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Preparing Patients for Oral Immunotherapy (PPOINT):
International Delphi consensus for procedural preparation and
consent
Douglas P. Mack, MD, MSca, Timothy E. Dribin, MDb, Paul J. Turner, FRCPCH, PhDc,
Richard L. Wasserman, MD, PhDd, Mariam A. Hanna, MDe, Marcus Shaker, MD, MScf, Mimi
L. K. Tang, MBBS, PhD, FRACP, FRCPA, FAAAIg, Pablo Rodríguez del Río, MD, PhDh,
Brad Sobolewski, MD, MEdi, Elissa M. Abrams, MD, MPHj, Aikaterini Anagnostou, MD,
PhDk, Stefania Arasi, MD, PhDl, Sakina Bajowala, MDm, Philippe Bégin, MD, PhDn, Scott B.
Cameron, MD, PhDo, Edmond S. Chan, MD, FRCPCp, Sharon Chinthrajah, MDq, Andrew T.
Clark, MB, BS, DMr, Paul Detjen, MDs, George du Toit, MBBCh, RCPCHt, Motohiro Ebisawa,
MD, PhDu, Arnon Elizur, MDv, Jeffrey M. Factor, MDw, Justin Greiwe, MDx, Jonathan O’B
Hourihane, MB, DMy, Sarah W. Hughes, MPAS, PA-Cz, Douglas H. Jones, MDaa, Antonella
Muraro, MD, PhDbb, Anna Nowak-Wegrzyn, MD, PhDcc, Nandinee B. Patel, MD, PhDdd, Amy
M. Scurlock, MDee, Atul N. Shah, MD, FACAAI, FAAAAIff, Sayantani B. Sindher, MDgg,
Stephen Tilles, MDhh, Brian P. Vickery, MDii, Julie Wang, MDjj, Hugh H. Windom, MDkk,
Matthew Greenhawt, MD, MBA, MScll
aDepartment of Pediatrics, McMaster University, Hamilton
bDivision of Emergency Medicine, Cincinnati Children’s Hospital Medical Center; and the
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati
cNational Heart & Lung Institute, Imperial College London, London
dMedical City Children’s Hospital, Dallas
eMcMaster University, Hamilton
fDartmouth-Hitchcock Medical Center; and Geisel School of Medicine at Dartmouth, Lebanon
gDepartment of Allergy Immunology, Murdoch Children’s Research Institute; the Department of
Paediatrics, University of Melbourne, Australia; and the Department of Allergy and Immunology,
the Royal Children’s Hospital Melbourne, Melbourne
hHospital Infantil Universitario Niño Jesús, Madrid
iDepartment of Pediatrics, Division of Emergency Medicine, Cincinnati Children’s Hospital Medical
Center, University of Cincinnati College of Medicine, Cincinnati
jDepartment of Pediatrics, Section of Allergy and Clinical Immunology, University of Manitoba,
Winnipeg
kTexas Children’s Hospital, Baylor College of Medicine, Houston
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Corresponding author: Douglas Paul Mack, MD, MSc, Halton Pediatric Allergy, 5500 N Service Rd, Ste 106, Burlington, Ontario,
L7L 6W6, Canada. mackd1@mcmaster.ca.
HHS Public Access
Author manuscript
J Allergy Clin Immunol
. Author manuscript; available in PMC 2024 October 09.
Published in final edited form as:
J Allergy Clin Immunol
. 2024 June ; 153(6): 1621–1633. doi:10.1016/j.jaci.2024.02.019.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
lPediatric Allergology Unit of the Allergy Diseases Research Area, Bambino Gesù Children’s
Hospital IRCCS, Rome
mKaneland Allergy and Asthma Center, North Aurora
nDepartment of Pediatrics, Section of Allergy, CHU Sainte-Justine; and the Department of
Medicine, Section of Allergy, CHUM, Montreal
oDepartment of Pediatrics, Division of Allergy and Immunology, University of British Columbia,
Vancouver
pDepartment of Pediatrics, Division of Allergy, University of British Columbia, BC Children’s
Hospital, Vancouver
qSean N. Parker Center for Allergy and Asthma Research, Stanford University, Stanford
rCambridge University Hospitals NHS Trust, Cambridge
sKenilworth Medical, Kenilworth
tDepartment of Paediatric Allergy, Division of Asthma, Allergy and Lung Biology, MRC and
Asthma UK Centre in Allergic Mechanisms of Asthma, King’s College London; and the Evelina
London Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London
uNational Hospital Organization, Sagamihara National Hospital, Yokosuka
vInstitute of Allergy, Immunology and Pediatric Pulmonology, Yitzhak Shamir Medical Center; and
the Department of Pediatrics, Faculty of Medicine, Tel Aviv University, Tel Aviv
wDepartment of Pediatrics, University of Connecticut School of Medicine, Farmington
xBernstein Allergy Group; the Department of Internal Medicine, Division of Immunology/Allergy
Section, the University of Cincinnati College of Medicine, Cincinnati
yPaediatrics and Child Health, Royal College of Surgeons in Ireland; and Children’s Health
Ireland, Dublin
zDartmouth-Hitchcock Medical Center, Lebanon
aaGlobal Food Initiative, Clearfield
bbFood Allergy Referral Centre Padua, University Hospital, Padua
ccNYU Grossman School of Medicine, Hassenfeld Children’s Hospital, New York; and the
Department of Pediatrics, Gastroenterology, and Nutrition, Collegium Medicum, University of
Warmia and Mazury, Olsztyn
ddNational Heart & Lung Institute, Imperial College London, London
eeDepartment of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children’s
Hospital and Research Institute, Little Rock
ffCenter for Asthma & Allergy, New York Food Allergy & Wellness, New York
ggSean N. Parker Center for Allergy and Asthma Research, Stanford University School of
Medicine, Stanford
hhAimmune Therapeutics, Brisbane; and the University of Washington, Seattle
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iiEmory University School of Medicine; and Children’s Healthcare of Atlanta, Atlanta
jjDepartment of Pediatrics, Division of Allergy & Immunology, Icahn School of Medicine at Mount
Sinai, New York
kkWindom Asthma Allergy & Sinus, Sarasota
llChildren’s Hospital Colorado, University of Colorado School of Medicine, Aurora
Abstract
Background: Despite the promise of oral immunotherapy (OIT) to treat food allergies, this
procedure is associated with potential risk. There is no current agreement about what elements
should be included in the preparatory or consent process.
Objective: We developed consensus recommendations about the OIT process considerations and
patient-specific factors that should be addressed before initiating OIT and developed a consensus
OIT consent process and information form.
Methods: We convened a 36-member Preparing Patients for Oral Immunotherapy (PPOINT)
panel of allergy experts to develop a consensus OIT patient preparation, informed consent
process, and framework form. Consensus for themes and statements was reached using Delphi
methodology, and the consent information form was developed.
Results: The expert panel reached consensus for 4 themes and 103 statements specific to
OIT preparatory procedures, of which 76 statements reached consensus for inclusion specific
to the following themes: general considerations for counseling patients about OIT; patient- and
family-specific factors that should be addressed before initiating OIT and during OIT; indications
for initiating OIT; and potential contraindications and precautions for OIT. The panel reached
consensus on 9 OIT consent form themes: benefits, risks, outcomes, alternatives, risk mitigation,
difficulties/challenges, discontinuation, office policies, and long-term management. From these
themes, 219 statements were proposed, of which 189 reached consensus, and 71 were included on
the consent information form.
Conclusion: We developed consensus recommendations to prepare and counsel patients for
safe and effective OIT in clinical practice with evidence-based risk mitigation. Adoption of these
recommendations may help standardize clinical care and improve patient outcomes and quality of
life.
Keywords
Allergy; anaphylaxis; Delphi; food allergy; oral immunotherapy; consent; patient preparation;
shared decision making; risk mitigation
Food allergy is a significant public health issue, affecting up to 5% to 10% of the
population.1,2 Reactions to accidental exposures are common and result in quality-of-life
concerns, potential for social isolation, nutritional limitations, and progressive psychological
burden for many families.3 Several immunotherapy options are emerging as reasonable food
allergy risk mitigation strategies.4 On the basis of phase 3 clinical trials and real-world
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experience, guidelines now support implementing oral immunotherapy (OIT) into routine
clinical practice, with varying global uptake.5–12
A shared decision-making (SDM) approach to OIT patient selection and preparation requires
grounding in a robust discussion to explore the patient’s goals and preferences, as well
as a thorough review of potential alternatives, outcomes, benefits, and risks.13,14 The
majority of OIT dosing is performed at home, without immediate medical supervision,
shifting a significant burden of responsibility for safety, adherence, and effectiveness
to patients and caregivers.15 OIT is generally regarded as safe, but there is a well-
recognized potential for severe dose-related reactions. Such reactions are often associated
with complicating cofactors such as illness or exercise, and attempts have been made
to mitigate these cofactors with safe-dosing rules.6,16 Nevertheless, patients require an
adequate understanding of OIT procedures and how potential cofactors may complicate
and affect dosing. There are few validated tools or published data for optimizing the key
elements that should be included in SDM discussions and the formal consent and counseling
process.17,18
We report the results of the first international Delphi consensus panel, the Preparing Patients
for Oral Immunotherapy (PPOINT), study, assembled to help define recommended optimal
components of an optimized OIT evaluation preparation, SDM, counseling, and informed
consent process to best prepare patients and caregivers for this therapy.
METHODS
The full methods used to develop the OIT Delphi PPOINT expert consensus panel
and the voting process are described in Fig E1 in the Online Repository available at
www.jacionline.org. From October 2021 through July 2023, we convened a 36-member
panel of allergy experts from 10 countries. Pediatric and adult allergists and immunologists
were selected on the basis of their clinical expertise and prior published research. Briefly,
after soliciting and iteratively developing themes and statements from participants, a
modified Delphi methodology was used to determine whether there was consensus for
candidate themes and statements. An anonymous electronic REDCap survey was sent to
panelists, who were asked to rate each theme and statement on the level of agreement (1 =
strongly disagree, 2 = agree, 3 = neutral, 4 = agree, 5 = strongly agree), or not applicable.
“Strongly agree” and “agree” were grouped, and “strongly disagree” and “disagree” were
grouped.19–21 Panelists were also encouraged to anonymously submit free-text comments.
Defining consensus
Consensus was defined as agreement or disagreement of ≥75% for themes and statements—
a common Delphi prespecified threshold.22–24 Wording adjustment and revoting continued
in additional rounds for each theme and statement until consensus was reached, or after
3 survey rounds. If the third round reached no consensus, the theme or statement was
categorized as “consensus not reached.” OIT contraindications that reached consensus were
further ranked by the participants as relative or absolute.
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Prioritizing statements to include in template OIT consent form
An additional survey was conducted to prioritize statements for inclusion in a template that
could be used to create a customizable OIT consent information form model, recognizing
that consent forms will be modified and tailored according to contextual provider and
practice differences, as well as local, regional, and national laws and regulations. Statements
that reached “consensus agree” were incorporated into an anonymous REDCap survey.
Using the clinical impact method, for each statement, panelists were asked to rate the
importance of including the statement in an OIT consent form using a 0-to-10 scale (0
= not important, 5 = neutral, 10 = very important).25 Panelists could also select “not
applicable.” The median importance score (0-10) with the corresponding interquartile range
was reported for each statement, and a sample customizable template OIT consent form
was developed incorporating statements that reached a median score of 9 or more. Where
necessary, statements selected for inclusion were modified on the final form to enhance
readability and formatting. This study was approved by the Cincinnati Children’s Hospital
institutional review board.
RESULTS
OIT Delphi panel participants and overview of Delphi voting process
The PPOINT OIT Delphi panel consisted of 36 experts in food OIT. A description of the
participants and their OIT experience is detailed in Table I. The expert panel proposed
322 separate statements, divided into 4 procedural themes (A-D; 103 statements) and 9
consent themes (E-M; 219 statements). Of these, 265 reached consensus for inclusion, 9
reached consensus for exclusion, and 49 did not meet consensus (see Table E1 in the Online
Repository available at www.jacionline.org). Percentages in the text below are listed in
parentheses as the proportion of participants who voted “agree/strongly agree” in the final
voting round and the number of rounds (1 to 3) required to reach consensus—for example,
(94.5%; 2).
General considerations for counseling patients about OIT
The panel strongly agreed that the counseling process should include a detailed discussion
about the steps in the OIT process (100%; 1), including the stages and timelines (97.2%;
1) (buildup, maintenance, and possible sustained unresponsiveness [SU] and remission) (see
Table E2 in the Online Repository available at www.jacionline.org). There was consensus
that oral food challenges be prioritized to confirm diagnosis, establish threshold, and assess
desensitization and SU (88.9%; 1). Panelists prioritized clearly understanding the patients’
and caregivers’ goals (97.2%; 1). Panel members reached consensus for robust education of
the patient and all relevant caregivers (100%; 1) through a detailed consent process (Fig 1,
A, and Table E2).
Patient- and family-specific factors to be addressed before and during OIT
Panelists highlighted control of comorbid allergic conditions, with all panelists agreeing
on the importance of optimal asthma control (100%; 1). Addressing anxiety surrounding
OIT with counseling support was also prioritized (94.4%; 1). Practical factors, including
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establishing adequate parental supervision for dosing (100%; 1) and assessing the feasibility
of activity restriction to comply with safe dosing rules (100%; 1), were also agreed
as important to address before initiating OIT. The panel reached consensus about the
importance of ensuring divorced or separated parents agree on OIT treatment plans (86.1%;
1) (Fig 1, B, and see Table E3 in the Online Repository available at www.jacionline.org).
Indications for initiating OIT
There was consensus regarding OIT being indicated for patients up to 17 years of age
(age under 1 year—77.1%; 3, age 1-4 years—83.3%; 1, age 4-17 years—88.9%; 1), but
no consensus was reached regarding indication for patients over 18 (66.7%; 3) (Fig 1,
C, and see Table E4 in the Online Repository available at www.jacionline.org). Having
multiple food allergies was considered an indication for OIT (77.8%; 1). While consensus
was reached regarding OIT being indicated for patients unlikely to outgrow their allergy
spontaneously (91.7%; 1), there was no consensus for patients likely to outgrow their allergy
(eg, milk, egg, soy) (63.9%; 3). The panel agreed that impairment in quality-of-life concerns
about accidental exposure (80%; 3) and nutritional burden (80.6%; 3) were indications for
OIT (Fig 1, C).
Potential contraindications and precautions for OIT
Active eosinophilic esophagitis (EoE) reached consensus as a contraindication (94.3%; 1),
with 57.6% considering this an absolute contraindication, but no consensus was reached
about EoE in remission’s being a contraindication (52.8%; 3) (Fig 2, and see Table
E5 in the Online Repository available at www.jacionline.org). Uncontrolled asthma was
unanimously considered a contraindication (100%; 1), with most participants considering
it an absolute contraindication (88.9%). Uncontrolled psychological disorders (86.1%;
1) (including eating disorders—83.3%; 1, anxiety—83.3%; 1, and obsessive-compulsive
disorder—86.1%; 2) were considered contraindications if poorly controlled but were
not considered contraindications if controlled. Social factors, including parental discord
(94.4%;1), poor parental communication (86.1%; 1), language barriers (77.8%; 1), and poor
prior adherence (94.4%; 1), were all considered contraindications. Unwillingness to use
epinephrine was a contraindication (97.2%; 1), with 94.3% considering this an absolute
contraindication (Fig 2).
Defining potential benefits of OIT
The panel reached consensus regarding the benefits of a reduced risk of reacting to
accidental exposures (94.4%; 1), reduced risk of a severe accidental reaction (88.9%; 1),
an increased threshold required to elicit a reaction (97.1%; 1), and improved quality of life
(88.9%; 1) and food-related anxiety among patients (83.3%; 1) and caregivers (88.9%; 1)
(Fig 3, and see Table E6 in the Online Repository available at www.jacionline.org).
Defining potential risks associated with OIT
Foremost, mild (97.2%; 1), severe (100%; 1), and even fatal (80.6%; 1) reactions were
identified as potential risks that should be clearly communicated to patients and caregivers
(see Table E7 in the Online Repository available at www.jacionline.org). The panel also
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agreed (83.3%; 2) that there is an increased risk of dose-related allergic reactions requiring
epinephrine during OIT if following strict allergen avoidance. In addition, EoE was
recognized as a potential risk of therapy requiring disclosure to the patient (97.2%; 1),
although this condition is typically reversible with OIT discontinuation or dose reduction
(97.2%; 1) (Fig 3).
Defining potential outcomes of OIT
Panelists agreed that OIT outcomes are variable (100%; 1), poorly predictable (77.8%; 1),
and may be allergen specific (94.4%; 1) (see Table E8 in the Online Repository available
at www.jacionline.org). The panel further agreed (83.3%; 1) on defining the scope of
desensitization, including limiting consumption to freely eating allergenic foods. While
remission (SU) as a discrete potential outcome reached consensus (77.8%; 1), free-text
comments tempered its inclusion, given concerns regarding the rarity of SU, inconsistency
of SU, its unclear definition, and its potential age dependence (see Fig E2 in the Online
Repository).
Alternative therapies and options to OIT to consider
The panel reached consensus that OIT alternatives include continued food avoidance
(100%; 1), epicutaneous immunotherapy (if this were to become available) (82.9%; 1), and
participation in a clinical trial for a potential therapy, if available (85.7%; 1) (see Table E9 in
the Online Repository available at www.jacionline.org). There was unanimous agreement to
discuss discontinuation of OIT at any time (100%; 1) (see Fig E3 in the Online Repository).
Practical risk mitigation strategies (including protocol modifications) for OIT
There was consensus for discussing that OIT should be supervised by an allergist (88.9%;
1) (see Table E10 in the Online Repository available at www.jacionline.org). Consensus was
reached recognizing the importance of caution with cofactors that may trigger or worsen
an allergic reaction during OIT (Fig 4), including active infection (88.9%; 1), uncontrolled
allergic disease (91.7%; 1), asthma exacerbation (88.9%; 1), exercise before (88.9; 2) and
after (88.9%; 1) the dose, hot showers or baths (83.3%; 1), tiredness or sleep deprivation
(77.8%; 1), menstruation (88.9%; 1), dental work or oral trauma (77.8%; 1), nonsteroidal
anti-inflammatory drugs (86.1%; 2), and alcohol (80.6%; 1) (Fig 4).
Difficulties and challenges during OIT
There were multiple statements regarding difficulties arising during OIT that reached
consensus, including difficulty with adherence (97.2%; 1), dosing fatigue (91.7%; 1), food
aversion (97.2%; 1), dose-related anxiety (91.7%; 1), extended time taking the dose (77.8%;
1), and exercise restrictions (86.1%; 1) (see Fig E4 and Table E11 in the Online Repository
available at www.jacionline.org).
OIT discontinuation
Multiple indications for discontinuation met consensus, including recurrent dose-related
systemic reactions (94.4%; 1), EoE (77.8%; 1), and uncontrolled asthma (94.4%; 1) (Fig
5, and see Table E12 in the Online Repository available at www.jacionline.org). Consensus
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was also reached surrounding poor protocol adherence (100%; 1), safety recommendations
(including not administering epinephrine when necessary) (86.1%; 1), or asthma treatment
(94.4%; 1) (Fig 5).
Options for long-term management of OIT
Consensus was reached regarding the implications and options for long-term OIT
management, specifically the importance of regular dose consumption (94.4%; 1) and that
dose quantity and dosing frequency should not be modified without medical advice (86.1%;
1). Continued requirement for epinephrine carriage reached consensus (88.9%; 1), as did the
potential for reactions even after years of maintenance dosing (91.7%; 1) (see Fig E6 and
Table E14 in the Online Repository available at www.jacionline.org).
Ranked importance of OIT consent information
The final voting stage was used to determine which consensus statements should be
included in the framework informed consent information form template. Of the 189 consent
statements, 71 were prioritized for inclusion in the consent form, having reached a median
importance score of ≥9 (Table II).
DISCUSSION
We convened a 36-member international expert PPOINT panel to develop a consensus
for themes and elements important for OIT patient preparation and counseling. This
is the first published study to develop a consensus-based sample template to assist in
developing an OIT informed consent information form using Delphi methodology and
clinical impact methods to define and prioritize topics for OIT consent, including detailed
risk-mitigation procedures. Our expansive expert panel with vast clinical and research
expertise will promote the dissemination and uptake of these findings into clinical care
to harmonize patient care procedures and optimize clinical outcomes. This study is the first
to systematically evaluate and attempt to standardize recommended elements for the OIT
evaluation, preparation, and counseling and consent process.
More than 322 potential statements were initially proposed, many of which came from
preexisting consent forms, processes, and standard operating procedures already in use.
This breadth of input highlights the substantial variability in current approaches, mirrors
the extensive number of issues that should be addressed, and represents the complexity
of a complete approach to counseling patients.15 Moreover, this heterogeneity reinforces
the need for more standardized recommendations of specific items to discuss during pre-
OIT patient evaluation and candidate selection with specific inclusion of a detailed SDM
framework to consider risks, benefits, and obligations inherent to participating in OIT.
Patient selection and preparation approach for OIT
A thorough OIT counseling and preparation process can help establish 2 critical goals: SDM
along with voluntary informed consent; and patient evaluation and preparation. A proposed
flow diagram of the OIT preparation process can be found in Fig 6. We recognize that
practicing clinicians will develop their own individual approaches that may include a very
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different structure and order. We suggest this as a guidance document on the basis of the
Delphi-based prioritization of this panel, and we emphasize the critical nature of a robust
preparation process.
The panel recognized the importance of optimal control of comorbidities. In particular,
poor asthma control has been highlighted as potentially increasing the risk of severe
OIT reactions, and our panel repeatedly prioritized this important medical condition.16,19
However, other comorbidities, such as allergic rhinitis, eczema, gastrointestinal disease,
and psychosocial factors, were also identified as important to assess for control, with
psychological and behavioral barriers explicitly recognized as being potential threats to
long-term OIT adherence and success.
Social and behavioral factors were also identified as priorities to address during the
OIT preparatory process. Familial factors such as parental disagreement and divorced
parental agreement were recognized as essential to address before beginning OIT. Parental
discordance regarding OIT knowledge has been previously reported.18 Although one parent
may be enthusiastic and knowledgeable about OIT, parental discord may lead to conflict
and/or medicolegal risk; most importantly, however, it may affect patient safety if the
process and safeguards are not well understood or accepted.
We also attempted to define the appropriate ages for initiating OIT. Currently, the only
registered product has an age indication of 4 to 17 years.5 However, several studies have
identified younger age groups as priority targets of OIT.12,20,21 Our group recognized that
OIT could be considered in younger age groups, even under 1 year of age, although the
level of agreement was highest for the approved indication. While our group did not reach
a consensus on patients over the age of 18, we recognize that this group may be suitable if
adequately informed and prepared. We note most participants were pediatric allergists, thus
potentially biasing the consideration of adult patients.
The benefits of OIT have been evaluated in multiple studies and meta-analyses and include
reduced risk of reaction and reaction severity and potentially improved quality of life and
anxiety, which also have aligned with prior research defining patient preferences and goals
of therapy.5–7,26 Our panel recognized and agreed that these outcomes may be variable
and depend on patient characteristics, such as age, baseline degree of sensitization, and
protocol. While patients may want to understand success rates, variability in baseline patient
characteristics and protocols makes such determinations challenging to specify to patients.
Contraindications, risk mitigation, and OIT discontinuation
One of the major outcomes of this study was delineating OIT contraindications, as well
as delineating whether experts considered contraindications to be absolute or relative.
Performing proper clinical trials to specifically assess contraindications is potentially
unethical, so contraindications can primarily be based on expert opinion or safety outcomes
from trials and real-world data.4,20 Opinions regarding these designations vary, and a lack of
clarity on such heterogeneity may affect OIT outcomes. Panelists agreed on a few absolute
contraindications: unwillingness to use epinephrine, uncontrolled asthma, and pregnancy.
However, there were differences in agreement regarding the degree of contraindication
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(relative vs absolute) with other potential concerns, such as active EoE, concurrent β-blocker
receipt, control of other allergic comorbidities, and prior severity of reactions. While other
groups have attempted to define absolute and relative contraindications for OIT, this is the
first published data to add granularity to these contraindications.4,20
There was strong consensus regarding the recommended inclusion of multiple statements
regarding risk and risk mitigation. While OIT remains a reasonably safe therapeutic process,
it is well documented that reactions tend to occur in the setting of cofactors, such as illness,
exercise, or uncontrolled asthma.4,27 This is the first panel using a Delphi methodology
to not only define recommended discussion of suitable risk mitigation strategies during
the consent process but also to rank each statement’s relative importance for inclusion
in the discussion before agreeing to OIT. Many of these risk-mitigating procedures result
in lifestyle limitations, including exercise restriction, and families must know about these
potential limitations before signing consent. On the basis of this feedback, we have
developed a practical list of strategies, in ranked order of perceived importance, that can be
incorporated into the consent process and used when guiding families through OIT treatment
(Fig 4).
There was strong consensus regarding discussion and disclosure of the risk of
discontinuation and acknowledgment that it can result from voluntary patient/caregiver
preference, medical necessity, or physician recommendation. Families and physicians
make considerable investments to ensure the success of the OIT process and to avoid
potential conflict down the road. A clear discussion about indications for discontinuing
OIT, including noncompliance, severe reaction, or emerging contraindications, should occur
before initiating OIT. Of note, while there are medical reasons for discontinuation, our
findings are unique in that many of these reasons for discontinuation are also related to
social and behavioral factors.
Informed consent
While the nature of informed consent necessitates that adequate information is provided
to the patient and family, communicating this information can take several forms, and
there is little standardized guidance regarding what topics and procedural information are
necessary and sufficient to include. Alarmingly, recent surveys have suggested that up to
one third of allergists offering OIT do not engage in informed consent.8,28 We present
OIT consensus statements recommended for families to discuss, consider, and understand
before providing written OIT consent (Table II). While these statements are recommended
items to include in a consent discussion or potentially incorporate into a formal consent
document, no individual statement or statements are intended to be substitute for a detailed
discussion of the risks and benefits of OIT. These statements represent a guideline that
may help clinicians create a tailored informed consent document, which would be used to
supplement the aforementioned SDM process. It is recommended that prescribers work with
their practice or institution to determine the final wording of any such document.
The dialogue between physician and patient represents the most critical element of
the consent process. Handouts (such as Table II) are supplemental tools to assist such
explanations and should ideally be provided before the consent discussion. Furthermore,
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the counseling clinician should document the discussion and provision of any supplemental
materials and include the signed consent form in the patient’s medical record. Formal
consent will also include a signed acknowledgment that these elements were adequately
discussed with the patient, family, and/or legal guardian and understood.
Limitations
While we developed a list of statements to be communicated to families during the consent
process, a limitation of our findings is that these statements are based on expert opinion,
collective experience, and educated investigator perspective; they may not have a firm
evidence base, and thus they serve as suggestions, not mandates. Additionally, the consensus
statements are likely not applicable to all populations or clinical scenarios, so consent
forms should be customized to one’s area of practice and the local medicolegal climate.
As evidence grows and practice variation regarding risks and outcomes is better clarified,
the consent process and elements included in the consent form will require modification.
Another limitation of this process is the lack of patient and caregiver input, but this was
designed to gather clinician-level consensus specific to support the safe provision of OIT.
Future evaluation of these recommendations among patients and caregivers will be an
important step for prospective validation and implementation. While we defined consensus
as ≥75%, raising or lowering the consensus threshold would have affected the number of
included statements, and we thus encourage clinicians to review the other statements in
Tables E2–E14. Importantly, providers may choose to include or exclude statements as
part of their counseling and consent process according to their own experience, patient
population, and regional and institutional requirements.
Conclusion
OIT necessitates high levels of patient knowledge, involvement, and shared responsibility.
To help support these needs, a thorough patient preparatory process is recommended to
ensure that OIT candidates and their caregivers are adequately evaluated and prepared for
the full range of potential risks and benefits, ideally through a SDM approach and informed
consent. This Delphi approach has been used to establish specifically recommended
fundamental elements of this preparatory consent process to optimize the safe and successful
implementation of OIT. Clinicians may implement all or part of this informed consent
process and consent form when evaluating and preparing families for their OIT treatment
journey.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
DISCLOSURE STATEMENT
Institutionally supported in part by the National Center for Advancing Translational Sciences of the National
Institutes of Health (NIH; award UL1TR001425); and the National Center for Advancing Translational Sciences of
the NIH (award KL2TR001426). The content is solely the responsibility of the authors and does not necessarily
represent the official views of the NIH.
Mack et al. Page 11
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Disclosure of potential conflict of interest:
D. P. Mack has provided consultation and speaker services for DBV Technologies (DBV), ALK-Abelló, and
Alladapt; and is an investigator for DBV and ALK-Abelló. P. J. Turner reports grants from UK Medical Research
Council, NIHR/Imperial BRC, and J. M. Charitable Foundation; and personal fees from UK Food Standards
Agency, Aimmune Therapeutics, Allergenis, and Aquestive Therapeutics outside the submitted work. R. L.
Wasserman has provided consultation and advisory board services to Aimmune. M. A. Hanna is an investigator
for DBV and ALK-Abelló. M. Shaker has participated in research funded by DBV; is an associate editor for
Annals of Allergy, Asthma & Immunology;
is a member of the Joint Task Force on Practice Parameters; and
serves on the editorial boards of the
Journal of Allergy and Clinical Immunology: In Practice
and the
Journal of
Food Allergy
. M. L. K. Tang reports consultant fees from Pfizer and Novartis; past employee (ended July 2022)
and share interest/options in Prota Therapeutic; member of medical advisory board of Anaphylaxis & Anaphylaxis
Australia; on the board of directors of Asia Pacific Association of Allergy Asthma and Clinical Immunology; past
member of the board of directors of the World Allergy Organization (WAO; ended 2019); membership of expert
committees of the American Academy of Allergy Asthma and Immunology (AAAAI), Asia Pacific Association
of Allergy Asthma and Clinical Immunology (APAAACI), and Australasian Society of Clinical Immunology
and Allergy (ASCIA); past membership of expert committees of WAO (ended 2019); and past membership of
the International Union of Immunological Societies (ended 2019). P. Rodríguez del Río reports research grants
from FAES and Aimmune Therapeutics; speaker honoraria from DBV, GSK, FAES, Novartis, ALK-Abelií, LETI
Pharma, Aimmune Therapeutics, Sanofi Regeneron, and Stallergenes; and consultant fees from FAES and Miravo
outside the submitted work. E. M. Abrams is a member of Joint Task Force on Practice Parameters; is an editorial
board member of the
Journal of Allergy and Clinical Immunology: In Practice;
serves on the board of directors of
the Canadian Society of Allergy and Clinical Immunology (CSACI); and is an employee of Public Health Agency
of Canada (views expressed are her own and not those of PHAC). A. Anagnostou has received institutional funding
from Aimmune and Novartis; consultation/speaker fees from ALK-Abelló, EPG Health, MJH, Adelphi, Aimmune
Therapeutics, Genentech, and Food Allergy Research and Education (FARE); and served as an advisory board
member for Ready,set,food and Novartis. S. Arasi has participated as advisory board member, consultant, and/or
speaker for Novartis, Aimmune, DBV, Ferrero, and Ulrich outside the submitted work. S. Bajowala has served as
consultant and advisory board member for Novartis; has served as a volunteer medical advisory board member
of FPIES Foundation; is a shareholder of Solid Starts LLC; and owns WisePrince LLC (medical technology for
oral immunotherapy [OIT]). P. Bégin reports grants from Novartis, Sanofi Regeneron, ALK-Abelló, and DBV; and
personal fees from Bausch Health, Pfizer, AstraZeneca, DBV, Novartis, Sanofi Regeneron, and ALK-Abelló. S.
B. Cameron reports membership on advisory boards for Medexus, Sanofi Regeneron, Bausch Health, Pfizer, and
Alladapt; and served as a committee member for the CSACI OIT guidelines. E. S. Chan has received research
support from DBV; has been a member of advisory boards for Pfizer, Miravo, Medexus, Leo Pharma, Kaleo,
DBV, AllerGenis, Sanofi Genzyme, Bausch Health, Avir Pharma, AstraZeneca, and ALK-Abelló; and was colead
of the CSACI OIT guidelines. S. Chinthrajah reports grants from National Institute of Allergy and Infectious
Diseases (NIAID), Consortium of Food Allergy Research (CoFAR), FARE, Stanford Maternal and Child Health
Research Institute, Genentech, and Regeneron; and personal fees from Alladapt Therapeutics, Novartis, Genentech,
Allergenis, Intrommune Therapeutics, IgGenix, and Phylaxis. A. T. Clark is chief medical officer and stockholder
in Camallergy Ltd (manufacturer of food OIT products). G. du Toit has received grants from NIAID, NIH, FARE,
MRC & Asthma UK Centre, Action Medical Research, and National Peanut Board; was scientific advisory board
member for Aimmune and Novartis; and was an investigator on pharma-sponsored allergy studies for Aimmune,
DBV, and Novartis. J. Greiwe has provided speaker services for AbbVie, AstraZeneca, Incyte, Mylan, Regeneron,
and Sanofi Genzyme; and has served on advisory boards for AbbVie, Aimmune, ALK-Abelló, AstraZeneca, DBV,
Dermavant, Genentech, GSK, Regeneron, and Sanofi Genzyme. J. O’B Hourihane reports consultancy and research
funding for Aimmune Therapeutics; research funding from DBV, Johnson & Johnson, Temple St Foundation,
Ireland, City of Dublin Skin and Cancer Hospital Charity, and National Children’s Research Centre, Ireland; board
membership for Clemens Von Pirquet Foundation Irish Food Allergy Network; and patent applications for Johnson
& Johnson. D. H. Jones reports being consultant, speaker, and/or member of advisory boards for Genentech,
Novartis, AstraZeneca, and Sanofi Regeneron. A. Muraro is a principal investigator (PI) for Aimmune, DBV,
Novartis, Sanofi Regeneron; and has served on advisory boards and/or received speaker fees from Aimmune, DBV,
Novartis, Sanofi Regeneron, Viatris, ALK-Abelló, Nestlé Heath Science, and Nutricia Danone. A. Nowak-Wegrzyn
reports receipt of research support from NIAID, DBV, Alladapt, Danone and Nestle; receipt of consultancy fees
from Regeneron, Novartis, Thermo Fisher Scientific, Aquestive, and Aimmune; and service as associate editor for
Annals of Allergy, Asthma & Immunology;
director of American Academy of Allergy, Asthma and Immunology
board of directors; and chair of medical advisory board of International FPIES Association. N. B. Patel reports
grants from UK Medical Research Council, NIHR/Imperial BRC, and J. M. Charitable Foundation; and personal
fees from UK Food Standards Agency, Aimmune Therapeutics, Allergenis, Aquestive Therapeutics and Novartis
outside of the submitted work. A. M. Scurlock receives grant funding from NIH/NIAID (CoFAR), FARE; and
clinical trial funding from Aimmune Therapeutics, DBV, Genentech, Novartis, Siolta Therapeutics, and Regeneron
Therapeutics. S. B. Sindher has received grant support to conduct trials from the National Institutes of Health,
DBV, Regeneron, Aimmune, Novartis, CoFAR, and FARE; and is advisor/consultant for Genentech and DBV.
S. Tilles is an employee of Aimmune Therapeutics. B. P. Vickery reports grants from Alladapt, AstraZeneca,
Genentech, NIAID/NIH, and Siolta; personal fees from Allergenis, Aravax, Reacta Biosciences, and Sanofi
Regeneron; both grants and personal fees from Aimmune, DBV, FARE, Novartis, and Regeneron; and stock
options from Moonlight Therapeutics outside the submitted work. J. Wang receives research support from NIAID,
Mack et al. Page 12
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Aimmune, DBV, and Siolta; and consultancy fees from ALK-Abelló, DBV, and Novartis. H. H. Windom serves
as a PI in clinical trials with Sanofi Regeneron, Novartis, GSK, Areteia, Chiesi, and AstraZeneca. M. Greenhawt
is a consultant for Aquestive; is a member of physician/medical advisory boards for DBV, Nutricia, Novartis,
Aquestive, Allergy Therapeutics, AstraZeneca, ALK-Abelló, Bryn, Genentech, and Prota; is an unpaid member of
the scientific advisory council for the National Peanut Board and the medical advisory board of the International
Food Protein Induced Enterocolitis Syndrome Association; is a member of the Brighton Collaboration Criteria
Vaccine Anaphylaxis 2.0 working group; is a senior associate editor for
Annals of Allergy, Asthma & Immunology;
is a member of the Joint Taskforce on Allergy Practice Parameters; and has received honoraria for lectures from
ImSci, Red Nucleus, Medscape, Paradigm Medical Communications, and multiple state/local allergy societies. The
rest of the authors declare that they have no relevant conflicts of interest.
Abbreviations used
EoE Eosinophilic esophagitis
OIT Oral immunotherapy
PPOINT Preparing Patients for Oral Immunotherapy
SDM Shared decision making
SU Sustained unresponsiveness
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Clinical implications:
Implementation of these international consensus recommendations for the OIT
preparation and consent process may standardize patient care, enhance education and
communication, improve OIT safety, and optimize risk mitigation and outcomes.
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FIG 1.
(A) Theme A key statements regarding general considerations for counseling patients about
OIT. (B) Theme B key statements regarding general considerations for counseling patients
about OIT. (C) Theme C key statements regarding general considerations for counseling
patients about OIT. Statement number and statement are listed. Percentage of participants
who voted for statement is represented by number and graphically as
blue circle
.
Blue dots
represent number of rounds to reach consensus. Full list of statements is provided in Tables
E2–E4.
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FIG 2.
Theme D ranked absolute and relative contraindications that reached consensus.
Circle
represents statement number. Voting percentages for absolute
(red)
and relative
(yellow)
listed in bars. Full list of statements is provided in Table E5.
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FIG 3.
Theme E and F key statements for general considerations for counseling patients about
OIT. Statement number and statement are listed. Percentage of participants who voted
for statement represented by number and graphically as
blue circle
.
Blue dots
represent
number of rounds to reach consensus. Median priority to include statement on consent form
represented with number and rainbow lever graphic representation. Interquartile range listed
below. Full list of statements is provided in Tables E6 and E7.
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FIG 4.
Theme I key statements for practical risk mitigation strategies for OIT. Statement number
and statement are listed. Percentage of participants who voted for statement represented
by number and graphically as
blue circle
.
Blue dots
represent number of rounds to reach
consensus. Median priority to include statement on consent form represented with number
and rainbow lever graphic representation. Interquartile range listed below. Full list of
statements is provided in Table E10.
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FIG 5.
Theme K key statements regarding “OIT may be discontinued by patient or practitioner
if…” Statement number and statement are listed. Percentage of participants who voted
for statement represented by number and graphically as
blue circle
.
Blue dots
represent
number of rounds to reach consensus. Median priority to include statement on consent form
represented with number and rainbow lever graphic representation. Interquartile range listed
below. Full list of statements is provided in Table E12.
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FIG 6.
Proposed flow diagram resulting from procedural and consent elements of PPOINT study.
AD
, Atopic dermatitis;
AR
, allergic rhinitis;
CSU
, chronic spontaneous urticaria;
EMA
,
European Medicines Agency;
FDA
, US Food and Drug Administration;
GAD
, general
anxiety;
GERD
, gastroesophageal reflux disease;
GI
, gastrointestinal;
IBD
, inflammatory
bowel disease;
NSAID
, nonsteroidal anti-inflammatory;
OCD
, obsessive-compulsive
disorder;
QOL
, quality of life;
SLIT
, sublingual immunotherapy.
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Author Manuscript Author Manuscript Author Manuscript Author Manuscript
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TABLE I.
Characteristics of 36 members of expert panel
Characteristic No. (%) or median [IQR]
Practice type
Academic 20 (55.6)
Private practice 9 (25.0)
Mixed/both 7 (19.4)
Patient profile
Child 21 (58.3)
Adult 0
Mixed/both 15 (41.7)
Years in practice 15.0 [10.0, 25.0]
Have you published peer-reviewed articles on OIT?
Yes 36 (100)
Do you perform OIT in your practice?
Yes 34 (94.4)
How many years have you performed OIT? 10.0 [7.0, 12.0]
Please estimate the number of patients you have managed with OIT. 400.0 [150.0, 800.0]
What allergens do you perform OIT for?
Peanut 34 (94.4)
Tree nuts 28 (77.8)
Milk 31 (86.1)
Egg 30 (83.3)
Sesame 24 (66.7)
Wheat 25 (69.4)
Other 14 (38.9)
In what context do you perform OIT?
Clinical practice 15 (44.1)
Clinical trial 2 (5.9)
Both 17 (50.0)
Do you obtain written informed consent before initiating OIT?
Yes 32 (94.1)
How long (minutes) on average do you estimate you spend obtaining informed consent for OIT? 30.0 [20.0, 60.0]
Who performs OIT consent discussion at your center?
Attending physician 30 (83.3)
Resident or fellow (physician in training) 7 (19.4)
Physician assistant 7 (19.4)
Nurse practitioner 7 (19.4)
Nurse 9 (25.0)
Other 3 (8.3)
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Characteristic No. (%) or median [IQR]
How is OIT funded at your center?
Public insurance 15 (41.7)
Private insurance 18 (50.0)
Direct payment (out of pocket) 13 (36.1)
Clinical trial 14 (38.9)
Other 3 (8.3)
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TABLE II.
Suggested statements with over 90% agreement for inclusion as part of model OIT consent information form
Potential benefits
□ There is a lower risk of reacting to accidental exposures to the food allergen.
□ Less severe allergic reactions occur with accidental exposure.
□ An increased amount of food allergen (threshold) is required to elicit a reaction.
□ Subjects may ingest foods with precautionary allergen (“may contain”) labeling.
Potential risks
□ Commonly occurring mild allergic reactions include oral symptoms (affecting mouth, tongue, lips, and/or throat), abdominal pain, rash, hives, and itchiness.
□ Anaphylaxis reactions may include swelling, wheezing, cough, shortness of breath, vomiting, diarrhea, and, in severe cases, low blood pressure and loss of consciousness.
□ Reactions can occur in the clinic or at home.
□ Epinephrine injection may be required for allergic reaction.
□ Emergency room/urgent care visit with or without hospitalization may be required for allergic reaction.
□ Eosinophilic gastrointestinal disorders such as EoE may occur.
□ Adverse reactions typically decrease during OIT maintenance phase but may occur at any time.
Potential outcomes
□ Patient response may be variable and poorly predictable, and may depend on patient and food being treated.
□ OIT effectiveness may be lost if the food is not eaten regularly or is discontinued.
□ Patients should expect to eat the allergenic food with some frequency indefinitely.
Alternatives and options
□ Continued food avoidance is a reasonable alternative.
□ OIT may be discontinued at any time.
Practical risk mitigation strategies
□ Adults should supervise dose administration.
□ OIT procedures should be supervised by allergists.
□ OIT dose increases should be performed under medical supervision in a facility equipped to treat anaphylactic reactions.
□ No active infection or signs of illness should be present when dose is administered or increased.
□ Doses should be reduced or deferred if patient is febrile, has gastroenteritis, or is experiencing asthma exacerbation.
□ Other allergic diseases should be controlled when dose is increased.
□ Patients should avoid exercise, alcohol, and hot showers or baths before or soon after the dose.
□ Patients should avoid taking the dose while tired or sleep deprived.
□ Doses may be reduced and may need to be resumed in a medical facility if not provided for an extended period of time.
□ Patients should have emergency medication with them at all times, and should treat any severe allergic reaction with epinephrine with potential activation of emergency medical services (eg, calling
911 or 999).
□ Patients and caregivers (depending on age) should be trained to administer rescue medication, including epinephrine/adrenaline autoinjectors.
□ Epinephrine-treated reactions should be reported to the treatment team immediately.
□ Because dosing errors can cause serious reactions, caregivers should be careful to administer the correct dose.
□ Doses may be reduced if there have been recurrent or severe reactions.
Difficulty encountered
□ Patients have trouble with adherence to daily dosing.
Reasons for discontinuation
□ Recurrent systemic reactions occur, despite adherence to dosing regimen and safety precautions.
□ Recurrent abdominal symptoms or development of confirmed EoE occur.
□ Eosinophilic gastrointestinal symptoms occur that do not resolve with dose reduction, dietary adjustment, and/or supportive medication.
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□ Asthma is not well controlled or family refuses to treat asthma.
□ Another medical condition arises that is a contraindication to OIT.
□ Adherence to therapy protocols or safety recommendations is suboptimal.
□ Epinephrine is not administered by caregivers during a systemic allergic reaction.
□ Adverse effects are not reported.
□ Patient requests to stop treatment.
□ Medical team judges the balance of adverse events to be too high or thinks it is in the patient’s best interest to stop OIT.
Office-specific policies, protocols, and procedures
□ Unscheduled clinic visits may be necessary for dose adjustments.
□ Buildup phase may last 4 to 12 months, or even longer.
□ Patients and caregivers are provided with guidance on how to contact health care providers with OIT-related questions, both during and outside of office hours and via phone, text, pager, or email.
□ Treating physicians must be notified of cases of significant adverse effects.
□ Patients and caregivers are expected to follow the allergist’s guidance in the event of an OIT-related reaction.
□ Any prolonged OIT dose deferral should be promptly communicated to the health care provider.
□ Patients are required to bring their epinephrine autoinjector to all dosing visits.
□ At least one adult per child is required during OIT visits.
□ Patients and caregivers agree not to share dosing protocols that may be used by individuals to attempt OIT without medical supervision.
Options for long-term management
□ Dose and frequency should not be modified without medical advice.
□ Epinephrine autoinjector carriage may still be required even when receiving maintenance dosing.
□ Adverse events might occur even after years of treatment and should be reported.
□ Changes to patient health status may affect OIT safety and should be reported to the treatment team.
□ Treatment decisions should be made in partnership and consultation with an allergist.
□ Recommendations for OIT treatment may change as experience with OIT grows and as additional food allergy treatments become available.
Statement text may be abridged for clarity. A complete list of statements with unabridged text, as well as free-text comments, are detailed in Tables E6–E14.
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