Probiotics for the Treatment of Peanut Allergies

Probiotics for the treatment of peanut allergy

The original study paper by Tang et al 2015 examines probiotic with peanut oral immunotherapy (PPOIT) for management of peanut allergy and was carried out in Australia.  The results from this can potentially be used to apply to the UK population.  The allocation of 62 patients is randomised and they were blinded to either receive the treatment or placebo.  Interestingly some of the patients underwent an open peanut challenge at entry to the study and it would have been helpful to compare if at the end of the treatment weather these patients were tolerating more, less or equal amount of peanut protein than at the beginning.  Authors have accounted for all participants and used sample power calculations to detect a difference.  The outcome assessors were also blinded.  The problem with this study design is it compares PPOIT against placebo whereas ideally, they should also be comparing PPOIT against peanut oral immunotherapy separately and even probiotic as another treatment arm to detect if combining therapies provides additional benefit.  I think it is not possible to conclude PPOIT is effective at inducing sustained unresponsiveness in 82.1% as it could have been achieved by the therapies separately.  Although the results were statistically significant, they are not precise given the wide confidence intervals for relative risk ratio.  In addition, sustained unresponsiveness which is the body’s ability to tolerate an allergen after treatment has stopped needs to be assessed at longer intervals and not just 2 weeks.  Conflicts of interest in this trial include involvement with the companies Danone and Nestle of which the latter company actually supplied the probiotic in the trial.

The second study by the same group (Hsiao et al 2017) attempts to address the longer-term outcomes at 4 years from the original study by Tang et al 2015.   They managed to enrol 86% of eligible participants but this results in an even smaller sample size.  They have detailed reasons into what happened to the other 14%.  However, the authors have not justified the timings as to why outcomes were measured after 4 years and why the food challenge was performed after 8-week elimination.  It could be argued that a longer period of elimination is needed to assess true sustained unresponsiveness.  The peanut intake and quality of life questionnaires were conducted by allergy nurses and unblinded potentially introducing bias.  The results are not reported in this paper.  There was a difference in skin prick test wheal size between the PPOIT treated and placebo group but it is difficult to translate this to clinical significance (Allergic Living 2017).  More importantly Hsiao et al 2017 report similar number of patients having allergic reactions between the placebo and treatment groups (6 vs 4 respectively).  In addition, it would have been useful to include details of the 2 patients in the PPOIT group and the 4 patients in the placebo group who experienced anaphylaxis during the food challenge requiring intramuscular adrenaline.  Anaphylaxis can be life-threatening and it is important to detail the reasons as to why these patients have experienced this as this can be deemed an unacceptable risk of treatment.   It would be interesting to look into more detail at the patients in the placebo group that had anaphylaxis.  Did they experience a true anaphylactic reaction and were most of the symptoms experienced subjective rather than objective?  I think it is also difficult to conclude that PPOIT induces long term sustained unresponsiveness after 4 years as although these patients were advised to have peanut in their diet freely, of the PPOIT group that were eating peanut 75% were eating more than 2g of peanut protein.  This could be continued desensitisation as they are having regular exposure to the allergen.  I would argue that data for sustained unresponsiveness can only be analysed after the 8-week elimination of peanut followed by food challenge.  If we look at this data only 50% took part and of those only 7 patients achieved sustained unresponsiveness.  This is a low number and difficult to extrapolate to a larger population.  It is clear that further larger multicentre studies with multiple treatment arms are needed before we can apply this to clinical practice.  Also, longer term sustained unresponsiveness needs to be assessed and not just at 8 weeks.

Other literature regarding probiotics in allergy

Currently, the mainstay of treatment for food allergy involves dietary avoidance and symptomatic treatment.  Apart from immunotherapy, other new treatment directions for allergy include biologicals like Omalizumab and probiotics.  The food and agriculture organisation (FAO) and world health organisation (WHO) 2002 p.8 define probiotics as ‘live microorganisms which when administered in adequate amounts confer a health benefit on the host’.  The theory is that by restoring the gut microbiome which has a complex role in the immune system, the allergic response is redirected towards sustained unresponsiveness and eventually tolerance (Castellazi 2013).

Probiotics have been studied for the prevention of allergy as well as treatment.  The EAACI (European Academy of Allergy and Clinical Immunology) guidelines by Muraro et al 2014 found insufficient evidence to recommend probiotics antenatally, postnatally while breastfeeding or as a supplement in infancy.   A more recent systematic review and meta-analysis by Zhang et al 2016 p.1 reported ‘probiotics administered prenatally and postnatally could reduce the risk of food hypersensitivity’.  Looking at the forest plot of the 9 trials that looked at food sensitisation, they all have confidence intervals crossing 1 for risk ratio which would mean no significant effect.  However once pooled together a difference is detected.  Evaluating the different food allergens that were skin prick tested or had specific IgE would have provided interesting results.  This was a secondary outcome measure in this review and as food sensitisation does not always mean food allergy more studies are needed in this field looking at the use of blinded food challenges as an outcome measure of confirming food allergy.

Looking at the research on probiotics in allergy treatment besides the studies discussed, there are no other trials looking at peanut allergy and probiotics as a treatment.  Cow’s milk allergy and probiotics has been researched more extensively.   A meta-analysis by Tan-Lim et al 2018 found probiotics could improve symptoms in cow’s milk allergy but only a scoring index for eczema was used rather than a validated food allergy questionnaire.  Other allergic symptoms were not pooled so again enough robust evidence is not provided for effect.  The secondary outcome measure was tolerance but there was no adjustment for the natural resolution of this type of allergy so may not be the acquisition of tolerance.  In clinical practice we do on occasion recommend probiotics to parents whose infants have cow’s milk allergy and eczema and are struggling with eczema control despite good cream management or as a preventative measure antenatally/postnatally to mothers in infants with a high risk of eczema.  The safety profile of probiotics is good and is one of its main attractions for its use clinically.  However, there are a wide variety of commercially available products not subject to the same regulations as medicinal products and reports of bacteraemia in susceptible populations (Wang et al 2019).  Therefore without further evidence they should be used cautiously and not routinely.

Application in clinical practice

The first essential part of deciding whether an allergy to a particular food has occurred is to take a good history.  Amelie has not been seen in clinic for several years and it would be worth going through the symptoms she developed following ingestion of peanut.  Specifically, we need to look at time of onset, symptoms, duration and treatment given.  The circumstances surrounding the event for example season, location or was she unwell at the time.  We need to clarify previous history of food allergy or atopy.  Is her asthma well controlled on her current medication? It would be worth looking at a dietary history from birth and family history.  Is she ingesting other nuts with no reaction?  Once a thorough history is taken we can decide whether this is likely IgE mediated or non IgE mediated allergy.  Certainly, from the limited history this could be IgE mediated.  However, as there are only respiratory symptoms mentioned its worth thinking about whether this could have been an asthma exacerbation rather than peanut allergy.  The two conditions can co-exist and it would be important to ensure good asthma control as uncontrolled asthma and food allergy lead to a higher risk of fatal anaphylaxis (Wang 2011).

Secondly if IgE mediated peanut allergy is suspected we need to look at Amelie’s previous investigations if any.  Skin prick tests or specific IgE component testing to peanut can help guide management.  If results were negative then it would be worth considering a hospital challenge to peanut as she may have outgrown her allergy although it is known that this is less likely with peanut allergy.  If investigations confirmed ongoing allergy the advice would be continual avoidance along with an allergy action plan and adrenaline autoinjector training.  Once this has been done, we can start to address the question Amelie’s mother is posing about probiotics.

There is no data looking at probiotics alone as a treatment for food allergy.  Rather, it is used in conjunction with immunotherapy to help desensitise children.  This would involve the child taking regular amounts of the allergen to maintain desensitisation.  There is not enough long-term data looking at sustained unresponsiveness where children would be safe to consume peanuts on an adhoc basis without reaction.  I would advise that currently oral immunotherapy for peanut allergy is not available on the NHS and the benefits of probiotics in allergy is still being investigated.  Certainly there are trials which show benefits of peanut immunotherapy in reducing symptom severity (PALISADE 2018).  I would explain the results of the PPOIT trial show promise but that the added benefit of probiotics is still unknown as this was not investigated in the study.  Possibly the effect could have been attributed to oral immunotherapy alone.  It is possible these therapies will be recommended in the future following more research.

References

• Allergic Living (2017) Reality Check: The facts beyond the hype over peanut allergy and probiotics.  Available at: https://www.allergicliving.com/2017/08/25/reality-check-the-facts-beyond-the-hype-over-peanut-allergy-and-probiotics/ (Accessed 23^rd August 2019).
• Castellazi AM, Valsecchi C, Caimmi S, Licari A, Marseglia A, Leoni MC, Caimmi D, Giudice MMD, Leonardi S, Rosa ML, Marseglia DL. (2013) ‘Probiotics and food allergy’, Ital J pediatr, 39, pp.47.  https://doi.org/10.1186/1824-7288-39-47.
• Critical Appraisal Skills Programme (2018).  CASP Randomised Controlled Trial Checklist.  Available at: http://casp-uk.net/wp-content/uploads/2018/01/CASP-Randomised-Controlled-Trial-Checklist-2018.pdf (Accessed 23rd August 2019).
• Food and Agriculture Organisation, World Health Organisation (2002).  Guidelines for the evaluation of probiotics in food.  In: Report of a joint FAO/WHO working group on drafting guidelines for the evaluation of probiotics in food.  Available at: http://www.who.int/foodsafety/fs_management/en/probiotic_guidelines.pdf (Accessed 23rd August 2019).
• Hsiao K-C, Ponsonby A-L, Axelrad C, Pitkin S, Tang MLK. (2017) ‘Long-term clinical and immunological effects of probiotic and peanut oral immunotherapy after treatment cessation: 4-year follow-up of a randomised, double-blind, placebo-controlled trial’, The Lancet Child & Adolescent Health, 1(2), pp. 97-105.
• Muraro A, Halken S, Arshad SH, Beyer K, Dubois AE, Du Toit G, Eigenmann PA, Grimshaw KE, Hoest A, Lack G, O’Mahony L, Papadopoulos NG, Panesar S, Prescott S, Roberts G, De Silva D, Venter C, Verhasselt V, Akdis AC, Sheikh A. (2014) ‘EAACI Food Allergy and Anaphylaxis Guidelines. Primary prevention of food allergy’, Allergy, 69, pp.590-601.
• PALISADE Group of Clinical Investigators.  (2018) ‘AR101 oral immunotherapy for peanut allergy’, N Engl J Med, 379(21), pp.1991-2001.
• Tang ML, Ponsonby AL, Orsini F, Tey D, Robinson M, Su EL, Licciardi P, Burks W, Donath S. (2015) ‘Administration of a probiotic with peanut oral immunotherapy: a randomized trial’, J Allergy Clin Immunol, 135, pp. 737-744.
• Tan-Lim CSC, Esteban-Ipac NAR. (2018) ‘Probiotics as treatment for food allergies among pediatric patients: a meta-analysis’, World Allergy Organization Journal, 11, 25. https://doi.org/10.1186/s40413-018-0204-5.
• Wang HT, Anvari S, Anagnostou K. (2019) ‘The role of probiotics in preventing allergic disease’, Children, 6, 24.  https://doi.org/10.3390/children6020024.
• Wang J, Liu AH.  (2011) ‘Food allergies and asthma’, Curr Opin Allergy Clin Immunol, 11(3), pp.249-254.
• Zhang GQ, Hu HJ, Liu CY, Zhang Q, Shakya S, Li ZY. (2016) ‘Probiotics for prevention of atopy and food hypersensitivity in early childhood’, Medicine, 95(8), pp.1-10. doi: 10.1097/MD.0000000000002562.