Peanut Allergy: Is Oral Immunotherapy With Probiotic a Cure?

Diana Swift

August 24, 2017

Australian researchers may have taken the treatment of peanut allergies in children a step closer to long-term tolerance and control, results of a small follow-up study suggest.

Four years after treatment stopped, 70% of patients who were desensitized via 18 months of treatment with combined probiotic and peanut oral immunotherapy (PPOIT) in a randomized controlled trial remain unresponsive to peanut protein despite no intervening therapy. The findings were reported in an article published online August 15 in the Lancet Child & Adolescent Health.

"[O]ur results suggest that PPOIT is effective at inducing long-term sustained unresponsiveness that persists for up to 4 years after completing treatment and is safe," write pediatric immunologist Kuang-Chih Hsiao, MBChB, from Murdoch Childrens Research Institute in Melbourne, Victoria, Australia, and colleagues. "Furthermore, the finding that sustained unresponsiveness was maintained without the need to follow a regular prespecified ingestion schedule provides a compelling argument that PPOIT-induced immune tolerance."

Dr Hsiao and coauthors note that although children frequently outgrow allergies to egg, milk, wheat, and soy, nut and seafood allergies often persist into adulthood, with substantial detriment to quality of life.

The participants in the newly reported follow-up study were initially treated in a randomized trial completed in 2013. In that trial, 62 children, approximately 12 years of age, were randomly assigned to receive large doses of the probiotic Lactobacillus rhamnosus plus 2 g peanut protein (PPOIT) or placebo once daily for 18 months.

L rhamnosus was chosen for its ability to induce regulatory T cells, antigen-specific immunoglobulin A (IgA), and regulatory and T helper 1 cytokine responses.

The researchers hypothesized that combining this probiotic with oral immunotherapy "would support redirection of the peanut-specific allergic response towards tolerance by providing a tolerogenic milieu at the time of antigen uptake and processing by antigen-presenting cells."

As reported by Medscape Medical News at the time, 82.1% of participants in the PPOIT group passed a double-blind, placebo-controlled food challenge at the end of treatment and were told they could eat peanut freely. In contrast, just 3.6% of those in the placebo group passed the challenge (P <.001).

Among those who completed the initial study, 48 agreed to participate in the follow-up study. At a mean of 4.2 years after treatment, 16 of 24 participants in the PPOIT group reported continuing to eat peanuts vs one of 24 in the placebo group (P = .001).

Moreover, participants in the PPOIT group were significantly less likely to report having had an allergic reaction in the time since treatment compared with those in the placebo group (17% vs 25%). However, the overall number of reactions was higher among those in the active therapy group vs placebo (11 vs 9); all those in the PPOIT group occurred after intentional consumption, and all those in the placebo group were after accidental ingestion.

The authors note that all the reactions were minor, with no anaphylaxis or adrenaline treatment required in either treatment group. The mild reactions among those intentionally eating peanuts suggest "that those who achieved PPOIT-induced sustained unresponsiveness can safely continue peanut ingestion," the authors write.

Other data also point to sustained protection from PPOIT. At baseline in the randomized trial, mean wheal size after a skin prick test was the same in the two groups, at 16.9 mm. In the follow-up study, mean wheal size was significantly smaller among those in the PPOIT group, at 8.1 vs 13.3 mm in the placebo group.

Participants in the PPOIT group also had significantly higher peanut-specific IgG4:IgE ratios compared with those in the placebo group, suggesting an attenuated immune response (geometric mean, 67.3 vs 5.2; P = .031).

Finally, most of the participants in the follow-up study consented to a double-blind, placebo-controlled food challenge after 8 weeks of avoiding peanuts. In the PPOIT group, 7 (58%) of 12 patients remained unresponsive compared with one (7%) of 15 patients in the placebo group (P = .012).

"This study is the first demonstration of such prolonged sustained unresponsiveness with any form of peanut oral immunotherapy, and the best data so far showing long-term efficacy of oral immunotherapy for any food allergen," writes pediatric allergist/immunologist Matthew J. Greenhawt, MD, from Children's Hospital Colorado in Aurora, Colorado, in an accompanying editorial comment.

"The therapeutic effect shown is remarkable and redefines the notion of sustained unresponsiveness," he continues. "The broader context of what these findings potentially represent is a demonstration of true tolerance, whereby patients could mimic the eating habits of non-allergic individuals."

He notes that peanut allergy affects 1% to 5% of children, and although oral immunotherapy can safely desensitize most of these in the short term, very few achieve sustained unresponsiveness, and few data are available on the long-term outcomes of oral immunotherapy.

Although noting that the current study is small, from a single center, and did not include a baseline food challenge before treatment, Dr Greenhawt writes, "Successful replication of these data could lead to broader questions of generalisability of the probiotic plus oral immunotherapy approach to other allergens and possible abandonment of oral immunotherapy without probiotic coadministration."

To that end, Australian researchers have launched a three-arm multicenter randomized controlled trial to compare PPOIT vs oral immunotherapy vs placebo to confirm whether adding a probiotic component yields greater benefit than oral immunotherapy alone. And in a future study, the Murdoch Center investigators will analyze the microbial composition of stool samples for potential effects of PPOIT therapy on the intestinal microbiome, an increasingly important focus of the study of immune response.

According to a news article from the Murdoch Childrens Research Center, the capital investment firm OneVentures has provided funding to establish a joint biotech company, Prota Therapeutics, to develop PPOIT into a product approved by the US Food and Drug Administration.

The follow-up study was funded by the Murdoch Childrens Research Institute and the Australian Food Allergy Foundation. Study senior author Dr Tang has reported financial ties to private sector organizations such as Nestlé, the Nutrition Institute, Danone Nutricia, GLG Consulting, Deerfield Consulting, Bayer, Prota Therapeutics, and Wiley. She also holds a patent on a method for inducing tolerance. The remaining authors have disclosed no relevant financial relationships. Dr Greenhawt has reported ties to Aimmune Therapeutics, Danone Nutricia, Kaleo Pharmaceuticals, Nestlé, and Monsanto, as well as to the National Peanut Board.

Lancet Child Adolesc Health. Published online August 15, 2017. Article abstract, Editorial extract

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