Derek Chu, MD, PhD, on Whether the Risks of Peanut Oral Immunotherapy Outweigh the Benefits
Although avoidance is recommended as standard-of-care for peanut allergy, experimental therapies like peanut oral immunotherapy (OIT) have emerged with the aim of desensitization in the event of trace exposure to peanuts and alleviation of patient anxieties that can accompany the vigilance required to avoid their allergen.
Despite the recent buzz around peanut OIT, a new study published in The Lancet has shown that current forms of this experimental therapy may not be a risk-free option compared with avoidance.1 In the PACE study, Derek K. Chu, MD, PhD, from McMaster University in Ontario, Canada, and colleagues found that peanut OIT was associated with increased risk and frequency of anaphylaxis, increased epinephrine use, and increased risk of serious adverse events and non-anaphylactic reactions compared with placebo or avoidance.1
Consultant360 spoke with Dr Chu about the clinical significance of these findings.
Consultant360: What compelled you to study the safety of peanut OIT?
Dr Chu: Within the past decade or so, there has been a very strong interest in OIT as a potential treatment for peanut allergy. The principle aim of peanut OIT is to decrease the incidence of allergic and anaphylactic reactions in those with this allergy. These reactions can often come from accidental exposures, which has an incidence of about 7% in some reasonably well-conducted observational studies of patients with peanut allergy.2,3
There are a number of considerations with peanut OIT that help put the PACE study into context. First, this therapy is experimental, and there is no licensed OIT product anywhere in the world. Second, there has been conflicting and confusing information about precisely what OIT can and cannot do, what its indications are, and exactly what the outcomes are. This is important because observational studies are often mixed together with randomized controlled trials (RCTs) when describing benefits and harms of OIT, so it is not always apparent to patients, providers, policy makers, or even funders what exactly the harms and benefits are in this field. We sought to clarify the evidence on the efficacy and safety of peanut OIT. It is established in the field of medicine that well-done RCTs provide the most trustworthy information on the efficacy and safety of any given therapy.
In the PACE study, we systematically reviewed all available RCTs that have been conducted around the world, including unpublished trials, and we meta-analyzed close to 1100 participants who were randomly assigned to peanut OIT vs either placebo or avoidance. On average, patients were aged 5 to 12 years, but a number were younger or older. In combination, these data show that peanut OITs can often cause partial desensitization to peanut in a controlled clinical setting, but the level of protection fluctuates and is incomplete. Further, patients on OIT had a higher risk of anaphylactic and allergic events in real-world settings compared with avoidance.
C360: Can the data from your study definitively say that the harms of peanut OIT outweigh the benefits?
Dr Chu: There has been strong anecdotal evidence in both camps in favor of and against peanut OIT. Hence, anecdote alone should not inform decision-making. The PACE study shows with high-quality evidence that the risk for anaphylaxis is approximately 23% for peanut OIT compared with 7% for avoidance.1 To put this into context, the anaphylaxis rate of 23% for peanut OIT is significantly higher than that of immunotherapy for other conditions, such as subcutaneous aeroallergen immunotherapy for asthma or allergic rhinitis, which is typically in the range of 1% to 7%.4 Likewise, the rate of anaphylaxis during subcutaneous venom immunotherapy is approximately 2.5% for wasps.5
On the other hand, our study shows that the rate of passing an in-office supervised food challenge is approximately 4% to 7% in the avoidance group compared with approximately 40% to 50% in those that underwent peanut OIT.1 No patient was cured in the included studies. No patient died either, but life-threatening serious adverse events were approximately doubled among those on peanut OIT compared with those on avoidance.
Ultimately, I think the risk/benefit ratio for OIT might depend on how one measures success. One perspective is that measures of success can be impacted by surrogate endpoints, or proxies for patient outcomes. Interventions such as hormone replacement therapy for post-menopausal cardiovascular protection, activated protein C for sepsis, or intensive glucose control in the critically ill or for diabetes, among others, have all shown that placing too much focus on the surrogate endpoints can be misleading and potentially dangerous.
Regarding peanut OIT, some providers and patients may hold the view that the most important outcome is minimizing allergic and anaphylactic reactions as much as possible. If this is the case, then those providers and patients should favor allergen avoidance over the experimental forms of OIT that are present today due to the elevated risks of allergic and anaphylactic reactions associated with OIT. However, there may be other individuals who view the possibility of taking a peanut dose everyday – even if it means variable protection that could end up unpredictably harming them by causing a reaction – as more important than the risk of having more numerous allergic and anaphylactic reactions. The PACE study very clearly illuminates the critical need to have a comprehensive assessment of patients’ values, preferences, and desired outcomes across the full spectrum of patient perspectives.
It is important to note that we do not know who is most likely to benefit from or be harmed by peanut OIT. In the approximately 10 subgroups we analyzed in the PACE study, we did not find any evidence of effect modification by age, severity of previous disease, sex, allergen sensitivity (ie. the threshold to elicit allergic symptoms), the dose used in the protocol, any number of different permutations of protocol, or whether patients were being built up or on maintenance dosing. The only factor that was useful in discriminating those who completed the entire peanut OIT procedure without adverse events were those who did not have their peanut allergy status confirmed upon study entry. We found that up to 40% of patients recruited into OIT studies, despite having a compelling clinical and/or testing history, did not actually have a peanut allergy when they had their allergy status checked during screening with a food challenge. Indeed, about 20% to 30% of patients with a peanut allergy diagnosis will outgrow it. Hence, it is very critical to have the precise diagnosis when considering peanut OIT.
For the future, we need to determine who are the best and worst candidates for peanut OIT and find other ways to improve its efficacy and safety, if it is to be offered routinely. Overall, the current message is that a number of people may be able to be desensitized, but just because it can be done does not mean it should be done en masse. For many individuals, current forms of peanut OIT may be riskier than avoidance.
C360: Quality of life is an important aspect of managing food allergy, especially since food allergy can be accompanied by significant anxieties. What was quality of life like for participants on OIT?
Dr Chu: Three RCTs included in our systematic review reported quality of life. Within those 3 RCTs, quality of life on OIT was no better than with placebo or avoidance. On OIT, patients were not permitted to eat peanut freely. Patients were actually given the exact same instructions as those who were practicing avoidance: they could not eat peanut outside of the study medication, and they had to carry their epinephrine auto-injector at all times. They had to practice the same level of vigilance as those on avoidance.
Patients on OIT also had a number of additional physical restrictions. They could not consume peanut within 2 to 4 hours of exercising or taking a hot shower or bath. Patients could have reacted to previously tolerated doses during menses and may have had to decrease their dose if they were menstruating in order to avoid a reaction. Similarly, they could react to previously tolerated doses if they had an infection or fever, if they felt tired that day, or if they consumed peanut on an empty stomach. Because protection from peanut OIT can fluctuate and is incomplete, there is concern that OIT could lead to a false sense of security.
Furthermore, there was an unpredictability aspect as to which dose would lead to an allergic reaction. For example, the cases described in the manuscripts we reviewed included that of a patient taking a dose of peanut one day and being protected but exercising the next day and having an allergic reaction. There are still many more questions to answer, and most importantly, patients need and deserve proven therapies that translate into improved patient-centered outcomes.
C360: How might clinicians translate the findings from your study into practice?
Dr Chu: The implications for current practice are very important because surveys regarding OIT have been conducted primarily in the United States, indicating that a minority of practitioners perform OIT due to safety concerns and the lack of a standardized or approved drug. Current guidelines around the world also do not recommend peanut OIT as a standard-of-care approach. In fact, avoidance is currently recommended as standard-of-care for peanut allergy. There could be room for significant improvement in avoidance, as well as the potential for new peanut allergy treatments.
For a number of practitioners, the data presented in the PACE study may inform their decisions regarding whether to conduct current forms of this experimental procedure. More importantly, however, are 2 points.
First, deliver sound, evidence-based advice to your patients. Having the best information available through a systematic review is critical (an online, interactive summary of our findings is available here), and all evidence in this systematic review should be interpreted in terms of patient values and preferences. If a patient wants to go forward with peanut OIT after a thorough discussion about the current experimental nature of this therapy, the existing state of the evidence, and its practical implications, I would strongly advise that practitioners recommend patients to join an RCT. It has been consistently shown that patients enrolled in a clinical trial will fare better than those receiving experimental therapy outside of a clinical trial, partly due to increased monitoring and the rigorous standards of conducting an RCT. It also removes the potential for conflict of interest and cost. Additionally, contributing to an RCT not only benefits the patient, but it will also help inform future therapies for the millions of people around the world with peanut allergy.
Second, if a claim for a successful peanut allergy treatment is made, I strongly encourage all stakeholders to demand that such claims are proven to the high standards of medicine through large, rigorous RCTs. The unfortunate reality is that there is some predatory behavior out there targeting patients seeking new food allergy management options. Bold claims should be backed up by rigorous evidence. After all, if a fool-proof and highly-effective peanut allergy exists, it should then be easily and transparently provable to the high standards of medicine in large, well-done RCTs. It is imperative that we get new treatments for food allergy right instead of rushing them.
Derek Chu, MD, PhD, is a Royal College of Physicians and Surgeons of Canada-certified Internal Medicine Specialist, PGY5 Fellow in Clinical Immunology and Allergy in the Department of Medicine at McMaster University in Hamilton, Ontario, Canada, EAACI Research Methodology Board member, and AAAAI Anaphylaxis and Food Allergy committees member.
1. Chu DK, Wood RA, French S, et al. Oral immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and safety [Published online April 25, 2019]. Lancet. https://doi.org/10.1016/S0140-6736(19)30420-9.
2. Vander Leek TK, Liu AH, Stefanski K, Blacker B, Bock SA. The natural history of peanut allergy in young children and its association with serum peanut-specific IgE. J Pediatr. 2000; 137(6):749-55. https://doi.org/10.1067/mpd.2000.109376.
3. Cherkaoui S, Ben-Shoshan M, Alizadehfar R, et al. Accidental exposures to peanut in a large cohort of Canadian children with peanut allergy. Clin Transl Allergy. 2015;5:16. https://doi.org/10.1186/s13601-015-0055-x.
4. Durham SR, Penagos M. Sublingual or subcutaneous immunotherapy for allergic rhinitis? J Allergy Clin Immunol. 2016; 137(2):339-49.e10. https://doi.org/10.1016/j.jaci.2015.12.1298.
5. Golden DBK, Demain J, Freeman T, et al. Stinging insect hypersensitivity. Ann Allergy Asthma Immunol. 2017;118(1):28-54. https://doi.org/10.1016/j.anai.2016.10.031.