Use of Biologics in Severe Food Allergies

Alessandro Fiocchi; Valentina Pecora; Rocco L. Valluzzi; Vincenzo Fierro; Maurizio Mennini


Curr Opin Allergy Clin Immunol. 2017;17(3):232-238. 

In This Article

Abstract and Introduction


Purpose of review: Severe cases of food allergy account for the majority of the burden in terms of risks, quality of life, and resource expenditure. The traditional approach to these forms has been strict avoidance. More recently, Oral ImmunoTherapy (OIT) has gained a role in their management. However, in severe food allergies OIT is often infeasible.

Recent findings: Case reports, observational, and prospective studies have recently proposed different approaches to severe food allergy. The majority of them include the use of biologics. Omalizumab has been the most studied drug for severe food allergies, and its role as adjuvant treatment to OIT is well established. Interest has been raised on other biologics, as dupilumab, reslizumab, and mepolizumab. Toll-like receptor agonists, and gene therapy using adeno-associated virus coding for Omalizumab are promising alternatives.

Summary: The recent studies are deeply influencing the clinical practice. We review the modifications of the clinical approach to severe food allergies so far available. We indicate the possible evolutions of treatment with biologics in severe food allergies.


Definitions of allergy are very clear,[1] but the scoring of their severity varies across the allergic manifestations. For rhinitis, the severity assessment relies mainly on symptom scores, visual analogue scales (VAS), and quality of life (QoL), but objective measures as measurements of nasal obstruction, measurements of inflammation, reactivity measurements, and measurements of the sense of smell are available.[2] Asthma severity is indicated by the level of treatment required to control symptoms and exacerbations. Patients with asthma requiring Step 4 or 5 treatment, e.g. high-dose ICS/LABA, to prevent it from becoming 'uncontrolled', or asthma that remains 'uncontrolled' despite these treatments, are considered severe.[3] Rhinitis and asthma definitions of severity are not static features and may change over months or years. In asthma, a clear difference has been established among patients with 'difficult to treat asthma' and the truly severe conditions. Patients with inadequate or inappropriate treatment, lack of adherence, comorbidities such as chronic rhinosinusitis or obesity, have not a severe form, but a 'difficult to treat' asthma. The definition of severe asthma should be reserved for patients with refractory asthma and those in whom response to treatment of comorbidities is incomplete.[4] 'Severe' is often also used to describe the intensity of asthma symptoms, the magnitude of airflow limitation, or the nature of an exacerbation.

A similar classification has not be adopted in food allergy, where a shared definition of severity does not exist. The U.S. NIAID guidelines allude in many points to the severity of gastrointestinal, dermatological, respiratory manifestations, and in particular to the severity of immediate anaphylactic reactions. It is stated that 'no tests are available to predict severity of IgE-mediated reactions'. It is reported that food allergy is associated with severe asthma.[5] However, the severity of food allergy in general is not defined. Similar considerations apply to the EAACI food allergy guidelines.[6]

One of the difficulties in defining severe food allergy is that this conditions has many faces, and severity should be indicated for each of them. For instance, every anaphylactic reaction is a severe event by definition ('a serious, life-threatening, generalized hypersensitivity reaction' [7]), but risk factors for the very severe, near-fatal reactions are known, varying age by age. In infancy, they include under-recognition and under-diagnosis of anaphylaxis. In adolescence, lack of compliance with asthma preventer medications and dietary advice, exercise, fasting, denial of symptoms, and delay in seeking help. In adult age, treatment with [beta]-blockers and ACE inhibitors, in particular when combined with cardiovascular disease and/or chronic obstructive pulmonary disease. In all age classes, the risk of severe anaphylaxis is increased by food-dependent, exercise-induced forms, by acetylsalicylic acid plus alcohol consumption, and by systemic mastocytosis.[8] Some of these criteria are similar to the criteria for 'difficult to treat' asthma.

In absence of a shared definition, what is a severe food allergy may vary across studies. As an example, in a study on the association among food allergy and celiac diseases, 'very severe' food allergy has been defined as 'a positive history of at least one severe allergic reaction (i.e., a reaction defined as classes 4 and 5 according to Clark's classification)' with 'elevated IgE levels against food proteins (IgE values > 85 kU/l).[9] Another possible criterion is the type of reaction to diagnostic challenges. For instance, a food reaction failing to improve after receiving intramuscular adrenaline (plus supporting measures) or presenting a severe rebound after initial improvement is indubitably a severe reaction. In a German experience, severe anaphylactic reactions requiring ICU transferal account for a 0.2% of Oral food Challenge (OFCs). Such severe reactions are more frequent in older children with peanut allergy,[10] but also hen's egg, cow's milk, and hazelnut may lead to severe anaphylactic reactions.[11]

Even more difficult is to give a definition of severity for non-IgE-mediated food allergies. For FPIES, severity stands in the definition ('a non-IgE, cell-mediated food allergic disorder that can be severe and lead to shock' [12]), but it appears that there are different degrees of severity in the number of offending foods and the characteristics of the reaction. A severe FPIES reaction is defined by 'repetitive, projectile emesis with or without diarrhea, pallor, lethargy, dehydration, hypotension, shock, methemoglobulinemia, metabolic acidosis'. In pathologies as eosinophilic esophagitis (EoE), Atopic dermatitis (AD), or allergic enterocolitis, the evaluation of severity must rely upon disparate subjective and objective parameters, so that probably the best definition of a severe food allergy is the evaluation of QoL.[13]

A definition of severe food allergy will be needed to establish a common approach to the treatment of these forms with biologics. Similar to severe asthma, associated with the greatest share of asthma morbidity and economic burden,[14] severe food allergies probably are responsible for the highest expenditure in terms of office and emergency visits, inpatient hospitalizations, ambulance runs, epinephrine devices,[15] and death.[16] The new treatments must focus on the most vulnerable fraction of patients, taking in account their risks, the pathogenesis of the specific forms, and the efficacy of single therapies.