Allergen‐specific oral immunotherapy for peanut allergy

Abstract

Background

Peanut allergy is one of the most common forms of food allergy encountered in clinical practice.  In most cases, it does not spontaneously resolve; furthermore, it is frequently implicated in acute life‐threatening reactions. The current management of peanut allergy centres on meticulous avoidance of peanuts and peanut‐containing foods. Allergen‐specific oral immunotherapy (OIT) for peanut allergy aims to induce desensitisation and then tolerance to peanut, and has the potential to revolutionise the management of peanut allergy. However, at present there is still considerable uncertainty about the effectiveness and safety of this approach.

Objectives

To establish the effectiveness and safety of OIT in people with IgE‐mediated peanut allergy who develop symptoms after peanut ingestion.

Search methods

We searched in the following databases: AMED, BIOSIS, CAB, CINAHL, The Cochrane Library, EMBASE, Global Health, Google Scholar, IndMed, ISI Web of Science, LILACS, MEDLINE, PakMediNet and TRIP. We also searched registers of on‐going and unpublished trials. The date of the most recent search was January 2012.

Selection criteria

Randomised controlled trials (RCTs), quasi‐RCTs or controlled clinical trials involving children or adults with clinical features indicative of IgE‐mediated peanut allergy treated with allergen‐specific OIT, compared with control group receiving either placebo or no treatment, were eligible for inclusion.

Data collection and analysis

Two review authors independently checked and reviewed titles and abstracts of identified studies and assessed risk of bias. The full text of potentially relevant trials was assessed. Data extraction was independently performed by two reviewers with disagreements resolved through discussion.

Main results

We found one small RCT, judged to be at low risk of bias, that enrolled 28 children aged 1 to 16 years with evidence of sensitisation to peanut and a clinical history of reaction to peanut within 60 minutes of exposure. The study did not include children who had moderate to severe asthma or who had a history of severe peanut anaphylaxis. Randomisation was in a 2:1 ratio resulting in 19 children being randomised to the intervention arm and nine to the placebo arm. Intervention arm children received OIT with peanut flour and control arm participants received placebo comprising of oat flour. The primary outcome was assessed using a double‐blind, placebo controlled oral food challenge (OFC) at approximately one year. No data were available on longer term outcomes beyond the OFC conducted at the end of the study.

Because of adverse events, three patients withdrew from the intervention arm before the completion of the study. Therefore, only 16 participants received the full course of peanut OIT, whereas all nine patients receiving placebo completed the trial. The per‐protocol analysis found a significant increase in the threshold dose of peanut allergen required to trigger a reaction in those in the intervention arm with all 16 participants able to ingest the maximum cumulative dose of 5000 mg of peanut protein (which the authors equate as being equivalent to approximately 20 peanuts) without developing symptoms, whereas in the placebo group they were able to ingest a median cumulative dose of 280 mg (range: 0 to 1900 mg, P < 0.001) before experiencing symptoms.  Per‐protocol analyses also demonstrated that peanut OIT resulted in reductions in skin prick test size (P < 0.001), interleukin‐5 (P = 0.01), interleukin‐13 (P = 0.02) and an increase in peanut‐specific immunoglobulin G₄ (IgG₄) (P < 0.01).

Children in the intervention arm experienced more adverse events during treatment than those in the placebo arm. In the initial day escalation phase, nine (47%) of the 19 participants initially enrolled in the OIT arm experienced clinically‐relevant adverse events which required treatment with H₁‐antihistamines, two of which required additional treatment with epinephrine (adrenaline).

Authors' conclusions

The one small RCT we found showed that allergen‐specific peanut OIT can result in desensitisation in children, and that this is associated with evidence of underlying immune‐modulation. However, this treatment approach was associated with a substantial risk of adverse events, although the majority of these were mild.  In view of the risk of adverse events and the lack of evidence of long‐term benefits, allergen‐specific peanut OIT cannot currently be recommended as a treatment for the management of patients with IgE‐mediated peanut allergy.  Larger RCTs are needed to investigate the acceptability, long‐term effectiveness and cost‐effectiveness of safer treatment regimens, particularly in relation to the induction of clinical and immunological tolerance.

Plain language summary

Oral immunotherapy for the treatment of peanut allergy

Allergy to peanut can result in potentially life‐threatening reactions and, on occasions, death. Unlike many other forms of food allergy, allergy to peanut is typically life‐long. There is currently no cure for peanut allergy and people with this allergy must constantly be careful to avoid accidentally eating peanut or peanut‐containing foods.  If a person with a peanut allergy accidentally ingests peanut, he or she may develop serious allergic reactions necessitating emergency treatment with epinephrine (adrenaline).

The overall goal of allergen‐specific oral immunotherapy (OIT) for peanut allergy is to reduce and, if possible, eliminate the risk of further reactions associated with exposure to peanuts. Most people who have reactions to peanut have an immediate type (also sometimes known as IgE‐mediated) reaction in which symptoms typically develop within minutes of exposure to peanut protein and it is for this group that allergen‐specific OIT is a potential treatment approach.  It is not considered suitable for those who experience more delayed (also sometimes known as non‐IgE mediated) reactions.  Treatment involves giving people with peanut allergy very small doses of peanut protein by mouth and gradually increasing the amount being administered (the build‐up phase). Once the desired dose has been achieved, this is followed by the patient taking the same dose of peanut every day for a set period of time (maintenance phase).  As giving doses of peanut to someone with a peanut allergy has the potential to introduce allergic reactions, participants' safety needs to be carefully monitored during studies of peanut OIT.

We found one small trial undertaken in 28 children aged 1 to 16 years with confirmed peanut allergy. The study did not include children who had moderate to severe asthma or who had had severe anaphylaxis (a severe allergic reaction that may result in death) because of their peanut allergy. The authors randomised children to intervention or placebo in a 2:1 ratio. Intervention arm children received peanut flour whereas control arm participants received oat flour. The 48‐week trial showed that treatment with peanut OIT enabled children receiving OIT to substantially increase the amount of peanut flour they ate in comparison with those in the placebo arm without having an allergic reaction.  However, almost half of the children (nine out of 19) receiving OIT had an allergic reaction due to the OIT which required antihistamines, and two had more serious reactions to the treatment which required adrenaline (epinephrine). 

Although promising, based on the findings of this one small trial, we cannot recommend that peanut OIT be used routinely for people with peanut allergy. There is a need for further larger studies investigating safer OIT regimens and establishing the long‐term effectiveness of OIT after treatment is stopped.

Background

Description of the condition

Peanut allergy is one of the most common food allergies in westernised countries affecting, for example, up to 1.8% of young children in the United Kingdom (Hourihane 2007) and approximately 1% of children and 0.6% of adults in North America (Sicherer 2010b). The prevalence of challenge‐proven peanut allergy was 3.0% in Australian infants (Osborne 2011). The prevalence of peanut allergy may (Mullins 2009; Sicherer 2010a) or may not (Ben‐Shoshan 2009; Kotz 2011) be increasing. 

Of the eight major allergenic proteins in peanut, the components Ara h1 and Ara h2 (particularly the latter) are the most important predictors of clinical symptoms on exposure (de Leon 2007; Nicolaou 2010). 

IgE antibody‐mediated allergic reactions to peanut involve specific sensitisation of tissue mast cells and blood basophils by the binding of IgE to the high‐affinity IgE receptors on these cells. On re‐exposure, peanut proteins bind to the IgE antibody specific to them and this triggers the release of histamine, tryptase and a variety of other inflammatory mediators (Burks 2008). Symptoms of an acute allergic reaction typically develop within minutes to a few hours after peanut ingestion. Severity is unpredictable and ranges from mild skin symptoms (e.g. hives, flushing), gastrointestinal symptoms (e.g. vomiting, abdominal pain, diarrhoea), to severe or fatal anaphylaxis involving obstruction of the upper or lower airways and respiratory distress and/or cardiovascular collapse (Burks 2008; Simons 2011; Soar 2008 ). 

There is currently no disease‐modifying treatment or cure for peanut allergy (Sheikh 2010). Current management involves strict avoidance of peanut in all forms, including the minute quantities present in many packaged foods, as well as more obvious sources such as desserts, cookies and candies. Accidental exposures occur annually in more than 15% of patients at risk (Clark 2008; Yu 2006). The quality of life of affected people and their caregivers can be substantially reduced due to fear of incorrect food choices, ingestion of food containing hidden allergens, and the ever‐present threat of anaphylaxis (Akeson 2007; King 2009; Cummings 2010). 

Pharmacological treatment of peanut allergy involves teaching patients and caregivers to recognise symptoms of anaphylaxis (Gallagher 2011), to promptly use an epinephrine (adrenaline) auto‐injector, and to activate emergency medical services (Simons 2009).  

Clinical peanut allergy is typically life‐long (Sicherer 2007). Therapeutic interventions that provide permanent protection against unintentional peanut ingestion are therefore needed. Two decades ago, placebo‐controlled trials of subcutaneous immunotherapy in patients with clinical peanut allergy showed promising results, but there was an unacceptably high rate of adverse events (Oppenheimer 1992; Nelson 1997). Peanut oral immunotherapy (OIT) has been studied recently in patients with clinical peanut allergy, building on an approach successfully used more than a century ago to desensitise a child with egg allergy (Schofield 1908). 

In peanut OIT, incremental doses of peanut protein are administered to carefully selected patients in physician‐monitored, controlled clinical settings. Up‐dosing in such settings is interspersed with periods of maintenance dosing at home (Burks 2008; Sicherer 2010b). The initial aim however is to provide clinical desensitisation – i.e. to increase the threshold dose of exposure to peanut, and reduce the risk of allergic reactions from unintentional ingestion of peanut. The ultimate aim is to produce clinical and immunologic tolerance through down‐regulation of the Th2 response to peanut that will endure irrespective of whether a previously clinically reactive patient continues to eat peanut on a regular basis or does not eat peanut at all (Clark 2009; Jones 2009). 

There are different types/regimens of OIT protocols (e.g. rush, slow). In peanut OIT, peanut allergen can be delivered in a range of forms (e.g. crushed roasted peanuts, peanut flour and whole peanut kernels) and is swallowed thereby facilitating contact of the allergen with the gastro‐intestinal mucosa.

Three non‐randomised open studies of peanut OIT have been published to‐date (Blumchen 2010; Clark 2009; Jones 2009) and the findings from these have been synthesised in an earlier systematic review (Sheikh 2012). Although at inherently high risk of bias, these studies suggested that peanut OIT may achieve desensitisation. For example, in one study, peanut OIT resulted in clinical desensitisation (defined as the ability to tolerate 3.9 g of peanut protein during an oral food challenge) for 27 of the 29 children who completed at least eight months of treatment. Down‐regulation of the Th2 response to peanut was also documented: by 6 to 12 months, the size of the peanut skin prick test (SPT) decreased, basophil activation by peanut decreased, and cytokine production from peripheral blood mononuclear cells stimulated with peanut was modulated and by 12 to 18 months, peanut specific IgE decreased and peanut specific IgG4 increased (Jones 2009). These studies also demonstrated the high risk of adverse events associated with OIT. 

Randomised, double‐blind, placebo‐controlled studies of peanut OIT are now ongoing.  Important questions that need to be addressed before such an approach can be considered for routine clinical use include issues to do with the effectiveness and cost‐effectiveness of OIT and the need to better appreciate the risks associated with treatment and how these can be minimised (Thyagarajan 2010).

Description of the intervention

As early as 1908, Schofield's case report suggested that OIT can lead to desensitisation in those with egg allergy (Schofield 1908). Over the last hundred years, there has been considerable use of immunotherapy, but the majority of this relates to the management of people with allergic rhinitis who have pollen and other inhalant allergies. It is typically delivered through the subcutaneous route and, more recently, by sublingual administration (Calderon 2011a; Calderon 2011b; Radulovic 2010). Two decades ago, small placebo‐controlled trials of subcutaneous immunotherapy in peanut allergy were undertaken. Although the results were in some respects promising, the frequency of adverse events was high (Oppenheimer 1992; Nelson 1997). OIT is now being investigated as an effective safer mode of immunotherapy in people with peanut allergy.

Recent studies using oral (and sublingual) immunotherapy appear to be promising. OIT is in particular of considerable interest as a possible treatment for peanut allergy (Sheikh 2010). The aim of treatment is initially to desensitise patients to peanut allergen, which by increasing the threshold dose of exposure, reduces the risk of reactions resulting from accidental ingestion whilst on treatment (Burks 2008). The ultimate aim is to induce a state of cure or tolerance, i.e. following the completion of OIT, allowing people to eat peanut whenever they want and in whatever quantity they want without developing symptoms. There is early evidence that OIT can induce significant longer‐term humoral and cellular changes, which are suggestive of the development of immunological tolerance (Clark 2009; Jones 2009).

How the intervention might work

OIT involves the administration of initially very small doses (usually micro or milligrams) of food allergen to food‐allergic patients in a controlled clinical setting. The dose of the administered food allergen is then systematically increased until a maximum tolerated dose of food allergen is achieved (Jones 2009). Regular dosing with this maximal dose is then maintained at home by the patient. Successful desensitisation is thought to induce immunological tolerance by generating allergen specific IL‐10 secreting Tr1 and/or TGF‐secreting Th3 regulatory T‐cells (Sicherer 2006; Moneret‐Vautrin 2011). OIT is intended for patients with IgE‐mediated peanut allergy. Mechanisms of non‐IgE mediated food allergy are less well understood and currently OIT is not an appropriate form of treatment for non‐IgE mediated disease.

Why it is important to do this review

OIT is a treatment approach that has the potential to revolutionise the management of people with peanut allergy. However, at present there is still considerable uncertainty about the effectiveness and safety of this approach (Sheikh 2010). There is therefore a need to systematically identify, critically appraise and summarise available evidence on the benefits and harms associated with OIT for the management of people with peanut allergy.

Objectives

To determine the effectiveness and safety of OIT in people with IgE‐mediated peanut allergy. In this context, effectiveness means that a patient who is sensitised to peanut and was previously unable to tolerate ingestion of peanut without developing symptoms within minutes or hours, is, after undergoing peanut OIT, able to ingest peanut and tolerate it without developing any clinical symptoms.

Methods

Criteria for considering studies for this review

Types of studies

We were primarily interested in randomised controlled trials (RCTs). However, anticipating a limited number of RCTs in this area, we also planned to include studies using quasi‐RCT and controlled clinical trial (CCT) designs. Our working definition for these designs are:

• RCTs: All participants are allocated at random (e.g. random number generation, coin flips).

• Quasi‐RCTs: The intervention is allocated in a way that is not truly random: for example, allocation by birth, day of the week, month of the year.

• CCTs: Trials that contains at least two groups, one which receives the treatment and one which acts as a comparison group. The comparison group receives placebo/no treatment other than usual care.

Types of participants

We were interested in studies conducted in children or adults with confirmed peanut allergy. For the purposes of this review, peanut allergy was defined as a history of systemic clinical symptoms within minutes to hours after the ingestion of peanut in those with objective evidence of sensitisation to peanut protein (Sicherer 2010b). Objective evidence of sensitisation consisted of an elevated serum peanut‐specific IgE (ImmunoCAP) level (using cut‐points defined by the centre/study) or a positive skin prick test (SPT) response to peanut, where this was defined as a wheal of ≥3 mm than that produced by the saline control.

Types of interventions

We were interested in studies investigating peanut OIT compared either with a placebo group, an alternative way of administering desensitisation therapy or treatment with a peanut avoidance control group. We did not include studies which investigated OIT in combination with another treatment if the effect of OIT could not be evaluated independently from the additional treatment.

Types of outcome measures

We consider outcomes measured at any time period during or after treatment. We only included studies which assessed either one or both of our primary outcomes of interest, but we did not restrict studies to those with pre‐/post‐intervention double‐blind, placebo‐controlled oral food challenge (OFC) (Plaut 2009).

Primary outcomes

Our primary outcome measures of interest were:

• Increase in the amount of peanut that can be ingested and tolerated while receiving OIT (i.e. evidence of desensitisation)

• Complete recovery from peanut allergy after completion of OIT whether or not peanut is eaten (i.e. induction of immunologic tolerance).

Secondary outcomes

Our secondary outcome measures of interest were:

• Changes in generic and disease specific quality of life

• Satisfaction (patients and carers)

• Frequency and severity of further reactions

• Adverse events

• Drop‐outs

• Impact on co‐morbidities

• Medication use

• Health care utilisation

• Cost‐effectiveness

• Immunological changes suggestive of the induction of tolerance (e.g. decreased peanut‐specific IgE, increased peanut specific IgG4, and modulation of cytokine production from peanut‐stimulated peripheral blood mononuclear cells).

Search methods for identification of studies

We conducted systematic searches for RCTs, quasi‐RCTs and CCTs regardless of language, geographical area or publication status. The date of the last search of all databases was 21 January 2011.

Electronic searches

We searched the following databases: AMED, BIOSIS, CAB, CINAHL, The Cochrane Library, EMBASE, Global Health, Google Scholar, IndMed, ISI Web of Science, LILACS, MEDLINE, PakMediNet, and TRIP. We restricted our searches to the period 1990 to 2012, as peanut OIT was not studied prior to 1990.

MEDLINE search strategies are detailed in Appendix 1 and the search strategies used for other databases are found in Appendix 2. We combined subject search strategies with adaptations of the highly sensitive search strategy designed by the Cochrane Collaboration for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook Version 5.1.0., Box 6.4.b, Higgins 2011).

Searching other resources

In order to identify unpublished and ongoing work we searched key relevant internet‐based databases: Current Controlled Trials (http://www.controlled‐trials.com); ClinicalTrials.gov (http://www.clinicaltrials.gov); and Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au). We contacted experts in the field for information on ongoing and unpublished work (Table 1). We also searched the references of all studies identified by the above methods.

1. List of experts contacted.

Name of author	Country
Dr. Egidio Barbi	Italy
Dr. Kirsten Beyer	Germany
Prof. Wesley Burks	USA
Dr. Andrew T Clark	UK
Dr. Ernesto Enrique	Spain
Dr. Mansouri	Iran
Dr. Paolo Meglio	Italy
Professor Moneret‐Vautrin DA	France
Dr. Martine Morisset	France
Prof. Bodo Niggemann	Germany
Prof. Giovanni Pajno	Italy
Prof. G Patriarca	Italy
Dr. Lydia Zapatero Remon	Spain
Dr. Fernandez‐Rivas	Spain
Prof. Robert A Wood	USA

Data collection and analysis

Selection of studies

Two reviewers (UN and IV) independently reviewed the titles and abstracts retrieved during the search process and selected all studies that potentially satisfied our inclusion criteria. Both reviewers (UN and IV) then independently assessed the full text copies of these potentially eligible studies against the inclusion criteria. Disagreements were resolved through discussion between UN and IV and AS arbitrated in instances where an agreement was not reached. For a PRISMA diagram of study selection, see Appendix 3.

Data extraction and management

We collected included study details using a form designed for this purpose. Two reviewers (UN and IV) only included data if there was an independently reached consensus. If no agreement was reached, a third reviewer (AS) arbitrated. 

The following data were, where available, independently extracted from the included study:

• Trial methods

• Country and setting

• Participants (N, mean age, age range)

• Description of intervention

• Outcome measures (primary and secondary)

• Study withdrawal

• Adverse events.

Assessment of risk of bias in included studies

Risk of bias was assessed and documented following the domain‐based evaluation described in the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 (Higgins 2011). We compared the evaluations and discussed and resolved any inconsistencies and disagreements. We assessed the following domains as low, high, or unclear risk of bias:

• Random sequence generation

• Allocation concealment

• Blinding of participants and personnel

• Blinding of outcome assessment

• Incomplete outcome data

• Selective reporting

• Other bias.

Data synthesis

Due to finding only one included study, we were unable to perform meta‐analysis in this review. Had sufficient data been available, we planned to use Review Manager for data analysis and quantitative data synthesis. For dichotomous data, we planned to calculate individual and pooled statistics as relative risks (RR) with 95% confidence intervals (CI). For continuous data, we planned to calculate individual and pooled statistics as mean differences (MD) and/or standardised mean differences (SMD) with 95% CI. We planned to conduct meta‐analysis using the fixed‐effect model. Quantitative analyses of outcomes are, wherever possible, on an intention to treat basis. If we had found sufficient studies, we would have assessed evidence of publication bias graphically using Funnel plots and statistically using Begg and Egger tests (Begg 1994; Egger 1997). 

Subgroup analysis and investigation of heterogeneity

We planned to considerthe appropriateness of meta‐analysis in the presence of significant clinical or statistical heterogeneity. In future iterations of this review, relevant heterogeneity will be tested for using the I² statistic and significant heterogeneity assumed if I² is greater than 40% (i.e. more than 40% of the variability in outcome between trials could not be explained by sampling variation).

In future updates of this review, if data allow, we plan to undertake subgroup analyses in relation to:

• Isolated peanut allergy vs. multiple food allergies

• Oral immunotherapy regimen (rush vs. standard)

• Duration of treatment

• Time since completion of treatment.

Sensitivity analysis

We did not find sufficient studies to conduct sensitivity analyses. We planned to undertake sensitivity analyses for the allocation of missing data by best and worst case analysis, and also to undertake a sensitivity analysis on the basis of only including studies judged to be at low risk of bias. We also planned to undertake sensitivity analysis using random effects modelling, comparing the pooled estimates with those derived from undertaking fixed‐effect meta‐analysis.

Systematic review protocol

The methods used in this review were specified in advance and documented in a protocol which has been published (Nurmatov 2011).

Results

Description of studies

Results of the search

Our searches identified a total of 746 titles, 16 of which we selected for more detailed interrogation. See Appendix 3 for a study flow diagram.

Included studies

We found one small, US‐based RCT (Varshney 2011) that enrolled 28 children aged 1 to 16 years: 19 in the intervention arm and nine in the placebo arm. Subjects were patients with a clinical history of peanut allergy and evidence of allergic sensitisation to peanut protein. The active treatment was peanut flour, compared with a placebo of oat flour. Patients with a history of severe peanut anaphylaxis, moderate‐to‐severe persistent asthma, poorly controlled atopic dermatitis, oat allergy (due to use as placebo) or inability to discontinue antihistamines for a short period of time were excluded from the study population. The average length of oral immunotherapy (OIT) was 48 weeks: the initial day escalation phase lasted two days; the dose escalation period (with home dosing and build‐up visits) lasted approximately 44 weeks and the maintenance phase lasted approximately four weeks. A double‐blind, placebo controlled oral food challenge (OFC) was conducted at week 48. Adverse events were recorded and peanut‐specific IgE, IgG and IgG₄ were measured. Secreted cytokine assays and T‐cell analyses were conducted in subsets of patients.

See Characteristics of included studies for further details.

Excluded studies

We excluded 15 of the 16 studies we identified from screening, as they did not meet our specified inclusion criteria. Eight studies were either case series or open trials without a control group (Anagnostou 2011; Blumchen 2010; Buchanan 2006; Clark 2009; Jones 2009; Moneret‐Vautrin 2010; Nash 2008; Wassermann 2010), two were case reports (Aruanno 2009; Mansfield 2006), two studied forms of immunotherapy other than OIT (Bird 2010; Kim 2011), and three did not report either of our primary outcomes (Hofmann 2009 and Weldon 2011 reported only on safety, and Thyagarajan 2008 reported only immunological outcomes).

See Characteristics of excluded studies for further information.

Ongoing studies

Searches of clinical trials registries revealed eight studies of peanut OIT for which results had yet to be published. Five of these eight studies were RCTs: NCT00815035 and NCT01324401 compare OIT with placebo and OIT with control, respectively; NCT01084174 compares OIT with sublingual immunotherapy; NCT00932282 compares two lengths of treatment with a combination of anti‐IgE therapy and OIT; and ACTRN12608000594325 studies the combination of a probiotic and OIT, with the intervention group receiving OIT and a probiotic and the control group receiving the same probiotic and placebo OIT. Further details can be found in Characteristics of ongoing studies.

Risk of bias in included studies

The one included RCT (Varshney 2011) was judged to be at low risk of bias in all domains. Further details of the risk of bias assessment can be found in the Characteristics of included studies table.

Effects of interventions

Effectiveness of OIT on increasing peanut threshold dose

During the initial day of treatment escalation, 26 out of 28 (93%) individuals reached the maximum cumulative dose of 12mg of peanut protein (equivalent to approximately 1/25^th of a peanut) or placebo. Two patients in the intervention arm did not reach the 1.5 mg dose and were therefore deemed initial day escalation failures. 

Because of adverse events, three patients withdrew from the intervention arm (i.e. the two escalation day failures and one additional patient); only 16 participants therefore received the full course of peanut OIT.  All nine patients in the placebo arm completed the trial. In those who completed the study, there was a significant increase in the threshold dose of peanut allergen required to trigger a reaction in those in the intervention arm compared to those in the placebo arm at the 48 week OFC. All 16 participants who received the full course of active treatment were able to ingest the maximum cumulative dose of 5000 mg (reported by the authors as equivalent to approximately 20 peanuts), compared to a median cumulative dose of 280 mg in the placebo group (range: 0 to 1900; P < 0.001), which equates to approximately one peanut.  

Adverse events

Forty‐seven per cent (n = 9) of subjects in the intervention arm experienced clinically relevant adverse events during initial day escalation. No placebo subjects had clinically relevant symptoms during initial day escalation. During the build‐up phase, peanut OIT subjects had clinically relevant symptoms after 1.2% of 407 build‐up doses. One subject treated with peanut OIT experienced mild gastrointestinal symptoms during up‐dosing. During home dosing, one placebo group subject experienced adverse events, but no further details about the nature of these symptoms were given. At OFC, one peanut OIT‐treated subject experienced mild upper respiratory symptoms and moderate urticaria. In the placebo treated group, eight subjects experienced clinically relevant symptoms: one had gastrointestinal symptoms and oral pruritus and a further three subjects had more severe symptoms, but no further details about the nature of these reactions of these were available. 

Medication use

Nine (47%) of the OIT subjects received antihistamine treatment during initial day escalation and two of these subjects required epinephrine. None of the placebo subjects required treatment during initial day escalation. During build‐up dosing, none of the subjects required medication. No detailed information about other medication use during this phase was given.  During home dosing, one of the children in the placebo group required treatment with epinephrine. During OFC, one of the peanut OIT treated subjects required antihistamines. Three of the placebo group subjects required treatment with epinephrine during OFC. No further details were given about the reason for the use of epinephrine. 

Titrated skin prick test (SPT)

In the peanut OIT group, the titrated SPT size decreased from a median of 7 mm (range: 5.5 to 15 mm) at baseline to 1.75 mm (range: 0 to10 mm) by the time of the OFC, which was performed after four weeks of maintenance therapy. In the placebo group, there was a smaller reduction in the titrated SPT size from 7 mm (range; 5.5 to 13 mm) at baseline to 4 mm (range: 0 to 12.5 mm) at OFC. 

Changes in peanut‐specific IgE

Peanut‐specific IgE was measured at the beginning of the study and then at two, six and nine months and at OFC. The median baseline peanut IgE levels in the peanut OIT and placebo groups were 104 kU/L (range; 31 to 685 kU/L) and 57 kU/L (range; 20 to 188 kU/L), respectively (P = 0.02). After two months, the median peanut‐specific IgE of peanut OIT subjects increased to 308 kU/L (P < 0.01). At OFC, median peanut‐specific IgE was not significantly different from baseline. Placebo subjects showed no changes. 

Changes in peanut‐specific IgG₄

Peanut‐specific IgG₄ significantly increased from baseline at all time‐points in peanut OIT treated subjects, but did not change in placebo subjects (P < 0.001). 

Other immunological changes

Peanut OIT treated subjects had an initial increase in specific‐IgE (P < 0.01), but did not show any significant changes from baseline by the time of the OFC.

Cytokines and T‐cell parameters were measured at baseline, nine months, and at the time of OFC in eight peanut subjects and nine placebo subjects who had cultured peripheral blood mononuclear cells (PBMCs) at these time points. At nine months and OFC, IL‐5 and IL‐13 were significantly decreased from baseline in peanut OIT subjects (P < 0.03). There was a transient increase in TGF‐β levels in peanut OIT subjects at 9 months (P = 0.03), but levels returned to baseline by the time of the OFC. In placebo arm subjects, there was no change in IL‐5, IL‐13 or TGF‐β. There was no significant change found in IL‐10 or IFN‐γ in either peanut OIT or placebo subjects.  

Drop‐outs

Two subjects in the peanut OIT treated arm did not reach the 1.5 mg dose and therefore did not continue the study. During the build‐up phase, one additional peanut OIT subject withdrew from the study after the first dose escalation because of mild gastrointestinal symptoms precluding further up‐dosing.

Other outcomes

No other outcomes specified in the protocol were reported in the included study.

Discussion

Summary of main results

This review identified one small RCT at low risk of bias. This RCT demonstrated that it is possible to induce desensitisation in children treated with allergen‐specific peanut OIT, enabling a substantial increase in the amount of peanut to be safely consumed whilst receiving OIT.  There was a significant increase in threshold dose of peanut allergen tolerated by children after peanut OIT; in the intervention group, the children ingested the maximum cumulative dose of 5000 mg (equivalent to approximately 20 peanuts), whereas in the placebo group the mean amount of peanut allergen ingested was 280 mg (range, 0 to 1900 mg, P < 0.001). Treatment was associated with relevant immune‐modulatory changes suggesting that OIT may have longer‐term benefits, but data were not available on induction of tolerance.  However, adverse events associated with treatment were common and in some cases these reactions were severe, raising important concerns about the safety of the OIT regimen employed in this trial. There is no evidence on the cost‐effectiveness of this treatment approach. Concerns around safety and cost‐effectiveness mean that although OIT for peanut allergy should at present be regarded as a promising line of enquiry, it is not as yet appropriate for incorporating into clinical care.

Overall completeness and applicability of evidence

Although the evidence identified in this review is consistent with that reported in our earlier systematic review of peanut OIT case series (Sheikh 2012), the only rigorous evidence on this subject comes from one small eligible RCT in children (Varshney 2011).  There is therefore at present only limited evidence to inform care provision and, given the concerns about safety, the applicability of this evidence is limited. We found no evidence in relation to the management of adults.

Quality of the evidence

The one included trial was well‐conducted, but it was small and involved children from only two centres (Varshney 2011), limiting its external validity.

Potential biases in the review process

We have undertaken comprehensive searches of a range of data sources.  That said, there remains the possibility that we may have failed to uncover some potentially eligible studies. We are not aware of any other sources of bias in the review process.

Agreements and disagreements with other studies or reviews

The findings from our systematic review are broadly consistent with other reviews on this subject (Fisher 2011; Sheikh 2012), which suggest that whilst desensitisation can be achieved through peanut OIT there is at present no evidence in relation to the induction of tolerance.  In a Phase I trial from the USA (Weldon 2011), 24 subjects aged 5 to 45 years old received 3777 doses of OIT. Twenty‐one out of 24 patients reported reactions; 85 per cent of those were mild and resolved with antihistamines (abdominal pain 28%, oropharyngeal pruritus 27% and lip pruritis 11%) and three reactions were severe and resolved with epinephrine.

Authors' conclusions

Implications for practice.

Peanut OIT represents a promising, potentially disease‐modifying therapeutic approach for the management of IgE‐mediated peanut allergy.  However, currently there is insufficient evidence in terms of long‐term effectiveness, safety and cost‐effectiveness of peanut OIT to recommend its routine use in clinical practice.

Implications for research.

Further research is needed to better establish the effectiveness, safety, and cost‐effectiveness of allergen‐specific peanut OIT.  In particular, future trials need to establish whether clinical and immunologic tolerance can successfully be achieved after OIT is discontinued, and to understand the impact of treatment on the quality of life of patients and relevant family members.  There is also a need to ensure that the full age spectrum of patients affected by peanut allergy is reflected in future trials. The results of on‐going trials will, in the future, shed light on long‐term oral immune tolerance issues in subjects with IgE‐mediated peanut allergy.

Appendices

Appendix 1. Medline search strategy

Nr.	Search term
1	Peanut Hypersensitivity (MESH)
2	Peanut allerg*
3	Peanut‐allergic
4	Arachis hypogaea allergy
5	Food allergy
6	Food hypersen*
7	1 OR 2 OR 3 OR 4 OR 5 OR 6
8	Desensitization, immunologic (MESH)
9	Desensiti*
10	Immunotherapy (MESH)
11	Immunotherapy
12	Oral immunotherapy
13	Oral desensiti*
14	Rush immunotherapy
15	Specific oral tolerance induction
16	8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15
17	Analytical stud*
18	Intervention studies (MESH)
19	Experimental stud*
20	Etiology
21	Trial
22	Clinical trial (MESH)
23	Clinical trial
24	Controlled clinical trial
25	Uncontrolled trial
26	Randomized controlled trial (MESH)
27	Randomi* controlled trial
28	Quasi‐randomi* controlled trial
29	Non‐randomi* trial
30	Placebos (MESH)
31	Random allocation (MESH)
32	Double‐blind method (MESH)
33	Double‐blind design
34	Single‐blind method
35	Random*
36	Controlled before after design
37	Interrupted time series
38	Case series
39	17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29 OR 30 OR 31 OR 32 OR 33 OR 34 OR 35 OR 36 OR 37 OR 38
40	7 AND 16 AND 39

Appendix 2. Other databases search strategy

Search terms for (The Cochrane Library, LILACS, TRIP, CINAHL, ISI Web of Science, BIOSIS, PakMediNet, IndMed, Google Scholar) 1990‐2012

 (peanut allergy or arachis hypogaea or legume* or nut allergy or food hypersensitivity or food allergy) 

AND  

(immunologic, desensiti* or immunotherapy or oral immunotherapy or oral desensiti* or specific oral tolerance induction or oral tolerance induction) 

AND 

(intervention stud* or experimental stud* or trial or clinical trial* or controlled clinical trial or random* or randomi* controlled trial or quasi randomi* or non randomi* or random allocation or single blind method or double blind method or triple blind method)

Appendix 3. PRISMA flow diagram of study selection

Figure 1

1.

PRISMA search flow diagram. Top level does not include searches that returned no results (AMED, PakMediNet, IndMed, LILACS).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Varshney 2011.

Methods	Randomised double‐blind, placebo‐controlled trial Setting: University health centres, USA
Participants	28 children aged 1 to 16 years from local allergy and immunology clinics or surrounding community physician offices (19 intervention, 9 control). Av. age 7 years Inclusion criteria: clinical history of reaction to peanut within 60min of ingestion; peanut CAP‐FEIA >15 kU/L or >7 kU/L if a significant reaction occurred within 6m of enrolment; positive skin prick test Excluded if: history of severe peanut anaphylaxis; moderate to severe persistent asthma; poorly controlled atopic dermatitis; oat allergy; or inability to discontinue antihistamines during OFC or skin testing
Interventions	Oral immunotherapy for approx. 48wks (home dosing/build‐up visits approx. 44wks; maintenance phase approx. 4wks; OFC at wk 48). Active = peanut flour; placebo = oat flour Initial day escalation phase: Day 1: dosing started at 0.1 mg peanut protein or placebo, approx. doubled every 30min until 6 mg reached/subject had symptoms. Day 2: Dosing began at highest tolerated dose during day 1 Home dosing: Children instructed to ingest each dose mixed in a food vehicle daily Dose escalations: Every 2 wks, doses increased 50 ‐ 100% until 75 mg dose, 25‐33% until 400 mg maintenance dose reached Maintenance phase: Ingest 400 mg dose daily for 1m
Outcomes	Double‐blind, placebo controlled OFC (increasing doses of peanut or oat flour every 10 to 20mins up to cumulative dose of 5000 mg); adverse events; peanut‐specific IgE, IgG, and IgG4; secreted cytokine assays and T‐cell analyses in subset of participants.
Notes	Small sample size Participants followed up after wk 48, investigating long‐term immune tolerance (data not yet available)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"A randomization table was generated to assign subjects in a 2:1 ratio to receive peanut flour or placebo"
Allocation concealment (selection bias)	Low risk	"Allocation was performed before enrolment and saved in a locked database accessible only by laboratory personnel to keep clinical staff and subjects unaware of upcoming assignments"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Investigators, subjects, and families remained blind to the assigned intervention as well laboratory studies until completion of the food challenge"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Challenges were administered by a nurse or physician who was also blind to testing materials"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Final data excludes 3 participants from treatment group who were removed from the study before completion due to adverse events.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported

m: month; min: minute; OFC: oral food challenge; OIT: oral immunotherapy; wk(s): week(s)

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Anagnostou 2011	Open trial without a control group
Aruanno 2009	Case reports
Bird 2010	Sublingual immunotherapy (not a study of OIT)
Blumchen 2010	Case series
Buchanan 2006	Case series
Clark 2009	Open trial without a control group
Hofmann 2009	Immunological outcomes only (tolerance and desensitisation not measured)
Jones 2009	Case series
Kim 2011	Sublingual immunothertapy (not a study of OIT)
Mansfield 2006	Case report
Moneret‐Vautrin 2010	Open trial without a control group
Nash 2008	Case series
Thyagarajan 2008	Immunological outcomes only (tolerance and desensitisation not measured)
Wassermann 2010	Case series
Weldon 2011	Safety analysis only (tolerance and desensitisation not measured)

Characteristics of ongoing studies [ordered by study ID]

ACTRN12608000594325.

Trial name or title	Study of the effectiveness of Probiotics and Peanut Oral Immunotherapy (P‐POIT) in inducing desensitisation or tolerance in children with peanut allergy
Methods	Randomized controlled trial
Participants	Approx. 90 children aged 1 to 10 with confirmed diagnosis of peanut allergy and no history of severe anaphylaxis to peanut
Interventions	Intervention: Lactobacillus rhamnosus GG (LGG) + peanut OIT Control: LGG + placebo OIT LGG: 2x10E10 daily for 18m OIT: 18m. Modified rush phase: increasing doses, starting at 0.1 mg peanut protein, doubling every 30min to reach dose of 12 mg of peanut protein. Build‐up phase: daily dose starting at 24 mg, increased every 2wks until dose of 2 g is reached (expected to take 8m). Dose then maintained at 2 g for approx 10m. Same for placebo OIT.
Outcomes	Primary: increase in tolerance by combining peanut OIT with probiotics Secondary: Desensitisation, immunologic changes
Starting date	December 2008
Contact information	A/Prof Mimi Tang: mimi.tang@rch.org.au
Notes	Expected completion date not specified

NCT00598039.

Trial name or title	Oral Peanut Immunotherapy for Peanut Allergic Patients
Methods	Safety/efficacy study, open label, no control group
Participants	Approx. 40 subjects 1 to 16 years old with diagnosed peanut allergy. Subjects with history of severe anaphylaxis to peanut excluded.
Interventions	Peanut OIT (open intervention), no further details provided
Outcomes	Primary: Double‐blind, placebo controlled OFC and second food challenge 1m after being off of peanut Secondary: IgE to peanut decrease below a level of 2
Starting date	March 2003
Contact information	Contact information not provided. PI: Wesley Burks, MD, Duke University
Notes	Est. study completion date July 2012

NCT00815035.

Trial name or title	Oral Immunotherapy for Peanut Allergy
Methods	Randomized, double‐blind, crossover safety/efficacy study
Participants	Approx. 60 participants aged 1 to 6 years with presence of peanut‐specific IgE and history of significant clinical symptoms occurring within 60mins of ingesting peanuts. Participants excluded if they have history of severe anaphylaxis to peanut.
Interventions	Intervention: Peanut OIT Control 1: Placebo OIT Control 2: No treatment Peanut OIT and placebo: modified rush immunotherapy on day 1 followed by daily dose with increase in dose at least every 2 wks up to maintenance dose of 4 g.
Outcomes	Primary: lower risk of anaphylactic reactions, long‐term tolerance Secondary: molecular level effect on humoral activity/response
Starting date	June 2009
Contact information	Contact information not provided. PI: Wesley Burks, MD, Duke University
Notes	Est. completion date Nov 2013

NCT00932282.

Trial name or title	Peanut Oral Immunotherapy and Anti‐IgE for Peanut Allergy
Methods	Randomized, open label safety/efficacy study
Participants	Approx. 10 subjects aged 12 or older with peanut‐specific IgE and history of clinical symptoms occurring within 60mins of peanut ingestion. Participants with history of severe anaphylaxis to peanut not included.
Interventions	Peanut OIT + omalizumab (anti‐IgE): 12m vs 24m maintenance therapy. 4m omalizumab treatment before peanut OIT, omalizumab continued until 1m post maintenance therapy. Initial desensitization phase over 2d to goal of 950 mg peanut powder followed by build up phase over 4m to goal maintenance dose of 8000 mg peanut powder.
Outcomes	Primary: Tolerate a dose of 20gm peanut flour during OFC Secondary: Incidence of adverse events during initial escalation and build up phase
Starting date	July 2009
Contact information	jane.hainline@duke.edu; alison.edie@duke.edu
Notes	Est. completion date July 2014

NCT01084174.

Trial name or title	A Randomized, Double‐Blind, Placebo‐Controlled Pilot Study of Sublingual/Oral Immunotherapy for the Treatment of Peanut Allergy
Methods	Randomized, double‐blind, parallel assignment safety/efficacy study
Participants	30 subjects aged 6 to 21 with clinical history of peanut allergy, confirmed by peanut specific IgE and skin prick test.
Interventions	Active sublingual immunotherapy (SLIT) for peanut allergy + placebo peanut OIT vs active peanut OIT + placebo SLIT SLIT and OIT dose increases for 16wks, then daily maintenance dose for 12m.
Outcomes	Primary: 10 fold increase in tolerance Secondary: Adverse events,  changes in clinical and mechanistic endpoints, peanut tolerance
Starting date	March 2010
Contact information	Contact information not provided, PI: Robert Wood, MD, Johns Hopkins University
Notes	Est. completion date Jan 2012

NCT01259804.

Trial name or title	Efficacy and Safety of High‐dose Peanut Oral Immunotherapy With Factors Predicting Outcome
Methods	Open pilot study, no control group
Participants	22 children with peanut allergy aged 7‐17
Interventions	Peanut OIT: gradual updosing with every 2 wks (8‐38wks) to 800 mg protein (5 peanuts/day); then 30wks maintenance
Outcomes	Primary: Pass/fail peanut challenge No secondary outcomes listed
Starting date	Jan 2008
Contact information	Contact information not provided. PI: Andrew T. Clark, Cambridge Biomedical Campus, University of Cambridge
Notes	Est. completion date Jan 2012

NCT01274429.

Trial name or title	Peanut Oral Immunotherapy (OIT) ‐ Initial Pilot Study in Adults
Methods	Open label, no control group
Participants	Approx. 20 adults aged 18 to 50 with diagnosis of peanut allergy or clinical history of peanut allergy, positive SPT, and peanut‐specific IgE. Subjects with severe anaphylaxis to peanut excluded.
Interventions	Peanut OIT (no control). Begins with modified rush (0.1 mg of peanut protein, dose doubled every 30min up to 6 mg peanut protein). Dose given daily, escalation visits every 2wks. Maintenance phase starts at 2300 mg, taken daily.
Outcomes	Primary: lower risk of anaphylactic reactions in adults, long‐term tolerance Secondary: molecular level effect on humoral activity/response in adults
Starting date	Dec 2010
Contact information	jane.hainline@duke.edu; alison.edie@duke.edu
Notes	Est. completion date Sept 2014

NCT01324401.

Trial name or title	Oral Peanut Immunotherapy
Methods	Randomized, open‐label, parallel‐assignment safety/efficacy study of clinical symptoms after ingestion of peanuts
Participants	32 subjects 7 to 12 years old with diagnosis of peanut allergy via skin prick test and history. Excludes participants with history of severe anaphylactic reaction to peanut requiring treatment with 2+ administrations of epinephrine or hospitalisation.
Interventions	Intervention: Peanut OIT, daily escalating dosages as determined in modified rush phase, escalated until daily dose of 4000 mg is reached Control: No treatment
Outcomes	Primary: tolerance Secondary: desensitisation; adverse events
Starting date	March 2011
Contact information	abrennan3@partners.org; skubala@partners.org
Notes	Est. completion date August 2012

OIT: oral immunotherapy; m: month; min: minutes; wk(s): week(s)

Differences between protocol and review

In the protocol, we implied but did not clearly specify that this review was focused on studying allergen‐specific OIT; the title and background have now been revised to better reflect the focus of this work. We have removed a reference from the protocol (Li 2001).

Contributions of authors

UN developed the protocol, undertook searches, study selection, critical appraisal and drafting the review. IV developed the protocol, undertook searches, study selection, critical appraisal and commented on drafts of the review. GD helped with the design of the review protocol and commented on drafts of the final review. FER helped with the drafting the review protocol and commented on drafts of the review manuscript. AS conceived this review, oversaw all aspects of the development of the protocol and the conducting of the review and commented on drafts of this review.

Sources of support

Internal sources

• No sources of support supplied

External sources

• Chief Scientist's Office of the Scottish Government, UK.

Declarations of interest

None known.

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