REVIEW

CURRENT
OPINION Allergy to food additives
Rocco Luigi Valluzzi, Vincenzo Fierro, Stefania Arasi,
Maurizio Mennini, Valentina Pecora, and Alessandro Fiocchi

Purpose of review
To provide an update of the studies concerning the diagnosis and management of food additives allergy.
Recent findings
Additives improve specific characteristics of food products, but they may induce allergic even life-
threatening reactions. Physical examination and medical history are basic to assess specific in-vivo and in-
vitro tests. The only treatment for allergic patients consists in avoiding the food containing culprit additives.
High-risk patients should be able to recognize severe reactions and self-manage them.
Summary
The prevalence of adverse reactions to food additives is low, and it may depend on comorbidities, like
asthma or chronic idiopathic urticaria. Food labels may help the correct identification of ingredients.
Natural additives like spices should cause immediate reactions because of a pollen-sensitization or
panallargen proteins presence. Additive-free diets may help the patient care, but the authors suggest
assessing an oral food challenge with the culprit substance if there are no contraindications.
Keywords
allergy, food additives, hypersensitivity

INTRODUCTION [4]. Despite their widespread use, only one large

Additives are compounds added to products to per-
form specific functions, such as coloring, sweeten-
ing, or preserving foods. In the United States, the
Food and Drug Administration (FDA) provides a list
of substances used in food production, distinguish-
ing Food Additives and Color Additives, listed in
FDA regulations, from Generally Recognized As Safe
(GRAS) ingredients, which are not considered food
additives [1].
In the European Union, an E number identified
a specific food additive. Product labeling must spec-
ify additive properties by referring to its name and E
number [2].
Food additives can induce allergic reactions,
which involve an immune mechanism (IgE-medi-
ated, non-IgE-mediated, and mixed IgE/non-IgE-
mediated reactions), and different clinical manifes-
tations, as reported in Table 1 [3].
This review aims to provide information on food
additives and to update the studies on the diagnosis
and management of food additives allergic reactions.
PREVALENCE
The prevalence of additive adverse reactions is diffi-
cult to estimate as symptoms are prone to subjectiv-
ity and there is a lack of reliable markers of reactivity
population-based study was carried out in Britain.
After collecting more than 11 000 questionnaires,
these authors reported a prevalence of only 0.026%
in the British population [5]. In Denmark, the prev-
alence of adverse reactions in healthy children was
1–2%, whereas in children with atopic symptoms it
ranged from 2% after double-blind placebo-con-
trolled food challenge (DBPCFC) to 7% after open
food challenge [6,7]. In a German study, food addi-
tives contributed only to a minority of pseudoaller-
gic reactions; the prevalence estimated of additive
adverse reactions was less than 0.18% [8].
In 100 patients with chronic urticaria, the prev-
alence of food additive adverse reactions was less
than 1% [9], whereas in 54 patients with various
allergic diseases, DBPCFC showed no significant
Division of Allergy, University Department of Pediatrics, Pediatric Hospital
Bambino Gesù, Rome, Vatican City, Italy
Correspondence to Rocco Luigi Valluzzi, MD, Division of Allergy, Depart-
ment of Pediatric Medicine, Bambino Gesù Children’s Research Hospi-
tal, Piazza S. Onofrio 4, Holy See, 00161 Rome, Italy.
Tel: + 39 6 6859 2296; fax: +39 2 6859 2300;
e-mail: rvalluzzi@gmail.com
Curr Opin Allergy Clin Immunol 2019, 19:256–262
DOI:10.1097/ACI.0000000000000528

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 Allergy to fo od additives Valluzzi et al.

dermatitis, 47 (64%) developed positive patch tests

KEY POINTS
 Food additives can induce allergic reactions.
 The prevalence of additives adverse reactions is difficult
to estimate because symptoms are prone to subjectivity
and there is a lack of reliable markers of reactivity.
 Additive-free diet may improve the patient care, but
physicians should perform an OFC with the culprit
additive in case of mild or inconsistent
reported symptoms.
difference between culprit additives and placebo
[10].
According to these studies, the rate of patient
perception far exceeds the estimated prevalence
rate.
FOOD ADDITIVES AND CLINICAL
MANIFESTATIONS
Most studies adopted a food additives classification
based on their properties as reported in Table 2 [11].
for propyl gallate, but only 4 (5%) reported local
allergic symptoms (tongue swelling and lips derma-
titis) after ingestion of gallate-containing food
items [14].
Stabilizers, emulsifiers
Gums are thickening agents, which increase mix-
ture viscosity without changing the taste of foods.
Guar gum is extracted from a vegetable that grows in
India (Cyamopsis tetragonolobus), and it has been
associated with occupational rhinitis and asthma
[15]. In a case report, a patient developed an ana-
phylactic shock after the concomitant ingestion of
acetylsalicylic acid and guar gum contained in a
meal substitute [16].
A retrospective study of the North American
Contact Dermatitis Group (NACDG) reported 78
allergic reactions to food-derived allergens in
10 061 patch-tested patients; propylene glycol was
the third most common cause of systemic contact
dermatitis associated with food ingestion (6.4%),
after nickel (48.7%) and balsam of Peru (20.6%) [17].

Antioxidants Monosodium glutamate

Antioxidants prevent lipids (margarine, vegetable
oil, animal fat, meat, fish, bakery and potato prod-
ucts, salad dressing) from oxidative degradation.
There are few studies concerning antioxidants
hypersensitivity reactions. Two studies identified
butylated hydroxyanisole (BHA) and butylated
hydroxytoluene (BHT) as triggers of exacerbations
in patients with chronic urticaria [12,13].
As reported in a recent systematic review, of 74
patients with a personal history of gallate contact
Monosodium glutamate (MSG) is a very used flavor
enhancer, which may induce the ‘Chinese restau-
rant syndrome’ [18], an example of nonallergic
reactions to additives, characterized by a wide vari-
ety of subjective dose-dependent symptoms (e.g.
heat, headache, dizziness, palpitation) for up 2 h
after food consumption.
In a multicenter study, of 130 patients with a
personal history of MSG sensitivity, 69 (53.1%)
reacted to DBPCFC with a hefty dose of MSG, and

Table 1. Food-induced allergic reactions

Ig-mediated reactions Mixed IgE and non-IgE reactions Non-IgE-mediated reactions

Skin Urticaria Atopic dermatitis Contact dermatitis

Angioedema Dermatitis herpetiform
Generalized flushing
Respiratory Allergic rhinoconjunctivitis Asthma Heiner’s syndrome
Laryngeal edema
Bronchospasm
Gastrointestinal Oral allergy syndrome Eosinophilic esophagitis Food protein-induced
enterocolitis syndrome
Acute colic Eosinophilic gastroenteritis Proctocolitis syndrome
Vomiting Entheropathy syndrome
Diarrhea Celiac disease
Generalized Anaphylaxis

Modified from Sampson [3].

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Food allergy

Table 2. Common food additives with properties and identification parameters

Additive properties Name FDA regulatory status E number

Antioxidants Butylated hydroxyanisole GRAS/FS E 320

Butylated hydroxytoluene GRAS E 321
Propyl gallate GRAS E 310
Stabilizers Guar gum GRAS/FS E 412
Miscellaneous Propylene glycol GRAS/FS E 1520
Flavoring Monosodium glutamate GRAS/FS, GMP E 621
Spices, essential oils Anise GRAS -
Cinnamon GRAS -
Coriander GRAS -
Cumin GRAS -
Fennel GRAS -
Ginger GRAS -
Mustard GRAS -
Nutmeg GRAS -
Paprika GRAS E 160c (extract)
Pepper GRAS -
Artificial sweeteners Aspartame REG, GMP E 951
Preservatives Benzoates GRAS/FS E 211–215, 218, 219
Nitrates REG E 251–252
Nitrites PS E 249–250
Sodium metabisulfite GRAS, GMP E 223
Dyes
Orange Annatto GMP E 160b
Red Carmine GMP E 120
Yellow Saffron GMP E 164
Tartrazine (yellow #5) GMP E 102

Modified from Wilson and Bahna [11]. FDA, Food and Drug Administration; FS, substances permitted as optional ingredient in a standardized food; GMP, in
accordance with good manufacturing practices; GRAS, generally recognized as safe; GRAS/FS, substances generally recognized as safe in foods but limited in
standardized foods; PS, substances for which prior sanction has been granted by FDA for specific uses; REG, food additives for which a regulation has been issued.

36 (27.7%) using placebo; all patients tolerated MSG
when given with food [19]. Some authors have tried
to describe a link between MSG consumption and
asthma, with no evidence of immediate or late
asthmatic reactions [20]. As detailed in a few reports,
MSG and other food additives may exacerbate
chronic rhinitis, but the pathogenesis is still uncer-
tain [21,22]. In a study on 65 subjects with a per-
sonal history of chronic urticaria, only two subjects
reacted after a single-blind challenge with MSG. All
patients tolerated this additive after DBPCFC [23].
Spices
Spices are aromatic additives derived from vegeta-
bles. Using seeds (sesame, sunflower, poppy, pump-
kin, flax, and mustard) in food production has
increased the risk of hypersensitivity reactions often
&
severe [24 ]. Despite spice allergy being rare, a study
on 589 food allergic patients reported a persistent
Apiaceae (coriander, caraway, fennel, celery) sensi-
tization rate of 23% in adults and 32% in children
[25]. Clinical reports and in-vitro cross-reactivity
studies on celery–birch–mugwort spice syndrome
(e.g. coriander seeds, fennel seeds, aniseed), mug-
wort spice syndrome (e.g. Apiaceae, paprika, pep-
per), and mugwort mustard allergy suggest a link
between spice allergy and pollen sensitizations [26].
The allergens responsible for cross-reactions are
homologs of the birch pollen allergen Bet v1-profi-
lin, seed storage proteins, or 2S albumins [27]. An
Italian study reported a significant association
between severe reactions to fennel and peach
because of a Lipid Transfer Protein (LTP) allergen
that is cross-reactive with Pru p3 [28].
Aspartame
Aspartame is a commonly used artificial sweetener.
Two well designed studies showed no difference

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between aspartame and placebo reactivity after
DBPCFC, both in patients with self-reported aspar-
tame reactions and in subjects with chronic idio-
pathic urticaria [9,29]. To date, there is only a case
report that described a case of aspartame-induced
urticaria confirmed by DBPCFC [30].
Preservatives and antimicrobials
Benzoates (benzoic acid, and its salts and esters) are
antimicrobials found in soft drinks and foods, linked
to different cutaneous (e.g. atopic dermatitis,
chronic urticaria), respiratory and anaphylactic
reactions [31]. However, well designed studies
showed that benzoates had no impact on both
atopic dermatitis [10] and chronic urticaria [9],
and that a benzoate-free diet did not improve the
clinical conditions of patients with persistent
asthma [32]. In an Italian study, of 226 patients
with chronic nonallergic rhinitis, only 20 developed
a positive DBPCFC to monosodium benzoate; all 20
patients improved their clinical symptoms after a 1-
month benzoate-free diet, with complete healing in
six of them [22].
The role of parabens (para-hydroxybenzoic acid
alkyl esters) in the etiology of systemic anaphylactic
reactions, chronic urticaria, angioedema, and aller-
gic vascular purpura remains undefined, whereas
their use in cosmetics and topical medications
may provoke contact dermatitis reactions more
than paraben-food consumption [33].
Sodium nitrate and sodium nitrite prevent the
growth of bacteria in meat products. There are only a
handful of case reports of a well demonstrated rela-
tionship between sodium nitrate and chronic pruri-
tus [34], chronic urticaria [35], or anaphylactic
shock [36].
Sulfites are antimicrobials and antibrowning
agents, used for soft drinks, wines, dire fruits, salads,
crustaceans, and meat production. Sulfite sensitivity
may exacerbate respiratory symptoms in patients
with asthma [37]. A single-blind placebo-controlled
study on 203 asthmatic patients showed a preva-
lence of 3.9% in steroid-dependent asthmatic
patients and of 0.8% in other asthmatic patients
[38]. In addition, a more recent review concerning
sulfite sensitivity in asthmatic patients suggested a
prevalence of between 3 and 10% [39]. In a study on
24 patients with a strong history of wine-induced
asthma, only 4 (16.7%) were positive after a single
dose challenge with sulfited wine [40].
Sulfite sensitivity may induce urticarial reac-
tions. A Korean study marked the coexistence of
two different phenotypes in 26 Korean patients with
diagnosed sulfite hypersensitivity: an asthmatic
phenotype and an urticarial one (69.2 and 30.8%,
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Allergy to fo od additives Valluzzi et al.
respectively) [41], whereas there are only a few cases
of anaphylaxis because of sulfite consumption [42].
The mechanism of sulfite hypersensitivity is still
unclear: the inhalation of the sulfur dioxide during
sulfite digestion may induce asthmatic reactions
[43], but other mechanisms may play a role in
growing symptoms, like IgE-mediated hypersensi-
tivity [44], deficiency of sulfite oxidase [45], release
of leukotrienes [46]. In a patient with mastocytosis,
sulfite consumption induced life-threatening ana-
phylaxis [47].
Food dyes
Dyes enhance or change the color of the food and
beverage products.
Natural dyes, such as carmine, annatto, and
saffron can develop IgE-mediated hypersensitivity
reactions [43].
Carmine is a red dye extracted from dried cochi-
neal insects (Dactylopius coccus). There are over 30
reported cases of IgE-mediated hypersensitivity reac-
tions because of carmine red, most with anaphylac-
tic reactions, and handful reports of delayed
hypersensitivity reactions, because of use of lip-
sticks, beverage, and food products [48]. Carmine
hypersensitivity and consuming food-containing
carmine may exacerbate childhood atopic eczema
[49].
Annatto is a yellowish orange pigment extracted
from the seeds of Bixa orellana. It is a common
ingredient in dairy and bakery products, vegetable
oils, and drinks. Some authors reported cases of
urticaria and anaphylaxis after annatto food con-
sumption [50]. In a case report, a patient with a
history of anaphylactic reaction to annatto-contain-
ing cheese developed both positive in-vivo (skin
tests) and in-vitro tests (IgE immunoblot and baso-
phil-activation test) [51].
Saffron is a yellow food coloring, extracted from
the dried stigma of the flower of the saffron crocus
(Crocus sativus) [52]. A study revealed an LTP (Cro 3)
in the saffron extract [53], which must lead to severe
systemic reactions or cross-reactivity to other LTP
allergens. In addition, as reported in an Italian case
report, a saffron profilin allergen (Cro 2) may induce
respiratory reactions [54].
Tartrazine is the most common artificial dye,
used in desserts, confectionery, beverages, snacks,
spreads, and other food preparations. Despite many
cases reported [55], there is no evidence that tartra-
zine ingestion makes asthma worse or its avoidance
makes asthma better [56]. Atopic manifestations,
such as allergic rhinitis, urticaria, and allergic or
pseudoallergic reactions to aspirin or others NSAIDs
do not seem to depend by tartrazine uptake [57].
www.co-allergy.com 259
Food allergy

Table 3. Oral challenges for food additives

Additive Challenge substance Placebo suggestions Vehicle Doses Time interval

Sulfites Potassium metabisulfite Powdered sucrose Capsules 1, 5, 25, 50, 100, and 20–30 min
200 mg (Bush et al. [37])
Monosodium Monosodium glutamate Lactose, microcrystalline Capsules or 200, 400, 800, 1600 mg 20–30 min
glutamate powder cellulose, citrus drink citrus drink (Wilson and Bahna [11])
as much as 5 g (Geha
et al. [19])
Tartrazine Tartrazine powder Lactose Opaque capsules Placebo, tartrazine 25 and 3h
50 mg (Stevenson et al.
[55])
Aspartame Aspartame Lactose, microcrystalline Capsules 100, 200, 400, 800 mg 3h
cellulose (Wilson and Bahna [11])
Others Sodium benzoate, butylated Lactose, one preservative Opaque and dye- 1, 25, 50, 100, and 20–30 min
hydroxyanisole, might be used as a free capsules 200 mg (Wilson and
butylated hydroxytoluene, placebo for another Bahna [11])
parabens, nitrates
and nitrites

Modified from Nowak-Wegrzyn et al. [59].

Diagnosis
Additives allergy follows the diagnostic criteria of
food allergy.
A detailed medical history is necessary. It must
specify the amount of consumed food, the time
interval between food intake and symptoms onset,
the clinical manifestations, and disease manage-
ment. Medical history should take into consider-
ation hidden or unidentified ingredients, using food
labels to find all the possible allergens ingested. It
could also reveal temporally related alcohol or drug
(e.g. NSAIDs) consumption, exercise, or other activ-
ities. Physical examination findings and medical
history are essential in suggesting specific diagnostic
tests [58].
Both in-vivo skin tests (prick test with food
extract and prick-prick test with the culprit additive)
and in-vitro tests (immunoassays for detecting IgE
antibodies, basophil activation test, and molecular or
component resolved diagnosis – CRD) are useful for
the study of immediate reactions. For natural addi-
tives, such as spices and dyes extracted from vegeta-
bles, a molecular sensitization profile could help to
verify a pollen-sensitization and to prevent cross-
reactivity reactions because of panallargens sensitiv-
ity. Patch tests may reveal a cell-mediated mecha-
nism in patients with nonimmediate reactions.
Additive-free diet can exclude the need to assess
an oral food challenge (OFC), but the patient’s
expectation may influence its outcome. OFC is
the gold standard test for the diagnosis of food
additive allergy, and its assessment must follow
the same indications reported in the food allergy
guidelines [11,58,59]. Table 3 reported some exam-
ples of oral challenges for food additives.
Management
Authors do not recommend an additive-free diet in
patients with chronic idiopathic urticaria [9,10].
Asthmatic patients who did not have reactions to
sulfites, must not avoid these or other food addi-
tives [39].
Patients with a well diagnosed allergy should
follow a rigorous diet without culprit additives and
offending foods. However, given the unpredictability
of allergen exposure and the widespread of additives
in food preparations, self-injectable epinephrine
should be available for all patients with a history of
severe systemic reactions to these products. Despite
sodium metabisulphite in epinephrine formulations,
in an emergency, such as anaphylaxis, potential
adverse effects would not justify restricting its admin-
istration [58].
To date, there are no studies on pollen immu-
notherapy and its effect on natural additive aller-
gies. Guidelines recommend this therapy only for
respiratory symptom treatment [26].
CONCLUSION
Despite the frequency reported by patients, additives
allergy is not frequent, but it may trigger immediate
even life-threatening manifestations. Physical exam-
ination and medical history are necessary to decide
the most suitable tests. Additive-free diet may
improve the patient care, but physicians should per-
form an OFC with the culprit additive in case of mild
or inconsistent reported symptoms. Allergic patients
will have to avoid all the possible offending foods by
paying attention to the labels of food products. Rec-
ognition of IgE-mediated reactions is essential;

260 www.co-allergy.com Volume 19  Number 3  June 2019

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physicians should inform caregivers and high-risk
patients about self-care management techniques
and treatment of anaphylaxis.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 19  Number 3  June 2019