- The document discusses reactions to food and drug additives. It provides an overview of labeling requirements for additives, prevalence of reactions, and diagnosis of adverse reactions. - Common food additives that can cause reactions include tartrazine/synthetic dyes, sulfites, natural colors like annatto and carmine, and MSG. Drug additives like polyethylene glycol (PEG) have also been implicated. - Diagnosis involves challenge testing. IgE mechanisms can be evaluated via skin prick or IgE testing for some additives. Adverse reactions are generally mild but sulfites can provoke severe asthma.

1. Reactions to Food and
Drug Additives
Pornsiri sae-lim , MD
Pediatric Allergy and Immunology Department
King Chulalongkorn Memorial Hospital

2. Overview
• Introduction
• Labeling of Additives
• Prevalence of Reactions to Additives
• Diagnosis of Adverse Reactions to Additives
• Food & Drug Additives Known or Suspected to Cause Adverse Reactions

3. Introduction

4. Food additives :
• Purposes : nutrients or agents for
coloring, flavoring, or antimicrobial
purposes
• Serve more than one technical
function
• Typically minor ingredients of the
composite food
BURKS, A. Wesley, et al. Middleton's : Principles and Practice. Elsevier Health Sciences, 2019

5. Drug additives
• Purposes : agents of coloring, flavoring,
emulsification, thickening, binding, and
preservation
• often comprise the majority of the
product
• Active pharmaceutical ingredients are
frequently present as a small fraction of
the total mass of the product.

6. Labeling of Additives
• Food labels : identifies virtually all of the intentional ingredients
• The composite food product in descending order of predominance
• Few groups of ingredients are allowed to be declared collectively without a listing of
all of the individual components
• Examples include spices, natural flavors, and artificial flavors

7. • In the United States the Food Allergen
• Labeling and Consumer Protection Act mandates
• Ingredient derived from a commonly allergenic food (defined as peanut, tree
nuts soybeans, wheat, milk, egg, fish, and crustacean shellfish [e.g., shrimp,
crab, lobster]) be labeled clearly by source
• Examples of proper labeling would be lactose (milk) or soybean lecithin.
• the presence of any flavors derived from commonly allergenic sources must be
declared. An example would be “natural flavoring (milk and fish)

8. PREVALENCE OF REACTIONS TO ADDITIVES
• Ranging from lethargy to severe asthma and anaphylaxis.
• Many of these adverse reactions have not been verified by appropriate diagnostic
challenge procedures
Food
• The assessment of the prevalence of adverse reactions to food additives is difficult because the
reactions are often linked to chronic disorders such as asthma, chronic urticaria, and atopic
dermatitis
• Suggested that adverse reactions to food additives affect 0.01% to 0.23% of the general population,
but the prevalence may be higher in patients with atopic disease (2%-7%)

9. Drug
• Less common than food additive reactions
• Sulfites used as antioxidants in drugs are well recognized as causing asthma and other adverse
reactions
• Ethylenediamine is associated primarily with contact dermatitis, and sensitization occurs through
cutaneous exposure
• Ethylenediamine is also a component of aminophylline and has produced urticaria, exfoliative dermatitis,
and anaphylaxis in sensitized individuals

10. Jessica P.,The Journal of Allergy and Clinical Immunology: In Practice,Volume 2, Issue 2,2014
OBJECTIVE: To determine the prevalence of reactions to food and drug additives in patients with CIU
METHODS:
- Challenged 100 patients in our allergy/ immunology division with CIU
- All of the patients had a history of CIU for longer than 6 weeks
- 43 reported possible history of food or drug additive sensitivity
- 11 additives most commonly associated with reactions
- Single-blind challenges to all of the additives were performed in the clinic and skin scores were
recorded
- Subjects with positive challenge tests underwent double-blind placebo controlled challenges

11. RESULTS:
- 100 subjects, only 2 had a positive urticarial
response on single-blind challenge
- Neither of these patients had a positive
urticarial response on double-blind placebo-
controlled challenge
- There were no gastrointestinal, respiratory,
or other symptom, and no patients reported
late reactions.
CONCLUSION:
- 95% confidence intervals that sensitivity to any of the 11 food and drug additives occurs in fewer than 1% of
patients with CIU.
- Food and drug additives appear to be a rare cause of CIU, and avoidance is not recommended.

12. DIAGNOSIS OF ADVERSE REACTIONS
TO ADDITIVES
• Challenge testing has been the most common approach to the confirmation of
adverse reactions to food and drug additives
• IgE-based mechanism :
• Prick skin testing or serum specific IgE assays may be helpful in diagnosing
adverse reactions to a limited number of food additives
• basophil activation test (BAT) : chronic urticaria
• Contact dermatitis : Patch testing
• Additive Challenge Studies: Urticaria and Asthma

13. FOOD AND DRUG ADDITIVES KNOWN OR
SUSPECTED TO CAUSE ADVERSE REACTIONS
• Food Colorants
• Sulfites
• Other Additives

14. Food Colorants
• Synthetic Colorants (Dyes)
• Tartrazine
• Natural Food Colorants
• Annatto
• Carmine

15. Tartrazine
• Various food sensitivity reactions, but especially in asthma and chronic urticaria
• possible factor in persistent rhinitis
• Studies of these food and drug colors have had the methodologic flaws :
• no compelling evidence for the involvement of these colors in urticaria,
angioedema, asthma, or atopic dermatitis
• chronic urticaria , asthma : high likelihood of breakthrough urticaria from the
withdrawal of antihistamine, medication

17. Natural Food Colorants
• Not used to any extent in pharmaceutical applications
• Several studies have reported positive reactions after challenges with mixtures of
natural colors or mixtures of natural and synthetic colors
• The adverse reactions were asthma, urticaria, atopic dermatitis, colic, and
vomiting
• No one color can be identified as the causative factor when challenges are
conducted with mixtures

18. Natural Food Colorants : Annatto
• Extract from the seeds of the fruit of the Central and South American tree, Bixa Orellana
• red in color
• often used to impart an orange or deep-yellow color to the finished food
• Case reports of probable IgE-mediated sensitivity to annatto have noted patient reactions to
crackers, cheese, and breakfast cereal.
• Clinical reactions to annatto have been confirmed by positive prick skin tests, basophil activation,
and IgE-binding

19. Natural Food Colorants: Carmine
• Derived from dried female cochineal insects
: Dactylopius coccus Costa
• Aqueous-alcoholic extract of the dried insects is made and concentrated
• Red in color
• Widely used in cosmetics, but only a few cases of dermatologic reactions have
been attributed to it
• Cases of urticaria and angioedema with positive prick skin tests and serum
specific-IgE to carmine have been described in the literature
• Diagnosis of carmine allergy can be difficult because of the nature of the
protein residues and interactions with carminic acid
• Oral challenges may be necessary to confirm carmine allergy

20. Sulfites
• Sulfur dioxide (SO2), sodium and potassium metabisulfite (Na2S2O5, K2S2O5),
sodium and potassium bisulfite (NaHSO3, KHSO3), and sodium sulfite (Na2SO3)
• Used as food additives
• also occur naturally in many foods, particularly fermented beverages such as
wines
• wide range of use levels and residual sulfite concentrations
• wide variety of applications as food additives
• Used as drug additives
• Because of concerns over sulfite-induced asthma, sulfites have been removed
from many drugs, especially asthmatic patients
• routinely added to epinephrine
• not been reported to have any adverse effects
• epinephrine should never be denied or avoided by sulfite-sensitive

22. Sulfites
• Clinical Manifestations :
• more robust evidence linking sulfites with asthma and anaphylaxis
• sulfites can provoke acute bronchospasm and severe asthma
• Not appear to play a role in patients with idiopathic anaphylaxis, systemic mastocytosis
• Mechanisms of Sensitivity
• Not known
• inhalation of less than 1.0 ppm of sulfur dioxide, patients with asthma respond with
significant bronchoconstriction
• Furthermore, inhalation of sulfur dioxide and bisulfite (HSO3 2 ) but not sulfite (SO3)
causes bronchoconstriction to develop in patients with asthma
• Treatment
• Sulfite-sensitive asthmatic patients should be instructed to avoid the more highly sulfited
foods with an excess of 100 ppm of SO2 equivalents
• Regulatory Restrictions
• Labeling is required of packaged products and alcoholic beverages containing sulfite residues
in excess of 10 ppm
• No regulations restrict the use of sulfites in medications
• Attempted to reduce sulfite-containing medications used for asthma treatment

23. Other Additives Known or Suspected
to Cause Reactions
• Monosodium Glutamate
• Aspartame
• Acesulfame Potassium
• Protein Hydrolysates
• Taurine
• Benzoates/Parabens
• Sorbate/Sorbic Acid
• Butylated Hydroxyanisole and Butylated
Hydroxytoluene
• Nitrate and Nitrite
• Flavoring Agents
• Lecithin
• Papain
• Lysozyme
• Gums
• Mannitol
• Erythritol
• Maltitol
• Gelatin
• Inulin
• Wheat Starch
• Edible Oils
• Polyethylene Glycol (PEG)
• Propylene Glycol

24. Polyethylene Glycol (PEG)
• Water-soluble ingredient in a wide variety of commercial products including some vaccines and
more than 1000 FDA approved medications
• The primary ingredient in commonly used
• Colonoscopy preparations (Golytely)
• Constipation treatment (Miralax)
• Intraveous medications such as PEGylated medications
• Also used in ultrasound gel and injectable steroid injections such as methylprednisolone acetate
• Reactions to PEG are exceedingly rare, but anaphylaxis has been reported
BANERJI, et al. The Journal of Allergy and Clinical Immunology: In Practice, 2021, 9.4: 1423-1437.

26. COVID -19 vaccination
• Spike-protein S was identified as main vaccine target as it contains the receptor-binding domain
that allows for host cell entry
• Neutralizing antibodies against the spike protein have been described following SARS-CoV and
most recently in SARSCoV-2 vaccination
• Vaccine platforms :
• Inducing strong CD4+ and CD8+ T-cell responses (to rapidly curtail viral infection and reduce
complications)
• and/or high titers of neutralizing antibodies
• genetic (mRNA/DNA) and vector vaccines mostly induce potent T-cell responses—with
variable titers of neutralizing antibodies
Eberhardt CS, Pediatric Allergy and Immunology. 2021 Jan;32(1):9-16

29. BANERJI, et al. The Journal of Allergy and Clinical Immunology: In Practice, 2021, 9.4: 1423-1437.

30. CLINICAL TRIAL DATA
US FDA’s Emergency use authorization : December 2020
• Pfizer BioNTech : 2-dose vaccine regimen ( day 0 & 21 ) 16 yrs and older
• 95% efficacyat preventingsymptomatic COVID-19 infection,measured from 7 days afterthe second dose
• Equally protective across age groups as well as racial andethnic groups
• Severe systemic events were reported inless than 2% of recipientsafter either dose
• except for 3.8% reportingfatigue and 2.0% reportingheadache after the second dose
• Moderna : 2-dose vaccine regimen( day 0 & 28 ) 18 yrs and older
• 94% effective at preventing symptomaticCOVID19, measuredfrom 14 days afterthe second dose
• Slightly lower in people 65 years and older
• Equally effectiveacross different racial and ethnic groups
• Most adverse eventsreportedafter receivingvaccinewere mild or moderate inseverity
Currently insufficientdata for efficacy, safety, and effectivenessof these vaccinesin children under 16 years of age but studiesare ongoing

31. US REGULATORY APPROVAL AND GUIDANCE
• FDA EUA guidance
• Don’t : history of a severe allergic reaction (eg, anaphylaxis) to any component
of the Pfizer-BioNTech COVID-19 vaccine
• Observed for 15 minutes after COVID-19 vaccination
• Staff must be trained to manage anaphylaxis
• CDC
• Further recommendations “that persons who have had an immediate allergic
reaction of any severity to any vaccine or injectable therapy (intramuscular,
intravenous, or subcutaneous) discuss the risk of receiving the vaccine with
their doctors and be monitored for 30 minutes
• who have an immediate (within 4 hours) or severe allergic reaction (eg,
anaphylaxis) to an mRNA COVID-19 vaccine should not receive a second dose

32. US POSTMARKETING EXPERIENCE
• At April 2021 , there have been 21 confirmed anaphylactic reactions to the Pfizer-
BioNTech vaccine across almost 1.9 million doses administered in the United States
• CDC-confirmed anaphylactic reactions (86%, 18/21) occurred within a 30-minute
observation window, and patients were treated immediately with complete
resolution of symptoms
• To date, there are no fatalities associated with reported allergic reactions to any
COVID-19 mRNA vaccine
BANERJI, et al. The Journal of Allergy and Clinical Immunology: In Practice, 2021, 9.4: 1423-1437.

33. EPIDEMIOLOGY OF ALLERGIC
REACTIONS TO VACCINES
• Allergic reactions to vaccines are generally described as occurring at a rate of 1.31
(95% CI, 0.90-1.84) cases per million vaccine doses from a large population-based
study
• No fatalities reported
• Similar when stratified by age and sex, although slightly higher frequencies have
been observed in females
• Not all immediate reactions that occur in association with vaccines are true allergic
reactions (eg, flushing, transient dyspnea)

34. ETIOLOGY OF ALLERGIC
REACTIONS TO VACCINES
• Confirmed allergic reactions to vaccines are not frequently
• Excipients represent the major contributor to specific IgE mediated and immediate
reactions associated with vaccines
• Excipients : including egg protein, gelatin, formaldehyde, thimerosal, or neomycin.
• To a vaccine for specific purposes such as stimulating a stronger immune
response
• Preventing contamination by bacteria
• Stabilizing the potency of the vaccine during transportation and storage

35. • polyethylene glycol (PEG) and polysorbate are used to improve water solubility in
drugs and vaccines
• PEG itself has not previously been used in a vaccine
• polysorbate has been identified as a rare cause of allergic reactions to vaccines
• Pfizer BioNTech and Moderna COVID-19 mRNA vaccines
• not formulated with any food, drugs, or latex
• contain excipient PEG for the purpose of stabilizing the lipid nanoparticle
containing the mRNA
• First-dose reactions to vaccines containing polysorbates may have occurred
because of previous sensitization from polysorbate 80.
ETIOLOGY OF ALLERGIC
REACTIONS TO VACCINES

36. ETIOLOGY OF ALLERGIC
REACTIONS TO VACCINES
First-dose reactions to vaccines containing polysorbates may have occurred because of
previous sensitization from polysorbate 80
Numerous FDA-approved and over-the-counter products contain PEG
- including medications, skin creams, and personal lubricants
foods using PEG as an antifoaming agent
- PEG3350 is the active ingredient in several medications prescribed
for treating constipation) and in bowel preps used before colonoscopy

37. polyethylene glycol
• The general population showed
• 5% to 9% of 1721 serum samples tested were positive for anti-PEG IgG
• 3% to 6% of 948 such samples tested were positive for anti-PEG IgM
• 2 of 2091 (0.1%) samples tested were positive for anti-PEG IgE.
• Reactions to PEG containing products on the first exposure suggest previous sensitization to PEG
• Review of FDA voluntary reporting data
• from 2005 through 2017 identified an average of just 4 cases (range, 2-8 cases) per year of
PEG-associated anaphylaxis during colonoscopy preparation or laxative use
• More subtle PEG allergies are usually discovered during allergist evaluation of patients being
evaluated for reactions to seemingly unrelated products, including injectable steroids, processed
foods, cosmetics, drugs, and other substances that contain PEG
ZHOU, Zhao-Hua, et The Journal of Allergy and Clinical Immunology: In Practice, 2020.

38. • Although an exact threshold of reactivity based on the molecular weight of PEG is not known,
tolerance of PEG with molecular weight less than 400 has been described in those who have
documented anaphylaxis to PEG3350.11 It has been reported that those who lose reactivity to
lower molecular weight PEG over time may still remain sensitized to very high molecular weight
PEG.18 Additionally, there appears to be an increased incidence of allergic reactions in patients
who receive intravenous PEG compared to the intramuscular route.1

41. Polysorbate
• Structurally similar to PEG with polyether domains
• Clinical cross-reactivity
• Excipient in a multitude of medical preparations (eg, vitamin oils, vaccines, and anticancer agents),
creams, ointments, lotions, and medication tablets
• At least 70% of injectable biological agents and mAb treatments contain a polysorbate, most
typically polysorbate 80
AstraZeneca and Johnson & Johnson COVID-19
vaccines contain the excipient polysorbate 80

42. Host factors leading to mast cell hyperresponsiveness
• Individuals experiencing anaphylactic reactions to the COVID-19 mRNA vaccines have been
strikingly female
• Allergic response to the COVID mRNA vaccine towards the female sex may be secondary to
estrogen effects in promoting a TH2 response, or conversely, testosterone and progesterone’s
known role in diminishing TH2 responses
• Atopic individuals also appear to be over-represented in those suffering anaphylaxes to the COVID
mRNA vaccines
• Stress : Corticotropin releasing hormone (CRH) and neurotensin are secreted by neurons in
response to acute and chronic stress and they lower the threshold for mast cell degranulation
Substance P is also released by neurons adjacent to mast cells and leads to degranulation during a
stress response
• use of opiates or non- steroidal antiinflammatory drugs may enhance mast cell activation and/or
vascular responsiveness
Potential Mechanisms of Anaphylaxis to COVID-19 mRNA Vaccines

43. large local reactions
• Begin hours after the vaccination or even the next day
• The skin at the site of vaccination can become sore, swollen, red, and painful.
• The symptoms can last several days.
• Not an allergic reaction to the vaccine, there is no risk of an allergic reaction with
the next vaccination, and an allergist consultation is not necessary

45. EVALUATION OF PATIENTS WITH
SEVERE ALLERGY HISTORIES
• Recent data showing that the majority (81%, 17/21) of patients with confirmed anaphylaxis to the
Pfizer-BioNTech mRNA vaccine
• a prior allergy history and 33% (7/21) had a prior history of anaphylaxis
• risk stratify patients based on a clinical assessment
• Four screening questions are presented to patients before the initial vaccination to assess risk:
1. Do you have a history of a severe allergic reaction to an injectable medication (intravenous,
intramuscular, or subcutaneous)?
2. Do you have a history of a severe allergic reaction to a previous vaccine?
3. Do you have a history of a severe allergic reaction to another allergen (eg, food, venom, or
latex)?
4. Do you have a history of an immediate or severe allergic reaction to PEG-, a polysorbate-, or
polyoxyl ?

46. GUIDANCE FOR INITIAL
ADMINISTRATION OF COVID-19 VACCINE

50. EVALUATION
• Do not recommend vaccine skin testing at this time because of limited vaccine
supply, lack of information on sensitivity or specificity, unclear safety of skin testing
• At April 2021 , mRNA vaccines are under EUA and remain unlicensed for skin
testing.

51. MANAGEMENT OF PATIENTS
WITH POTENTIAL REACTIONS TO THE COVID-19
VACCINES
• Pretreatment with fexofenadine 180-360 mg or cetirizine 10-20 mg 1-2 hours
• prior to the second dose of COVID-19 vaccination can be considered in
individuals with mild allergic symptoms (ie, pruritus or urticaria only)
• All patients with potential allergic reactions should be reported through formal
processes, which include the Vaccine Adverse Event Reporting System (VAER)

53. MANAGEMENT OF PATIENTS
WITH POTENTIAL REACTIONS TO THE COVID-19
VACCINES
• For other vaccines for which there is much more allergy experience
• Split-dose challenges (eg, 10%- 25% of the dose followed 30 minutes later by the remaining
75%-90% of the dose) have been used
• Although some groups have indicated their intent to implement split dosing of the mRNA
vaccines
• there are no supportive efficacy or safety data
• for both the Pfizer-BioNTech and Moderna vaccines
• Neither the stability of the vaccine diluted nor the safety and immunogenicity at altered doses
or concentration have been studied
• It should be remembered that these are not simple protein vaccines but instead are mRNA
vaccines and subject to degradation
• The Pfizer-BioNTech vaccine indeed is only 0.3 mL
• no data, to date, for either mRNA vaccine showing split-dosing efficacy

54. SUPPORTING SAFE VACCINATION AND ADDRESSING
PUBLIC CONCERN: A ROLE FOR THE
ALLERGIST
• Education on the diagnosis of anaphylaxis >> differentiating vasovagal and anxiety reactions from
anaphylaxis
• Education on the treatment of anaphylaxis. >> review epinephrine use and anaphylaxis-kit
contents
• Providing at-the-elbow support to vaccination programs
• Providing support to individuals with benign symptoms after discharge
• Up to 80% of individuals in the vaccine clinical trials had local symptoms after vaccination
• Large local reactions with symptoms of pain, itching, burning, or swelling at the site of injection do not
preclude an individual from getting the vaccine again
• Delayed local hypersensitivity reactions, with onset after Day 8, have been observed specifically with
Moderna's vaccine
• Nonsteroidal antiinflammatory drugs used to treat fever or myalgias may precipitate urticaria that could
be misattributed to the vaccine
• Allergists can provide assessments and reassurance and encourage completion of vaccination.

55. Flavoring Agents
• Flavorings that contain allergenic proteins are rare
• Traces of milk protein were found in hot dogs and bologna incriminated in reactions involving
four milk-allergic patients
• The milk protein emanated from use of a hydrolyzed sodium caseinate ingredient as a
flavor enhancer in the cured meats
• soup mix that contained peanut flour as a component of the natural flavoring
• The level of allergen resulting from flavors would be extremely low and likely insufficient to provoke
allergic reactions in every case
Mannitol
• A sugar alcohol that has many applications as a pharmaceutical excipient
• Associated with acute onset of urticaria and angioedema in a patient taking paracetamol orally
• May act as a hapten binding to proteins and acting through an IgE-mediated mechanism