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\begin{document}

\title{Title: Current options in the management of tree nut allergy, focusing
on, but not limited to immunotherapy: A systematic review.}



\author[1]{Maria Pasioti}%
\author[1]{PARASKEVI XEPAPADAKI}%
\author[2]{Alexander  Mathioudakis}%
\author[1]{John Lakoumentas}%
\author[1]{Elvira Efstathiou}%
\author[1]{Nikolaos Papadopoulos}%
\affil[1]{Allergy Department 2nd Paediatric Clinic National and Kapodistrian University of Athens Athens Greece}%
\affil[2]{The University of Manchester Faculty of Biology Medicine and Health}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
This systematic review evaluates the potential therapeutic options for
desensitization of patients with IgE-mediated tree nut allergy,
focusing, but not limited to, on immunotherapy. We searched three
bibliographic databases for studies published until July 2022 for active
treatments of IgE-mediated allergy to tree nuts (walnut, hazelnut,
pistachio, cashew, and almond) with allergen-specific immunotherapy
(AIT) using oral (OIT), sublingual (SLIT), epicutaneous (EPIT) or
subcutaneous (SCIT) delivery, or with other disease-modifying
treatments. We included 26 studies, but the heterogeneity of the studies
prevented pooling and meta-analysis. Immunotherapy with hazel pollen
extracts might benefit patients with a secondary nut allergy due to
cross-reactivity with PR-10 or profilin panallergens but is unlikely to
be beneficial in patients with a severe nut allergy caused by seed
storage proteins. Sublingual immunotherapy has a moderate efficacy but a
favorable safety profile. Oral immunotherapy (OIT), single, or
multi-nut, with or without omalizumab, is the most studied approach. In
general, tree nut OIT is effective in conferring protection from
accidental exposures, with safety similar to that demonstrated by peanut
OIT. The observed cross-desensitization between tree nuts straightly
affects the management options for multi-nut allergic patients.%
\end{abstract}%



\sloppy


\textbf{Title:} Current options in the management of tree nut allergy,
focusing on, but not limited to immunotherapy: A systematic review.

\textbf{Short Title:} Tree Nut Immunotherapy

\textbf{Authors:} Maria Pasioti\textsuperscript{1}, Paraskevi
Xepapadaki\textsuperscript{1}, Alexander G.
Mathioudakis\textsuperscript{2,3}, John Lakoumentas\textsuperscript{1},
Elvira Efstathiou\textsuperscript{1}, Nikolaos G.
Papadopoulos\textsuperscript{1,4}

\textbf{Affiliations:}

\textsuperscript{1}Allergy Department, 2nd Paediatric Clinic, National
and Kapodistrian University of Athens, Athens, Greece

\textsuperscript{2}Division of Infection, Immunity and Respiratory
Medicine, Faculty of Biology, Medicine and Health, The University of
Manchester, Manchester, UK

\textsuperscript{3}North West Lung Centre, Wythenshawe Hospital,
Manchester University NHS Foundation Trust, Manchester, UK

\textsuperscript{4}Division of Immunology, Immunity to Infection and
Respiratory Medicine, Faculty of Biology, Medicine and Health, The
University of Manchester, Manchester, UK

\textbf{ORCID ID:}

MP: 0000-0001-6658-4828

PX: 0000-0002-4448-3468

AGM: 0000-0002-4675-9616

JL: 0000-0003-0869-736X

EE: 0000-0002-0332-6810

NGP: 0000-0002-4448-3468

\textbf{Conflict of Interest:} MP, PX, AGM, JL, EE, and NGP declare no
conflicts of interest.

\textbf{Acknowledgments:} This work was supported by grants from the
Hellenic Society of Allergology and Clinical Immunology and was
co-financed by Greece and the European Union (European Social Fund-ESF)
through the Operational Programme ``Human Resources Development,
Education and Lifelong Learning'' in the context~of the Act ``Enhancing
Human Resources Research Potential by undertaking a Doctoral Research''
Sub-action 2: IKY Scholarship Programme for PhD candidates in the Greek
Universities. AGM was supported by the National Institute for Health and
Care Research Manchester Biomedical Research Centre (NIHR Manchester
BRC) and by an NIHR Clinical Lectureship in Respiratory Medicine.

\textbf{Keywords:} Allergy treatment, food allergy, immunotherapy,
management, tree nuts

\textbf{Abstract:} This systematic review evaluates the potential
therapeutic options for desensitization of patients with IgE-mediated
tree nut allergy, focusing, but not limited to, on immunotherapy. We
searched three bibliographic databases for studies published until July
2022 for active treatments of IgE-mediated allergy to tree nuts (walnut,
hazelnut, pistachio, cashew, and almond) with allergen-specific
immunotherapy (AIT) using oral (OIT), sublingual (SLIT), epicutaneous
(EPIT) or subcutaneous (SCIT) delivery, or with other disease-modifying
treatments. We included 26 studies, but the heterogeneity of the studies
prevented pooling and meta-analysis. Immunotherapy with hazel pollen
extracts might benefit patients with a secondary nut allergy due to
cross-reactivity with PR-10 or profilin panallergens but is unlikely to
be beneficial in patients with a severe nut allergy caused by seed
storage proteins. Sublingual immunotherapy has a moderate efficacy but a
favorable safety profile. Oral immunotherapy (OIT), single, or
multi-nut, with or without omalizumab, is the most studied approach. In
general, tree nut OIT is effective in conferring protection from
accidental exposures, with safety similar to that demonstrated by peanut
OIT. The observed cross-desensitization between tree nuts straightly
affects the management options for multi-nut allergic patients.

\textbf{Main Text}

\textbf{Word Count: 4425}

\textbf{INTRODUCTION/BACKGROUND}

Tree nuts belong to the group of the eight major allergenic foods and,
along with peanuts, have been implicated in severe fatal or near-fatal
allergic reactions\textsuperscript{1}. However, allergic manifestations
to nuts vary substantially, ranging from benign oropharyngeal symptoms
to life-threatening anaphylaxis, depending on several factors, such as
the implicated nut\textsuperscript{2,3}, the sensitization to distinct
allergen components, the presence of co-factors\textsuperscript{4-7},
and even the process of the nuts before consumption\textsuperscript{8}.
Unlike peanut allergy, allergy to tree nuts has been under-investigated.
Evidence on the prevalence, clinical manifestation, and natural history
of tree nut allergy is generally sparse, as has been recently
reviewed\textsuperscript{4,5,9}. Recent
studies\textsuperscript{10,11}suggest that, in many countries, allergy
to tree nuts is more common than peanut. As with other foods, the
management of tree nut allergy involves strict avoidance of the culprit
nut (and often of potentially cross-reacting foods) and symptomatic
treatment of accidental consumption. Food oral immunotherapy (OIT) is
actively investigated for the management of milk, egg, wheat, and peanut
allergy. FDA, EMA, and NICE have recently approved peanut OIT for
clinical practice. On the contrary, there is a lack of data on
desensitization approaches in managing tree nut allergy. This systematic
review aims to evaluate potential therapeutic options for
desensitization of patients with IgE-mediated tree nut allergy.

\textbf{Materials and Methods}

To answer the question ``Which are the therapeutic options for the
desensitization of patients with IgE-mediated walnut or cashew or
pistachio or hazelnut or almond allergy? What is the effectiveness and
safety of these options?'' we systematically searched three electronic
databases for active treatments of IgE-mediated allergy to tree nuts
(Appendix 1).

\textbf{RESULTS:}

The original search retrieved 689 unique citations, six additional
articles were found via references and three via Pubmed alerts, of which
44 were full-text screened. The final search retrieved 8 additional
articles which were full-text screened. Overall, 26 studies were
included (Fig. 1 and Table 1). Of them, five were randomized,
double-blinded, placebo-controlled (RDBPC)
studies\textsuperscript{12-16}, one non-randomized,
placebo-controlled\textsuperscript{17}, eight prospective cohorts,
including two conference abstracts\textsuperscript{18-25}, five
observational studies\textsuperscript{26-30}, three retrospective
studies\textsuperscript{31-33}, one follow-up study\textsuperscript{34},
and three case reports\textsuperscript{35-37}.

Participants with hazelnut allergy were included in 19 studies, walnut
18, cashew 16, pecan 13, almond 12, and pistachio 8 (Appendix 2).

\textbf{Efficacy and Safety}

\emph{Effect of Pollen-Specific Subcutaneous Immunotherapy (SCIT) on
Tree nut allergy (Table 2)}

Van Hoffen et al.\textsuperscript{15} contacted a DBPC study in adults
with birch pollen and hazelnut allergy. After a year on birch-
pollen-SCIT, no changes in eliciting dose (ED) and symptom score during
the exit double-blinded placebo-controlled food challenge (DBPCFC) were
noted.

Alonso et al.\textsuperscript{26} investigated the effect of 1 year of
plane-pollen-SCIT in 16 adults, including six with walnut allergy and
six with hazelnut allergy. Three walnut-allergic patients completed the
study, of which one increased the ED, and two reached the highest dose
of 25g at the exit oral food challenge (OFC). Five hazelnut allergic
patients underwent exit OFC; in one the ED decreased from 20 to 0,1gr,
in one remained unchanged, and the rest reached the highest dose.

\emph{Tree Nut Specific Immunotherapy}

Sublingual Immunotherapy (SLIT) (Table 3)

Initially, Enrique et al.\textsuperscript{14} investigated the efficacy
of hazelnut-SLIT in 12 allergic patients. After 2-3 months of therapy,
the ED increased from 2,29g to 11,56g, and 5 participants reached the
highest dose (20g of hazelnut), compared with 1 in placebo. Systemic
reactions occurred in 0,2\% of doses (3 reactions in 2 patients, one of
each group), only during the build-up phase. Local reactions, mainly
immediate oral itching, were observed in 7,4\% doses. Four patients in
treatment reported abdominal pain during the build-up phase. All
reactions during the maintenance phase were oral itching, in the same
patient.

In the follow-up study\textsuperscript{34}, seven patients were
reassessed after a year with hazelnut-SLIT. Three discontinued after 4
to 6 months. There was a further increase in ED to 14,57g, and five
patients reached the highest dose. One patient, who had tolerated the
highest dose at the original study, lost protection one year after. Less
than 2\% of patients reported oral itching. No systemic or
gastrointestinal reactions were reported.

Recently, Beitia et al\textsuperscript{24} prospectively assessed the
effect of 1-year Pru p 3-SLIT on 29 patients with LTP-syndrome,
including 5 patients with allergy to almond, 5 to walnut, 10 to
hazelnut, and 1 to cashew. Of them, 4 discontinued treatment before the
first year. Authors reported the results of three final OFCs with
hazelnut; 1 was successful. Of the overall 29 participants, 10,3\%
discontinued due to adverse reactions and 72,4\% reported mild oral
pruritus during the first weeks, which required no treatment.

Oral Immunotherapy (Table 4)

\emph{Single Tree Nut}

Bradatan et al.\textsuperscript{21} reported the results of 37 children
treated with tree nut/peanut-OIT for up to two years, to reach a target
daily dose of 4gr of nut/peanut. At 18 months 25 passed an OFC to their
respective tree nut. Three peanuts-, two cashew- and one hazelnut-OIT
children withdrew early because of allergic side effects. Most of the
reactions reported during the maintenance phase were transient and
required no treatment.

The NutCRACKER study\textsuperscript{22} described the results of walnut
OIT in 55 walnut allergic children; 49 reached maintenance (4000mg of
walnut protein) and were considered desensitized, three increased their
ED and were considered partially desensitized, and three did not
complete treatment (one due to anaphylactic reactions). At least one
adverse reaction was reported by 47 children at the hospital up-dosing,
and by 40 at the home-dosing, mostly mild, with respiratory and
gastrointestinal symptoms. Epinephrine was administered to 11 children
at the hospital and 8 at home. Three had symptoms compatible with oral
immunotherapy-induced gastrointestinal-and-eosinophilic responses
(OITGER), which subsided with temporary dose reduction. Nine children of
the control group began OIT, seven were desensitized and were included
in the subsequent analysis. After achieving walnut desensitization at
4000mg the maintenance dose decreased to 1200mg daily. 45 participants
followed up for at least six months, 11 reported mild allergic reactions
requiring antihistamines, and one required epinephrine. After six
months, all successfully consumed a single dose of 4000mg of walnut
protein.

The results of a low-dose walnut-OIT in 3 children were recently
reported by Sasamoto et al.\textsuperscript{37}. Children received an
individualized home starting dose and gradually reached the maintenance
dose of 75mg of walnut protein after 3, 4, and 3 months respectively.
The overall adverse reaction rate per intake at home dosing was 3.1\%,
including two anaphylactic reactions. No epinephrine use was required.

Hazelnut-OIT was first described by Morally et al.\textsuperscript{32}in
a retrospective study of 100 children. After six months on an
individualized up-dosing protocol to a low maintenance dose (half of
baseline ED), 34 were desensitized to a cumulative dose of 1635mg
hazelnut. Median ED increased by 417mg. The remaining 66 children had at
least doubled their baseline ED at six months. Side effects were
retrospectively reported by 76 children; 30 reported at least one
non-severe reaction. Symptoms suggesting eosinophilic esophagitis (EoE)
or serious side effects were not reported.

Sabouraud et al.\textsuperscript{33} reviewed the medical records of 70
children undergoing hazelnut-OIT, including four children with hazelnut
sensitization, but no history of ingestion. At baseline, a low-dose OFC
with hazelnut was used to establish an individualized, intermediate,
6-months target dose. The procedure was repeated every 6 months until a
final individualized dose was reached. At 1 year, 16 children had
reached maintenance, and 36 ingesting \textgreater{}120mg of hazelnut
protein. The cumulative reaction dose increased from 13mg to 741mg. 40
children had at least 1 adverse effect at home, of which half were mild,
17 developed hazelnut aversion, and 14 reported recurrent abdominal
pain. Severe systemic reactions were reported by two children, one of
whom required epinephrine. Among 212 OFCs performed, seven severe
systemic reactions were recorded, with four requiring epinephrine. One
child developed EoE.

Cashew-OIT was described by Elizur et al.\textsuperscript{25} in 50
cashew-allergic patients. At a median time of 12 months, 44 reached the
target dose of 4000mg cashew protein and were considered fully
desensitized, three tolerated 1200mg and considered partially
desensitized, and three discontinued. The 44 desensitized participants
were instructed to consume daily 1200mg of cashew protein. After 6
months they were all successfully challenged to 4000mg. At the
in-hospital build-up 44 participants experienced at least one allergic
reaction, mainly mild to moderate, while epinephrine was required in 9
participants. At home dosing, 26 participants reported allergic
reactions, mostly mild, and three reported epinephrine administration.
One patient developed OITGER symptoms and one developed EoE.

\emph{Multi-OIT}

Begin et al.\textsuperscript{20} first investigated the safety of the
approach in 25 children in comparison to peanut-only-OIT. After an
initial escalation day (IED), the dose was increased every two weeks
until maintenance (2gr protein per food). In the multi-OIT group, 13
participants included cashew in their regimen, 14 walnut, 7 pecan, 3
hazelnut, and 5 almond. There was no statistical difference in dose
progression comparing the number or the combinations of foods in the OIT
mix. All participants reached a 10-fold increase in their ED. Adverse
reactions did not differ between peanut-only and multi-OIT groups. Most
reactions were mild, regarding mainly abdominal pain. Epinephrine was
required during home dosing for two participants in each group.

In the follow-up study by Andorf et al.\textsuperscript{28}, 46
participants, on a maintenance dose of 2gr per food, were followed up
for up to 72 months to evaluate the feasibility of SU on lowering the
dose from 2gr to 300mg and/or altering the frequency of dosing. In the
''high'' maintenance group, cashew was included in 13 participants;
walnut in 3, pecan in 3, none had hazelnut, and 2 had almond. In the
''low'' maintenance group none had cashew, 10 had walnut, 5 had pecan, 3
had hazelnut, and 3 almond. Of the 25 participants with more than one
food in their OIT, 10 were on a low, and 10 were on a high maintenance
dose for all foods at the end of the follow-up. At the end of the study,
the proportion of participants per allergen on the low dose was 66,6\%
for walnut, 62,5\% for pecan, 100\% for hazelnut, 60\% for almond, and
46,2\% for cashew. Each participant could tolerate [?] 2g protein in an
OFC of his respective food allergens, independent of the high or the low
dose. During the study, 1207 reactions were observed, with a median of
25 reactions per participant. The reactions were mainly mild, 129 were
moderate, and 5 were severe, with nasal congestion and skin symptoms
only. Neither fatal nor serious adverse events nor epinephrine
administration were described. The frequency of allergic adverse events
decreased over time. Safety did not differ between groups.

Eapen et al.\textsuperscript{31} reported their two years' experience
with multi-food OIT in 45 children. OIT protocol and maintenance dose
were individualized. The multi-OIT regimen contained cashew/pistachio in
34 children, walnut/pecan in 25, hazelnut in 13, and almond in 8. At 18
months, 35 children were on daily maintenance, four were on three times
per week after 6, 8, 10, and 24 months on daily maintenance, and six had
discontinued. Allergic reactions occurred in 22 children during the
up-dosing or in the first three months of maintenance. Most reactions
were of grade 1, according to Sampson's grading, 9\% were grade 2, and
none was grade 3. The reactions resolved with no medication in 29
children and with antihistamines in 22. One child needed albuterol, and
three epinephrine administrations were reported, all at home. Four
children visited the Emergency Department for food allergy reactions,
compared to 7 out of 44 children on a waiting list to start OIT during a
similar period of 18 months.

\emph{Multi OIT with Omalizumab}

In 2014 Begin et al.\textsuperscript{19} first described a rush OIT
protocol for up to five foods using omalizumab in 25 children. Cashew
was included in 14 children, walnut in 9, pecan in 7, hazelnut in 3, and
almond in 6. All children reached a 10-fold increase in their ED by two
months on OIT and the maintenance dose (4000gm per food allergen) by
nine months. During IED 13 children developed mild reactions. At
hospital escalations, 13 mild reactions occurred per 227 doses. At-home
dosing, 401 reactions were reported per 7530 doses, of which 385 were
mild, 15 were moderate, and 1 was severe and required epinephrine. Home
reactions occurred more frequently in the first months of therapy.

In a subsequent follow-up \textsuperscript{27}, 34 children were
followed for over five years. After reaching maintenance with 2g protein
for each food, the dose was reduced to 300mg for some participants based
on a team-based decision. Participants were followed every 6-12 months,
up to 62 months, through standard oral food challenges (OFCs), SPTs, and
blood tests. Of the 18 children with cashew in OIT, 17 reduced the
maintenance dose to 300mg. The corresponding numbers for walnut and
hazelnut were 8/10 and 6/7 respectively. All children with pecan in
their OIT continued the high dose, and all six children with almond in
OIT changed to the low dose. At the end of the follow-up, each child was
able to tolerate at least 2g protein during an OFC of their respective
allergens, independent of the high or low dose. During the study, 1126
reactions were recorded. Of those most were mild, 40 were moderate, and
5 were severe. All severe reactions occurred in the high dose within the
first 19 months of maintenance and involved skin and nasal symptoms.
There were no serious adverse events or anaphylactic reactions.
Epinephrine was used for mild-moderate reactions. The number of allergic
reactions decreased over time. Safety did not differ between the low and
the high-dose groups.

In a RDBPC multi-OIT study by Andorf et al.\textsuperscript{12}, cashew
was included in the OIT of 36 children, walnut in 25, hazelnut in 24,
and almond in 7. After 36 weeks of OIT, a DBPCFC to implicated food was
performed. In the omalizumab group, the proportion of children who
passed a 2gr food protein per allergen was 20/25 for cashew, 17/20 for
walnut, 16/17 for hazelnut, and 4/6 for almond. The corresponding
numbers for the placebo group were 4/11 for cashew, 0/5 for walnut, 3/7
for hazelnut, and 0/1 for almond. Maintenance was achieved at 12 weeks
in the omalizumab group versus 20 weeks in the placebo group. Throughout
the study, there were no serious or severe adverse events. All patients
in both groups experienced at least one adverse reaction during weeks
8-16. The omalizumab group had a significantly lower median
per-participant percentage of OIT doses associated with any adverse
events and a significantly lower median per-participant percentage of
OIT doses associated with gastrointestinal and respiratory adverse
events. There were 11 epinephrine uses, 5 in the omalizumab group and 6
in the placebo group.

Subsequently, the same group compared the efficacy of alternative
maintenance dosing for six weeks on SU\textsuperscript{13}. Having
completed 30 months of omalizumab-facilitated multi-OIT and passed an
OFC to at least 2gr per allergen, 60 participants were randomized to
blindly receive 1g, 300mg, or 0mg per allergen as the maintenance dose
for six weeks, followed by OFC to at least 2gr per allergen. In the 1gr
group, desensitization was documented for 9/10 participants treated for
cashew, 11/ 11 for walnut, 6/7 for hazelnut, and 2/2 for almond. The
corresponding numbers for the 300mg group were 12/13 for cashew, 9/9 for
walnut, 3/4 for hazelnut, and 1/1 for almond. During weeks 8-16, where
OIT was co-administered with omalizumab, 42 participants reported at
least one adverse event. Thereafter, all 60 participants had at least
one adverse event, all but one classified as grade 1 or 2. Epinephrine
was used eight times by six participants. No cases of life-threatening
anaphylaxis or EoE were reported.

\emph{Other treatments}

The effect of a 4-month treatment with omalizumab for severe asthma on
the thresholds of food allergic reactions was investigated in a
real-life study of 15 children with asthma and food
allergies\textsuperscript{30}. Among participants, there was a child
with allergies to walnut, hazelnut allergies, peanut, peach, and
apricot. Omalizumab administration for four months resulted in an
elevation in hazelnut ED from 13,8 to 35,3mg of protein. Walnut was not
evaluated.

In a similar study\textsuperscript{29} of 5 children with multiple food
allergies, administration of omalizumab for at least six months resulted
in tolerance for hazelnut in 3/5 children, for walnut in 1/3, for cashew
in 1/2, and for almond in 2/3. One child with pistachio allergy remained
allergic.

Rial et al.\textsuperscript{36} reported a case of a 30-year-old woman
with severe atopic dermatitis and LTP-syndrome with multiple food
allergies, including almond, pistachio, hazelnut, and walnut, and a
positive OFC to pistachio. Three months after initiating treatment with
dupilumab for atopic dermatitis, she reported accidental ingestion of
pistachio without reaction. Tolerability was confirmed by an OFC to 50
gr pistachio.

Traditional Chinese Medicine\textsuperscript{35}, and Chinese Herbal
Medicine {[}Food Allergy Herbal Formula-2
(FAHF-2){]}\textsuperscript{16}, have been investigated in
multi-allergic children, with inconclusive results.

\textbf{Sustained Unresponsiveness}

In a conference abstract, Scurlock et al.\textsuperscript{23} reported
the results of 8 children with walnut and another tree nut allergy
undergoing walnut-OIT for approximately three years. SU at four weeks
off therapy to both walnut and another tested Tree Nut (tTN) was
achieved by four subjects, to walnut only by six, and to a tTN only by
five.

In the case series of Sasamoto et al.\textsuperscript{37}, all children
achieved two weeks SU to 450 mg after 24, 14, and 12 months on daily
maintenance with 75 mg walnut.

In the study of Andorf et al.\textsuperscript{13}, in the group which
discontinued OIT (0 gr protein) for six weeks, SU was documented in 2/11
participants treated for cashew allergy, 8/11 for walnut, 3/6 for
hazelnut, and 1/1 for almond.

Finally, in the study of Wang et al.\textsuperscript{16}, three months
of discontinuation of FAHF-2 retained unresponsiveness in 5/8
active-treated participants and in 3/10 placebo-treated participants.

\textbf{Cross-desensitization}

In the study of Scurlock et al.\textsuperscript{23}, three years of
walnut-OIT resulted in desensitization to both walnut and another tree
nut for 7/8 children.

In the walnut-OIT study of Elizur et al.\textsuperscript{22}, after
walnut desensitization, all 46 children co-allergic to pecan, eight of
fifteen co-allergic to hazelnut, and four of nineteen co-allergic to
cashew were also fully desensitized, while six and one children with
co-allergy to hazelnut and cashew respectively, were partially
desensitized.

In the cashew-OIT\textsuperscript{25}, 35 participants fully
desensitized to cashew were also allergic to pistachio and were
successfully challenged to 2500mg of pistachio protein. Ten participants
were co-allergic to walnut and offered an OFC to 4000mg of walnut. Two
refused the procedure. Of the eight challenged, four succeeded.

In multi-OIT studies, cross-desensitization has been assessed for walnut
and pecan, and cashew and pistachio. In the omalizumab-facilitated
multi-OIT study of Andorf et al.\textsuperscript{27}, of the 8
participants with pecan in their OIT and 10 with walnut, seven were
desensitized to both nuts.

In the subsequent trial\textsuperscript{12}, 20/24 participants with
cashew and pistachio allergy were desensitized to pistachio while
treated with cashew, and all seventeen participants with walnut and
pecan allergy were desensitized to pecan treated while treated with
walnut.

In the latest study of this team\textsuperscript{13}, 3/4 of
pecan-allergic participants and 8/8 of pistachio-allergic participants
were desensitized. Six weeks after randomization to 1000mg, 300mg, and 0
mg maintenance dose all four pecan allergic participants (1-1gr,
1-300mg, 2-0mg) and seven of eight pistachio allergic participants
(3-1gr, 3-300mg, 1/2-0mg) passed the food challenge.

\textbf{Quality of life assessment}

In the conference abstract by Bradatan et al\textsuperscript{21} an
improvement in QoL after OIT is reported without further information.

In the NutCRACKER study of walnut\textsuperscript{22}, age-appropriate
FAQLQ from 52 patients were assessed. Children desensitized to all
tested nuts reported significant improvement in the total FAQLQ and the
sub-scores of emotional impact, food anxiety, and social and dietary
limitation. In children remaining allergic to at least one nut,
statistically, but not clinically, significant improvement was noted
only for the social and dietary limitation scores.

Otani et al.\textsuperscript{17} compared the effect of multi-OIT with
and without omalizumab on Food Allergy Quality of Life-Parental Burden
(FAQL-PB) Questionnaire against food avoidance. FAQL improved in active
groups. In controls, FAQL worsened at six months and returned to
baseline levels at 18 months of follow-up.

Arasi et al.\textsuperscript{18} used the FAQL-PB questionnaire to
assess the effect of peanut or multi-OIT on food allergy-specific
health-related quality of life (HRQL) over a 24 month-follow-up in
caregivers of children. Scores improved significantly; 42\% of
caregivers reported improvement at six months, 71\% at 12 months, 76\%
at 18 months, and 92\% at 24 months. Changes in the HRQL between
baseline and 24 months were associated with older age, the absence of
asthma, the absence of dose-related respiratory allergic reactions, and
the greater number of foods in OIT.

Fiocchi et al.\textsuperscript{30}, used the ''Pediatric Quality of Life
Inventory'' (PedsQL) 4.0 questionnaire in 15 children. The total score,
the physical, emotional, social, and cognitive functioning, were
improved in children and parents after four months on omalizumab.

The Parent Form of the ''Food Allergy Quality of Life Questionnaire''
(FAQLQ-PF) was used by Crespo et al.\textsuperscript{29}. After two
years on omalizumab, parents perceived an improvement in the health
status of their children. The stress associated with the allergy was
reduced, and the limitations of the child's activities in their daily
life decreased.

In the study of Lisann et al.\textsuperscript{35}, the ''Food
hypersensitivity family impact'' (FLIP) questionnaire was improved in
the three participating children after six months of Traditional Chinese
Medicine.

Finally, Sabouraud et al.\textsuperscript{33} used a non-validated
Likert questionnaire (scale 1-7), addressed to 42 children
\textgreater{}8 y.o. and their caregivers, to assess children's
acceptance of OIT. The questionnaire was completed at a median of 47,5
months after the initial consultation. The median score for children's
satisfaction was 5. Children considered OIT effective (6) and reported
that would recommend it to another child with allergy (7). On the other
hand, children did not enjoy eating hazelnut every day (3), and OIT was
considered a strain (5) and medication (4).

\textbf{DISCUSSION}

Overall, although all included studies required food challenges or a
recent convincing history of reaction for recruitment and an exit oral
food challenge assessing outcomes, they were highly heterogenous
regarding the population, interventions used, primary outcomes, and
preferred methods of reporting results. While some studies aimed to
recruit both children and adults, most of the included participants are
children.

Besides that, one of the major drawbacks of all but three
studies\textsuperscript{22,25,37} is the lack of component resolved
characterization of tree nut allergy. Some studies addressed this issue
by requiring a low eliciting dose at the baseline food challenge, which
is unlikely to occur when the allergy is due to panallergens.

Immunotherapy with pollen extracts\textsuperscript{15,26} might benefit
patients with secondary nut allergy due to cross-reactivity with PR-10
or profilin panallergens, which are usually labile and are responsible
for mild reactions, limited to mouth and oropharynx\textsuperscript{38}.
This approach is unlikely to be beneficial in patients with primary tree
nut allergy to seed storage proteins, which are the cause of severe,
life-threatening reactions.

Sublingual immunotherapy has been investigated only for hazelnut
allergy, with moderate efficacy but a favorable safety
profile\textsuperscript{14,34}. Nevertheless, the sample size was small,
and the extract used was standardized for Cor a 1 (PR-10) and Cor a 8
(LTP) allergens, and not for Cor a 9 (legumin) or Cor a 14 (2S albumin),
which better predict severe hazelnut allergy\textsuperscript{39,40}. LTP
allergy has an extremely variable clinical
presentation\textsuperscript{41}, which could explain the loss of
protection described in one patient in the follow-up study after he had
tolerated the highest dose in the original study.

The same might account for the trials using omalizumab or dupilumab
without OIT in multi-allergic patients, in which tree nut allergy seems
to be a manifestation of the LTP-syndrome\textsuperscript{29,30,36}.

OIT trials varied substantially regarding the escalation protocol, the
maintenance dose, the definition of desensitization, and the method used
to report adverse reactions. In general, the efficacy and the safety of
tree nut OIT were found to be similar to that demonstrated by peanut OIT
trials\textsuperscript{42}, regardless of whether the intervention is
single tree nut-, multi-food-, or omalizumab-facilitated-OIT. Omalizumab
appears to allow for faster desensitization with fewer adverse
reactions, especially during the build-up phase. Maintenance doses,
between 300\textsuperscript{13} and 4000mg\textsuperscript{19}, seem to
be effective in achieving desensitization to the full range of tree nuts
(a full portion), while a maintenance dose as low as 75mg protein per
day may confer protection from accidental
ingestions\textsuperscript{37}.

As expected, sustained unresponsiveness depended on the length of
avoidance, with fewer participants maintaining their desensitization
over time\textsuperscript{13,23,37}. The current knowledge of immune
modulation during OIT\textsuperscript{43} does not support the
acquisition of a permanent tolerance phenotype. The frequency and the
dose required to maintain desensitization are probably dependent on
individual biomarkers, still not fully elucidated.

Cross-desensitization between cashew and pistachio, or walnut and
cashew, was described in multi-OIT and single-OIT
studies\textsuperscript{12,13,22,27}, attributed to the close
phylogenetic affinity of respective nuts\textsuperscript{38}.
Interestingly, cross-desensitization to distant phylogenetic nuts
through walnut and cashew OIT was also documented in three
studies\textsuperscript{22,23,25}, although details about the
implicating nuts lack in one of them\textsuperscript{23}. Linear and
structural homologies of vicilin, legumin, and 2S albumin epitopes of
tree nuts belonging to different botanical families have been
demonstrated\textsuperscript{38}. These homologies could contribute to
the observed cross-desensitization, which straightly affects the
management options for multi-nut allergic patients.

Managing tree nut allergy seems to have a positive effect on the quality
of life of patients and families, irrespectively of the intervention
used. The effect is pronounced when desensitization to more nuts is
achieved.

The heterogeneity of the studies included in this review prevented
pooling and meta-analysis. Only a small number of studies assessed
interventions specifically for tree nut allergy, while the majority
referred to multi-food allergic individuals, including subgroups with a
co-existing tree nut allergy. To overcome this obstacle, we had to
extrapolate the participants and the outcomes in interest, although they
were not fully characterized. Caution should also be taken when
reviewing the numbers of patients treated with multi-OIT, with or
without omalizumab, as most studies are originated by the same team,
thus the population might have been recycled.

Although there are recent reviews on the management and diagnosis of
tree nut allergy\textsuperscript{44-48}, this is the first systematic
review thoroughly investigating the available information on therapeutic
options for the desensitization of patients with IgE-mediated tree nut
allergy, other than peanut.

Even though strict avoidance remains the only approved care for patients
with tree nut allergy, alternative approaches have been tested in
clinical trials and real-life studies. Among them, oral immunotherapy
seems to be the most effective option, although not without the risk of
allergic reactions. The possibility to simultaneously achieve
desensitization to multiple nuts with only one nut in OIT is of great
interest for multi-nut allergic individuals and requires further
investigation.

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\textbf{Tables} : 4

\textbf{Figure 1 Legend:} PRISMA diagram for study selection

\textbf{Appendix 1: Search Strategy and Study Selection.}

We systematically searched PUBMED, SCOPUS and the COCHRANE LIBRARY
{[}search terms (WALNUT OR CASHEW OR PISTACHIO OR HAZELNUT OR ALMOND OR
TREENUT OR TREE NUT OR TREE NUTS OR TREENUTS) AND (ALLERGY OR
HYPERSENSITIVITY OR ANAPHYLAXIS) AND (MANAGEMENT OR THERAPY OR TREATMENT
OR IMMUNOTHERAPY){]} for active treatments of IgE-mediated allergy to
tree nuts (walnut, hazelnut, pistachio, cashew, and almond) with
allergen-specific immunotherapy (AIT) using oral (OIT), sublingual
(SLIT), epicutaneous (EPIT) or subcutaneous (SCIT) delivery or with
other disease-modifying treatments (PROSPERO registration number:
CRD42021248763). We followed the EAACI definition of allergen-specific
immunotherapy, which is ``repeated allergen exposure at regular
intervals to modulate the immune response, to reduce symptoms and the
need for medication for clinical allergies, and to prevent the
development of new allergies''.

The pre-specified inclusion criteria were randomized and non-randomized
comparative studies, one group non-randomized pre-post-studies,
descriptive studies which include analysis of outcomes (single-subject
design, case series) and case reports, of children and adults of any
age, with a diagnosis of IgE-mediated allergy to one or more tree nuts
(walnut, hazelnut, pistachio, cashew, almond), confirmed by IgE
sensitization (SPTs or/and sIgEs) and oral food challenge or a recent
(within two years) history of reactions.

The pre-specified exclusion criteria were studies in which the diagnosis
of IgE-mediated tree nut allergy was based solely on IgE sensitization
and/or distant (\textgreater{}2 years) history of reaction and studies
without an exit food challenge to the culprit nut to verify tolerance or
an increase in the tolerance threshold. We did not exclude studies in
which the IgE-mediated allergy diagnosis was based only on a recent
history reaction rather than a food challenge, because we expected that
this would result in a small number of retrieved studies.

This review's main outcome was desensitization, through the change in
the threshold of the tree nut in question required to elicit an allergic
reaction while on treatment, and sustained unresponsiveness, defined as
the ability to consume foods containing the tree nut in question after
discontinuing treatment.

The search was first performed on 10/02/2020 for PUBMED and SCOPUS
databases and 09/12/2020 for COHRANE LIBRARY and repeated regularly; the
last search was done on 13/07/2022.

Title and abstract screening and study selection were performed by three
authors (MP, PX, EE) independently. Relevant references of included
articles were also screened. Data extraction to standardized Excel forms
was performed by one investigator (MP).

\textbf{Appendix 2: Overall Characteristics of included studies.}

The population in question was adults in five
studies\textsuperscript{16,17,28,36,38}, children in
eleven\textsuperscript{14,23-25,31-35,37,39}, and both in
eight\textsuperscript{15,18,21,22,26,27,29,30}. Two studies were
addressed to the caregivers of children\textsuperscript{19,20}.

Two studies, including a RDBPC, investigated the effect of one-year
pollen subcutaneous immunotherapy on hazelnut and walnut
allergy\textsuperscript{17,28} in a total of 26 adults. Both studies
assessed tree nut allergy by food challenges at baseline. The RDBPC
trial used histamine injections as the placebo, while for the
prospective cohort, the baseline assessment was used as a comparator.
The primary outcome in both studies was the changes in Eliciting Dose
(ED) during the exit food challenge. One study assessed immunological
changes. No study assessed sustained unresponsiveness,
cross-desensitization, or changes in the quality of life.

Three studies investigated sublingual
immunotherapy\textsuperscript{16,26,36}. One RDBPC and a follow-up trial
were conducted by the same team and investigated sublingual
immunotherapy with hazelnut extracts, standardized in unit masses of the
major allergens Cor a 1 and Cor a 8\textsuperscript{16,36}, in 12 and 7
adults, after 8-12 weeks, and 11 months, respectively. All participants
had a positive double-blinded, placebo-control food challenge (DBPCFC)
at baseline. The primary outcome in both studies was the changes in
Eliciting Dose (ED) during the exit food challenge. The third
study\textsuperscript{26} investigated the effect of Pru p 3 SLIT in 29
children and adults with a history of an allergic reaction within the
previous year to several fruits with/without symptoms with vegetables,
and/or peanuts or nuts compared to 13 participants who followed the
standard of care/avoidance. The primary aim was to assess the
effectiveness of 1-year Pru p 3 SLIT by open oral food challenges (OFCs)
to unpeeled peach and nuts. Two studies\textsuperscript{16,36} assessed
immunological changes, and none assessed sustained unresponsiveness,
cross-desensitization, or changes in the quality of life

Seven reports, by five published
studies\textsuperscript{24,27,34,35,39}and two conference
abstracts\textsuperscript{23,25}, have investigated oral immunotherapy
(OIT) to a single tree nut. The implicated tree nut was walnut in three
studies\textsuperscript{24,25,39}, hazelnut in
two\textsuperscript{34,35}, cashew in one\textsuperscript{27}, and one
conference abstract reported peanut and/or tree nut OIT without further
information\textsuperscript{23}. All studies included children. In
total, 66 children received walnut OIT, 170 children received hazelnut
OIT, 50 children received cashew OIT\textsuperscript{27}, and 37
children reported in an abstract\textsuperscript{23} received peanut/
tree OIT, with no further information provided. Inclusion required a
positive oral food challenge, open or double-blinded, in three
studies\textsuperscript{23,34,39}, and a positive OFC or a history of a
recent reaction in three \textsuperscript{24,27,35}. In one study,
children with no history of reaction, but a strong immunological
suggestion of tree nut allergy, were also included\textsuperscript{35}.
In one abstract\textsuperscript{25}, inclusion criteria were not
reported. In three studies, the control group received standard of care
(avoidance)\textsuperscript{23,24,27}, and four studies used baseline
assessment as a comparator\textsuperscript{25,34,35,39}. The primary
outcome was desensitization in five
studies\textsuperscript{23,24,27,34,35}, sustained unresponsiveness in
one\textsuperscript{39}, and both in one\textsuperscript{25}. The oral
immunotherapy protocol, the maintenance dose, and the time of
intervention varied between studies. One study used antihistamine
premedication until the maintenance dose was
reached\textsuperscript{39}. Three studies assessed
cross-desensitization to another nut\textsuperscript{24,25,27}, two
studies assessed changes in quality of life\textsuperscript{23,24}, and
one study assessed the acceptance of children and their caregivers of
the OIT protocol\textsuperscript{35}.

Multiple oral Immunotherapy (multi-OIT), including tree nuts, was
reported in nine studies\textsuperscript{14,15,19-22,29,30,33}. Most
studies were generated from the same
group\textsuperscript{14,15,19-22,29,30}. Two studies included
children\textsuperscript{14,33}, five children and
adults\textsuperscript{15,21,22,29,30}, and two caregivers of
children\textsuperscript{19,20}. In total, 194 participants included
cashew in their OIT, pistachio, 156 walnut, 121 pecan, 58 hazelnut, and
47 almond. With one exception\textsuperscript{33}, the studies required
food challenges prior to intervention. Two studies used baseline
assessment as a comparator\textsuperscript{20,21}, and two used patients
on standard care or on a waiting list for multi-OIT. One study compared
multi OIT to single peanut OIT\textsuperscript{22}, one study compared
multi OIT with and without omalizumab with the standard of
care\textsuperscript{14}, and three compared different maintenance
doses\textsuperscript{15,29,30}. Safety was the main outcome in three
studies\textsuperscript{21,22,33}, efficacy in two
\textsuperscript{14,15}, and both in two \textsuperscript{29,30}. In two
studies, the change in the quality of life reported by caregivers was
the main outcome\textsuperscript{19,20}. No other study assessed quality
of life. The oral immunotherapy protocol, the maintenance dose, and the
time of intervention varied. One study used antihistamines as
adjuvant\textsuperscript{22}, and five used
omalizumab\textsuperscript{14,15,19,21,29}. One study assessed sustained
unresponsiveness\textsuperscript{15}, and three assessed
cross-desensitization \textsuperscript{14,15,29}.

The remaining studies investigated the effectiveness of other
interventions in multi-food allergic patients, including patients with a
tree nut allergy. Two studies used omalizumab as the intervention in
children, including two children allergic to cashew, one to pistachio,
four to walnut, six to hazelnut, and three to
almond\textsuperscript{31,32}. In a case report, dupilumab was used in
an adult with pistachio and corn allergy and sensitization to cashew,
walnut, hazelnut, and almond\textsuperscript{38}. Traditional Chinese
Medicine\textsuperscript{37} and Chinese Herbal Medicine (Food Allergy
Herbal Formula-2)\textsuperscript{18} were used in multi allergic
subjects in the remaining studies. Three studies performed OFCs prior to
intervention\textsuperscript{18,32,38}; one required a recent history of
allergic reaction\textsuperscript{37} and one a positive OFC and/ or
convincing history\textsuperscript{31}. One study assessed sustained
unresponsiveness\textsuperscript{18}, and three assessed changes in the
quality of life\textsuperscript{31,32,37} through different
questionnaires.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/PRISMA-TN-IT/PRISMA-TN-IT}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/518142/articles/592408-title-current-options-in-the-management-of-tree-nut-allergy-focusing-on-but-not-limited-to-immunotherapy-a-systematic-review}

\textbf{Hosted file}

\verb`Table 2.docx`  available at \url{https://authorea.com/users/518142/articles/592408-title-current-options-in-the-management-of-tree-nut-allergy-focusing-on-but-not-limited-to-immunotherapy-a-systematic-review}

\textbf{Hosted file}

\verb`Table 3.docx`  available at \url{https://authorea.com/users/518142/articles/592408-title-current-options-in-the-management-of-tree-nut-allergy-focusing-on-but-not-limited-to-immunotherapy-a-systematic-review}

\textbf{Hosted file}

\verb`Table 4.docx`  available at \url{https://authorea.com/users/518142/articles/592408-title-current-options-in-the-management-of-tree-nut-allergy-focusing-on-but-not-limited-to-immunotherapy-a-systematic-review}

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