorbed peanut protein may lead to IgE antibodies
that recognize a greater number or a specific pattern of sequential
epitopes [45] . This pattern may be indicative of clinical peanut
allergy rather than asymptomatic sensitization [48] and s­ tudies have
shown that greater IgE epitope diversity and/or higher affinity may
be suggestive of the persistence and severity of peanut allergy [49,50] .
Expert Rev. Clin. Immunol. 9(6), (2013)
Recent advances in the diagnosis & therapy of peanut allergy
In the future, combining component-resolved diagnostics, IgE
epitope mapping and high-throughput microarray platforms may
allow for an assay that will result in better d
­ iagnostic ­capability
and help identify patients at risk for persistent allergy.
Several functional assays such as the basophil activation tests [51]
and analysis of peanut-specific T-cell responses [52] are currently
being studied. However, currently there is a lack of evidence
­demonstrating that these tests have diagnostic value in peanut
allergy.
Advances in treatment of peanut allergy:
allergen‑specific approaches
The concept of approaching food allergy with strategies beyond
allergen avoidance is certainly not a new one and dates back more
than 100 years. Despite much effort through the years, there is
currently no approved treatment for peanut allergy.
Although subcutaneous immunotherapy is used effectively and
successfully to treat environmental allergies, this has not been a
popular approach for food allergy. A few earlier studies explored
the concept of subcutaneous peanut immunotherapy [53,54] .
Although there was some evidence that injected peanut allergen could induce desensitization, the high rate of severe adverse
reactions with subcutaneous peanut immunotherapy were considered unacceptable, and this approach was abandoned [54,55] .
Thus began the pursuit for alternative approaches for treatment
of peanut allergy.
Peanut oral immunotherapy
Oral immunotherapy (OIT) for peanut allergy in young children
is one of the most studied research options because of promising results that have been seen with OIT for other foods [56–58] .
During peanut OIT, doses of peanut allergen are mixed in a food
vehicle and ingested by the subject in gradual incremental doses.
Most OIT studies consist of an initial escalation phase that typically occurs in a closely supervised setting such as a research study
center, followed by buildup and maintenance phases carried out
at home.
When it comes to effective outcomes, there are two important
concepts to keep in mind while reviewing OIT studies. The first
is the concept of desensitization in which daily consumption of
food allergen is required in order to maintain protection or a desensitized state. As a result, the threshold of the amount of protein
needed to induce a clinical reaction is raised, but only as long as
regular ingestion is continued. The next concept is that of clinical
tolerance, which can be defined as the ability to ingest food protein
without allergic symptoms in the absence of daily OIT, despite prolonged periods of avoidance of food protein [59,60] . While the optimal way to measure clinical tolerance is unknown, development
of clinical tolerance in research studies is tested by interruption of
OIT dosing for at least 4 weeks or longer followed by a supervised
oral food challenge [59,61,62] . In large part, the results of the OIT
studies to date are dependent on the dose and length of treatment.
In 2009, Jones et al. reported results of an open-label, multicenter uncontrolled trial of peanut OIT [63] . Even though these
patients did not undergo an entry challenge, all subjects reacted at
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less than 50 mg of protein on the initial-day escalation indicating
their clinical sensitivity. The study showed that 93% (27 out of 29)
of subjects were desensitized, that is, they were able to successfully
consume the entire dose of 3900 mg when they were challenged
following 4–22 months on a maintenance daily dosing of 300 mg
of peanut protein. In terms of adverse effects, 92% of patients
experienced adverse symptoms during the initial-day escalation,
46% during the buildup period and 3.5% during home dosing.
These allergic side effects were mostly mild and involved the skin
and upper airways. Only two subjects received epinephrine after
one home dose each. While peanut OIT was shown to be safe in
this open-label cohort [64] , it must be mentioned that four subjects
withdrew from the study because of allergic reactions to OIT
that persisted despite dose reduction. This reinforces the fact that
peanut OIT may not be tolerated by all subjects. By 6 months,
immunologic changes associated with this desensitization, such
as decreased skin-prick tests and basophil hyporesponsiveness,
were evident [63] . By 12–18 months, peanut-specific IgE levels
decreased and peanut-specific IgG4 antibody levels increased significantly. The epitope-specific nature of the responses appeared
to show a shift from IgE to IgG4, so that the IgG4 was directed
at the same epitopes that were binding IgE prior to initiation of
peanut OIT [60] . At 12 months of OIT, numbers of CD4 +, CD25+,
FoxP3 + Tregs were increased, but began to return to baseline by
18 months [60] . It is hypothesized that this transient increase in
Tregs is what may drive the suppression of the Th2 response to
peanut allergens, and indeed, Th2 cytokines were shown to be
decreased after peanut OIT in this study [60] .
Subsequent studies have also shown that desensitization can
be accomplished by peanut OIT [65,66] . Blumchen et al. reported
results of an uncontrolled study of peanut OIT in 23 children,
whose peanut allergy was confirmed by means of DBPCFC prior
to initiating OIT with roasted peanut [66] . This study showed
a highly significant increase in threshold of peanut challenge
following OIT in 14 of 23 (60%) subjects who reached a maintenance dose of 500 mg of peanut. Immunologic parameters
revealed a significant increase in peanut-specific serum IgG4 and
a decrease in peanut-specific IL-5, IL-4 and IL-2 production by
peripheral blood mononuclear cells in vitro after OIT [66] .
Anagnostou et al. treated 22 peanut-allergic children whose
peanut allergy was confirmed with an entry oral peanut challenge,
with an open peanut OIT protocol [67] . In contrast to previous
OIT studies, this protocol omitted the initial rush dose-escalation
day and treatment began with gradual biweekly dose escalation
until a targeted maintenance dose of 800 mg of peanut protein
was reached. Nineteen subjects tolerated the maintenance dose
and when challenged after approximately 30 weeks of maintenance therapy, the mean tolerated dose was increased by 1000-fold
compared with baseline challenges. Sixty four percent (14 out of
22) subjects passed a 6600-mg peanut challenge with no symptoms, while four out of 22 subjects experienced mild or moderate
symptoms. One patient dropped out during the dosing phase and
two patients were unable to reach the 800-mg maintenance dose.
In 2011, Varshney et al. published the results of the first double-blind, placebo-controlled study of peanut OIT in which
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28 children were enrolled [68] . Sixteen of 19 subjects (84%) completed 12 months of peanut OIT treatment (maintenance dose:
4000 mg of peanut protein). This study showed that 100% of
subjects reaching maintenance (16 out of 19) were able to successfully pass a 5000-mg peanut oral food challenge. Three out
of 19 subjects (16%) were unable to complete the protocol (two
out of 19 failed the initial dose-escalation day, and one out of 19
dropped out after the first gradual dose escalation). Overall in this
study, peanut OIT was well tolerated by subjects, and no peanut
OIT subjects required epinephrine treatment with dose-escalation
visits or home OIT doses. Immunologic studies showed a decrease
in skin prick testing, a transient increase then decrease in peanutspecific IgE and an increase in peanut-specific IgG4. In addition,
peanut OIT was able to result in a decrease in Th2 cytokines (IL-5
and IL-13), with an increase in FoxP3hi :FoxP3intermediate CD4 +
CD25 + T cells at the time of oral food challenge.
These studies suggest that peanut OIT is a safe and effective
therapy that can induce desensitization with ongoing therapy. As
outlined earlier, mechanistic data from various studies (Table 1)
suggest a shift in allergen-specific cytokine production from a
Th2 to a Th1 profile, also pointing towards concurrent immuno­
modulation. While these results with desensitization are encouraging, little is known about long-term safety, efficacy and most
importantly development of clinical tolerance, which would be
the ultimate goal of such therapy. It is also important to keep in
mind that some subjects are unable to endure the allergic side
effects associated with peanut OIT, indicating that this therapy
may not be appropriate for all peanut-allergic individuals. The
major side effects with OIT are related to reports of approximately
10–20% of subjects across different studies who have been unable
to reach the maintenance phase of OIT because of gastrointestinal
symptoms, which also highlights the concerns for eosinophilic
esophagitis with OIT [69–71] . Based on these concerns, it must
be emphasized that peanut OIT is not yet ready for practical
everyday use in the clinic setting.
8.6% of placebo doses. As with OIT, peanut SLIT was associated with decreases in skin-prick tests and basophil activation
assays (Table 1) . Immunologic studies revealed a transient increase
in peanut-specific IgE levels over the first 4 months, which then
steadily decreased, and a significant increase in peanut-specific
IgG4. Th2 cytokines (IL-5 and IL-13) were decreased in those
on active treatment with peanut SLIT, and this was not observed
in placebo subjects.
Kulis et al. published a study exploring the mechanism of SLIT
in which they showed that persistent mucosal exposure of peanut
SLIT led to a rise in peanut-specific salivary IgA, further correlating this increase with results of oral food challenges in subjects
(p = 0.0011) [75] . Peanut-specific salivary IgA has been thought
to block antigen uptake and studies are ongoing to investigate
this further.
In a recently published randomized, double-blind, placebo-controlled multicenter trial of peanut SLIT with a crossover design in
which 40 subjects (age: 12–37 years) were enrolled, Fleischer et al.
showed that after receiving 44 weeks of peanut SLIT, 14 out of 20
(70%) subjects were able to consume tenfold more peanut protein
than baseline oral food challenge (median successfully consumed
dose increased from 3.5 to 496 mg) [76] , compared with three out
of 20 (15%) subjects receiving placebo. After 68 weeks of SLIT,
the median successfully consumed dose increased to 996 mg compared with 496 mg at the 44-week time point (p = 0.05). This
study demonstrated that peanut SLIT was well tolerated, with
mainly oropharyngeal symptoms as the notable adverse effects in
this study. While encouraging, these results show only a modest
level of desensitization with peanut SLIT, compared with results
that have been demonstrated with peanut OIT.
While there is evidence that peanut SLIT is safe and has a
beneficial treatment effect in peanut-allergic subjects, the level
of desensitization achieved may not be as robust as seen with
peanut OIT. However, it may serve as a viable option in subjects
who cannot tolerate peanut OIT, given the low dose of peanut
allergen required in treatment with peanut SLIT.
Peanut sublingual immunotherapy
Sublingual immunotherapy (SLIT) involves administration of
small drops of allergen extract under the tongue, which are then
swallowed (or in some studies spit out). SLIT has been used
effectively in Europe for a number of years for the treatment of
allergic rhinitis [72,73] . The typical dose of peanut protein used
in studies of peanut SLIT is approximately 1000-times less
compared with peanut OIT [71] . In 2011, Kim et al. published
the results of the first double-blind study of peanut SLIT in
which 18 peanut-allergic children were enrolled and underwent
dose escalation to a maintenance dose of 2 mg of peanut protein [74] . After 12 months of treatment, subjects on active treatment (n = 11) consumed a median of 1710 mg peanut protein
during oral food challenge (although the amount tolerated by
those in the active treatment varied significantly), while placebo subjects (n = 7) ingested 85 mg before having an allergic
reaction. There were no dropouts from adverse events related
to peanut dosing during this study and side effects were mainly
oropharyngeal symptoms, observed with 11.5% of active and
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Peanut epicutaneous therapy
Epicutaneous therapy (EPIT) for peanut allergy consists of a
small amount of peanut allergen delivered through a patch that
is applied to the skin. EPIT has been shown to have some success
in treatment of milk allergy based on results from a small pilot
study [77] , with common side effects mainly being pruritus and
eczema at the site of application of the patch. This type of treatment for peanut allergy has been studied in murine models [78] ,
and Phase II clinical trials of peanut EPIT are currently ongoing
[101,102] . This therapy offers the advantage of an alternative route
for delivery of peanut allergen; however, further studies are clearly
needed to determine the efficacy and safety of this therapy.
Immunotherapy with modified recombinant food
proteins
Immunotherapy with modified recombinant food proteins involves
delivery of allergenic proteins that have ­undergone point mutations
of key amino acid sequences, resulting in a­ lteration of IgE-binding
Expert Rev. Clin. Immunol. 9(6), (2013)
Recent advances in the diagnosis & therapy of peanut allergy
allergenic epitopes [59] . This technique
has been found to decrease/inhibit IgE
­a ntibodies that bind with major peanut
allergens [79] .
Bacterial adjuvants have been used to
increase the effects of modified recombinant protein immunotherapy and this has
been the focus of several studies. Li et al.
used subcutaneous heat-killed Listeria
monocytogenes and the modified peanut
proteins (mAra h 1, 2 and 3) in a peanutsensitized mouse model and showed a
marked decrease in incidence and severity
of peanut-induced anaphylaxis compared
with control mice [80] . This was thought
to occur due to a shift from Th2 towards
a Th1 profile based on decrease in IL-5
and IL-13 and increased levels of IFN-γ in
the treated mice. Next, preliminary testing in mice was initiated to investigate if
heat-killed Escherichia coli could serve as
an effective adjuvant when combined with
modified peanut proteins. Administration
of heat-killed E. coli through the subcutaneous route led to skin inflammation
[55] ; hence, subsequent studies focused on
­investigating rectal administration of heatkilled E. coli-mAra h 1, 2 and 3 in peanutsensitized mice [55,81] . Mice challenged
with peanut had decreased severity of anaphylaxis, and splenocytes from these mice
showed a trend towards deviation from a
Th2 to a Th1 cytokine profile. Currently,
a vaccine for humans, EMP-123, is in
Phase I clinical trials [103] . While the prospect of development of a vaccine for peanut
allergy is encouraging, additional studies
are needed to investigate this further.
Table 1. Immunologic changes seen with peanut oral immunotherapy
and peanut sublingual immunotherapy.
Study (year)
Age of subjects Immunologic changes
(years)
Ref.
Peanut OIT
Jones et al. (2009)
1–16
6 months: ↓ skin prick tests
[63]
6–12 months: ↑ IL-5, IL-10, IFN-γ and
TNF-α
12–18 months: ↓ peanut-specific IgE,
↑ peanut-specific IgG4
12 months: ↑ numbers of CD4 +, CD25 +,
FoxP3 + Tregs
18 months: ↓ numbers of CD4 +, CD25 +,
FoxP3 + Tregs and return to baseline
T-cell microarrays showed
downregulation in apoptosis-related
gene expression
Blumchen et al. (2010) 3–14
↑ peanut-specific IgG4
[66]
↓ IL-2, IL-4 and IL-5
Varshney et al. (2011)
1–16
↓ skin prick tests
[68]
Transient ↑ then ↓ in peanut-specific
IgE
↑ peanut-specific IgG4
↓ IL-5 and IL-13
↑ FoxP3hi:FoxP3intermediate CD4 + CD25 +
T cells
Peanut SLIT
Kim et al. (2011)
1–11
↓ skin prick test and basophil activation
assays
[74]
Transient ↑ peanut-specific IgE levels
over the first 4 months which then ↓
↑ peanut-specific IgG4
↓ IL-5 and IL-13
↑: Increase; ↓: Decrease; OIT: Oral immunotherapy; SLIT: Sublingual immunotherapy.
Advances in treatment of peanut allergy:
allergen‑nonspecific approaches
Anti-IgE monoclonal antibodies
The concept of nonspecific immunomodulation for peanut
allergy has been studied with humanized monoclonal murine
anti-IgE IgG1 antibodies that bind to IgE with high affinity,
hence preventing IgE from binding to FcεRI receptors on mast
cells and basophils. Anti-IgE therapy results in decrease in free
IgE, which subsequently leads to downregulation of the FcεRI
receptors on the surface of mast cells and basophils [82] .
In 2003, Leung et al. reported the results of a randomized,
double-blind, placebo-controlled study in which 84 challengeconfirmed peanut-allergic subjects were assigned to receive
therapy with either placebo or 150, 300 or 450 mg of an experimental anti-IgE drug called TNX-901 (also known as Hu-901)
subcutaneously, once a month for four doses [82] . Results showed
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that only the highest dose of 450 mg of this drug resulted in
a statistically significant improvement, increasing the reaction
threshold to peanut from 178 to 2805 mg. Approximately 25%
of subjects treated with the highest dose of this drug showed
no change in their threshold for peanut consumption, hence
suggesting that this therapy would not be able to benefit all
peanut-allergic subjects.
A separate randomized, double-blind, placebo-controlled
Phase II trial of a different anti-IgE humanized IgG1 molecule
omalizumab (Xolair®, Novartis, NJ, USA) in peanut-allergic subjects was prematurely terminated because of two serious allergic
reactions that raised safety concerns during entry peanut challenge (prior to the administration of study drug) [83] . Sampson
et al. recently published results from the 14 patients who completed 24 weeks of therapy followed by a second DBPCFC [83] .
Preliminary data suggested that subjects receiving Xolair had a
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Sheikh & Burks
trend towards greater tolerated dose of peanut protein than in
the placebo-treated group (p = 0.054). Given that the study was
initially powered to enroll 150 subjects, it is not surprising that
the results did not reach statistical significance.
Anti-IgE therapy for peanut allergy clearly remains a therapy
that warrants further study. If used in combination with peanut OIT, particularly as supplemental therapy during the doseescalation phase of immunotherapy, it could potentially have the
advantage of decreasing allergic reactions during peanut dosing.
Phase I/II studies of Xolair in combination with peanut OIT are
currently ongoing [104] .
Chinese herbal medicine
Herbs have been used for centuries in traditional Chinese
medicine to treat a variety of ailments; however, they have not
been used previously for treatment of food allergies. The Food
Allergy Herbal Formula (FAHF)-1 was developed using the
extracts of 11 herbs with anti-inflammatory properties, which
have been used for hundreds of years by practitioners of traditional Chinese ­medicine to treat conditions such as asthma and
gastroenteritis [84] .
Li et al. showed that FAHF-1 blocks peanut-induced anaphylaxis in a murine model [85] . A simplified formula called FAHF-2
consisting of nine herbs was subsequently developed and results
similar to the previous study were seen regarding reduction of
anaphylaxis in peanut-sensitized mice [86] . In addition, mechanistic studies showed significantly decreased levels of plasma histamine, peanut-specific IgE and Th2 cytokines (IL-4, IL-5 and
IL-13) in FAHF-2 treated mice, with significantly increased levels
of IFN-γ, suggesting a shift from Th2 to Th1 cytokine profile.
A Phase I, randomized, double-blind, placebo-controlled, doseescalation study in 19 human subjects with peanut and tree nut
allergy demonstrated that FAHF-2 was safe and well tolerated
during 7 days of therapy [87] . In terms of adverse effects, one
subject in the FAHF-2 group and one subject in the placebo group
reported only mild gastrointestinal symptoms. In an extended
Phase I study, Patil et al. showed that daily dosing of FAHF-2 was
safe and tolerated well by subjects [88] . Srivastava et al. showed
that in mice, a butanol-extracted version of FAHF-2 reduced the
volume of the dose by approximately fivefold but was able to
maintain its efficacy [89] . This would be an important application
for human subjects, given that the large tablet load of FAHF-2
(ten tablets three-times a day) is a barrier to compliance and
serves as a potential limitation for this therapy. Srivastava et al.
recently investigated the use of FAHF-2 in a murine model of
multiple food allergies, showing that FAHF-2 was able to block
anaphylaxis from three food allergens (peanut, codfish and egg)
after sensitized mice were treated with FAHF-2 for 7 weeks [90] .
A multicenter, double-blind, placebo-controlled Phase II trial of
FAHF-2 is currently ongoing [105] .
The concept of using Chinese herbal medicine and the development of FAHF-2 is one of the most exciting advances in the field
of food allergy. It has been found to be safe and well tolerated in
humans and offers the additional advantage of potentially treating
multiple food allergies with one therapy.
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Expert commentary & five-year view
The diagnosis and treatment of peanut allergy is an area that has
eluded allergists for years. Millions of individuals suffer from peanut allergy, and while the prevalence of peanut allergy continues
to increase, there is currently no approved treatment.
The accurate diagnosis of peanut allergy remains a critical first
step in order to correctly identify subjects at risk for having an
allergic reaction. However, none of the current diagnostic tools
have been able to achieve sufficiently high predictive values to
allow any one test to serve as an accurate diagnostic modality.
While DBPCFC remains the gold standard for diagnosis, these
remain difficult for clinicians to conduct routinely in the office
setting. Recently, several studies have suggested that component-resolved diagnostics could improve the specificity of peanut allergy testing and have shown that compared with whole
peanut-specific IgE levels currently used for in vitro testing,
Ara h 2-specific IgE levels provide higher accuracy in diagnosing peanut allergy. While component-resolved diagnostics might
be used as a supplement to existing diagnostic tests for peanut
allergy, it does not appear to be ready to replace them at this
time. The new molecular diagnostic techniques that are being
studied are promising, but before they can be implemented in
the clinical setting, these assays will need to be studied in larger
clinical trials and validated against the current gold standard.
While not ready for prime time, combining component-resolved
diagnostics, IgE epitope mapping and high-throughput microarray platforms may in the future allow for an assay that will result
in better diagnostic capability and help identify patients at risk
of persistent allergy.
There is a strong recognition of the unmet need to develop
effective treatments for peanut allergy and much progress has
been made in the development of novel therapies. Several studies
have shown the safety and efficacy of peanut OIT and demonstrated its ability to induce desensitization with ongoing therapy,
with immunologic changes during peanut OIT showing a shift
in allergen-specific cytokine production away from a Th2 profile and also pointing towards concurrent immunomodulation.
While desensitization would be able to provide much needed protection against accidental peanut ingestion, the ultimate goal of
peanut OIT would be to help subjects achieve long-term clinical
and long-lasting immunologic tolerance, which still needs to be
investigated. There is evidence that peanut SLIT is safe, efficacious and well tolerated and may be a viable option in peanutallergic subjects who cannot tolerate OIT, given the low dose of
peanut allergen required in SLIT. However, the level of desensitization achieved may not be as robust as seen with peanut OIT.
Anti-IgE therapy for peanut allergy clearly remains a therapy
that warrants further study and might find a role as adjunct or
supplemental therapy in combination with peanut OIT, and
studies are ongoing to address this further. The application of
Chinese herbal medicine and the development of FAHF-2 is
perhaps one of the most exciting advances in the field. It has
been found to be safe and well tolerated in humans and offers
the additional advantage of potentially treating multiple food
allergies with one therapy.
Expert Rev. Clin. Immunol. 9(6), (2013)
Recent advances in the diagnosis & therapy of peanut allergy
It is important to note that many of the outlined studies for peanut allergy have limitations and this should be kept in mind when
interpreting the literature. First, these studies exclude subjects
with a history of previous anaphylactic reactions to peanut due
to safety concerns, giving rise to the argument that individuals
who possibly need these therapies the most are excluded from the
outset. Including young children in whom remission of peanut
allergy may occur during the study period may often confound
studies. Given that many of the studies are pilot studies, the sample size is small and the lack of a placebo group makes it difficult
to establish causality as a result of the therapy. While studies are
currently ongoing, the development of prolonged true clinical
tolerance to peanut as a result of any of these therapies has not yet
been achieved; hence this remains a major clinical and research
goal. This question would ideally be answered through conducting a prospective, randomized, double-blind, placebo-controlled
trial that is powered to evaluate tolerance as the primary outcome.
Therefore, before any of these therapies can be implemented in
clinical practice, many issues need to be addressed and large, well
designed, randomized, double-blind, placebo-controlled clinical
trials are needed to determine risks that may be ­associated with
ongoing therapy, optimal dosing regimens, efficacy and dosing
for different age groups, ideal duration of therapy and a­ ppropriate
patient selection for different therapies.
In conclusion, several treatment modalities for peanut allergy
are showing promise, in the hands of experienced investigators
who are able to carry out these clinical trials in the appropriate
research setting. While the initial data for these studies appear
to be encouraging, it must be kept in mind that there is little
Review
long-term data available and many questions remain unanswered,
regarding both long-term safety and efficacy. It must be emphasized that none of these therapies are ready for use in the clinic
setting at this time. While there is currently no approved treatment available for peanut allergy, given the amount of work that
is being done in the field and several therapies on the horizon,
it is plausible that further investigation in the next 5 years will
lead us closer to the development of a disease-modifying therapy
for peanut allergy. It is our hope that during this process of discovery, we will gain better understanding of the pathogenesis
of peanut allergy as well as immunologic changes induced by
different therapies.
Financial & competing interests disclosure
AW Burks is on the boards of the American Academy of Allergy, Asthma and
Immunology and the Food Allergy & Anaphylaxis Network; is on the Medical
Advisory Board for the Food Allergy Initiative; is a study section member
for the NIH Hypersensitivity, Autoimmunity and Immune-Mediated section; and serves on Merck’s US Allergy Immunotherapy Allergist Advisory
Board. He also serves as a consultant for Dow AgroSciences, Dynavax
Technologies Corp, ExploraMed Development, LLC, Genalyte, Hycor
Biomedical, Merck, Nordic Biotech Advisors ApS and PBN Nutritionals.
He is a minority stockholder of Allertein, a speaker for Mylan Specialty
and has received royalties from UpToDate. AW Burks holds grants from
the NIH and Wallace Research Foundation. The authors have no other
relevant affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
• A double-blind placebo-controlled oral food challenge is the gold standard for diagnosis of peanut allergy.
• While not ready for prime time, combining component-resolved diagnostics, IgE epitope mapping and high-throughput microarray
platforms may in the future allow for an assay that will result in better diagnostic capability and help identify patients at risk of
persistent allergy.
• Peanut oral immunotherapy (OIT) has been shown to be relatively safe and efficacious and has demonstrated its ability to induce
desensitization with ongoing therapy, with immunologic parameters showing a shift in allergen-specific cytokine production away from
a Th2 profile.
• Peanut sublingual immunotherapy is safe and may be a viable option in peanut-allergic subjects who cannot tolerate OIT; however, the
level of desensitization achieved may not be as robust as seen with peanut OIT.
• Anti-IgE therapy for peanut allergy remains a therapy that warrants further study and might find a role as adjunct or supplemental
therapy in combination with peanut OIT.
• The application of Chinese herbal medicine and the development of Food Allergy Herbal Formula-2 is one of the most exciting
advances in the field, offering the advantage of potentially treating multiple food allergies with one therapy.
• There is currently no approved treatment available for peanut allergy and none of the above experimental therapies are ready for
everyday use in clinical practice. Data are lacking regarding long-term safety and efficacy.
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