Download Reactions to ASA/NSAIDS/and Additives

Reactions to ASA/NSAIDS/and Additives –
How Do We Evaluate?
PAAA
Hershey, PA 6/21/13
R. Simon, MD
Head, Division Allergy Asthma and Immunology
Scripps Clinic
Adj. Member, Dept. Mol. & Exp. Med.
The Scripps Research Institute
La Jolla,
Jolla CA
Member, NIAID Expert Food Panel
Disclosures
• None for this talk
Objectives
• Following completion of this presentation,
attendees should be able to:
• 1. Diagnose and treat patients with a history of reactions to
ASA/NSAID’s
• 2. Recognize and evaluate patients with a history of
reactions to food & drug chemical additives
• 3.
3 Recognize and diagnose patients with a history of
anaphylaxis to natural food addtives
ASA/NSAID Reactions and Their Management
PAAA
Hershey, PA 6/20/08
Ronald A. Simon, MD
Head, Div. Allergy, Asthma and Immunology
S i
Scripps
Clinic
Cli i
Adjunct Member, The Scripps Research Institute
Dept. Mol. & Exp. Med.
La Jolla, California
Classification of Cutaneous Reactions
to Cox
Cox-1
1 Inhibitors
Inhibitors- SIMPLIFIED
• NSAID-Induced urticaria/angioedema
g
— Any Cox-1 inh;
normals
CIUA
• Single drug-induced
drug induced urticaria/angioedema
— Single drug-induced anaphylaxis
• Other/ “blended” reactions
Approach to Cutaneous Reactors to
Cox 1 Inhibitors
Cox-1
• NSAID-Induced urticaria/angioedema
g
— Any Cox-1 inh;
— Normals: can be desensitized
— CIUA: cannot be desensitized
• Single drug-induced urticaria/angioedema/anaphylaxis
— ASA OK
— Give a different NSAID
— If unknown: ASA challenge
• Other/ “blended” reactions
• Celecoxib (& other highly selective Cox2 inh) always OK
Approach to Cutaneous Reactors to
Cox 1 Inhibitors
Cox-1
• Provocation tests with offending NSAID
— 159 patients to start
— Only 17 patients (10.69%) had +
reaction to challenge
— Only 8 had – challenge to another
Cox1 inh (0.05%)
Way to
W
t few
f
to
t conclude
l d it is
i safe
f to
t
challenge with historically + Cox1 inh
Zia, G et al Allergy Asthma Proc 2012;33:421-426.
Approach to Cutaneous Reactors to
C
Cox-1
1 IInhibitors
hibit
• Approach in patients with cardiac
emergency
— White AA,, Stevenson DD,, Woessner KM,,
Simon RA. Allergy Asthma Proc.
2013;34:138-42
• Prevention
P
ti off reactions
ti
in
i outpatient
t ti t
setting
— Desloratidine/montelukast pre-treatment
— 1/65 reacted
— Nosbaum,
Nosbaum A et al Ann Allergy Asthma &
Immunol 2013;110:263-266.
Specific Food Additives
• Preservatives
• Food coloring
• Stabilizers
• Flavoring agents
• Co
Conditioners
dto e s
• Antioxidants
• Thickening agents • Miscellaneous
food additives
• Sweetening
S
t i agents
t
Contents of Premarin Tablets
(Brown, 0.625mg)
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Methylcellulose 15 CPS
T l Titurate
Talc
Tit
t
Lactose
Magnesium stearate
P l th l
Polyethylene
glycol
l
l 20,000
20 000
Glyceryl monooleate
Shellac
C l i
Calcium
sulfate
lf t
Titanium dioxide
Stearic acid
Edibl black
Edible
bl k ink
i k (Food
(F d grade)
d )
Carnuba wax
Corn starch
S
Sucrose
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Gum acacia
Talc
Sodium benzoate
Gelatin
Tween 60
Propyl paraben
FD&C Yellow #5
Calcium carbonate
Tricalcium phosphate
Soda floc
(Cellulose type material)
Sodium acetate
Sodium chloride
Neutral steroids
Estrogens
Additives Most Commonlyy Associated
With Adverse Reactions
• FD&C Dyes
• Tartrazine (FD&C yellow #5)
• Parabens
• Parahydroxy benzoic acid
• Methyl
• Ethyl Butyl
• Parabens
• Sodium benzoate
• Butylated hydroxyanisole (BHA)
• Butylated hydroxytoluene (BHT)
• Nitrates/Nitrites
• Monosodium glutamate (MSG)
• Sulfites
S lfi
– Sulfur Dioxide
• Sodium
• Potassium
• Sulfite
• Bisulfite
Bi lfi
• Metabisulfite
• Aspartame
p
(Nutrasweet)
(
)
NaO3S
N=N
COONa
N
HO
N
SO3Na
Tartrazine (FD & C Yellow No. 5)
Tartrazine and Initial Reports
of Adverse Reaction
– Purpose:
p
Coloring
g Agent
g
– Dosage:
0.1–
0.1–25mg
– Reactions Reported:
Asthma Urticaria
• Three patients with history of reaction to meds
containing tartrazine1:
– Patient #1:
In midst of generalized cutaneous eruption not
tartrazine related; no challenge
– Patient
P ti t #2:
#2
Ch ll
Challenged;
d open sublingual;
bli
l reacted
t d
– Patient #3:
Challenged; open, sublingual; mild complaints
localized to mouth
1. Lockey S. Ann Allergy 1959:17;719-725.
Reactions to Additives
• High Risk Groups
– Chronic Urticaria
– Asthma
Additive Challenges in CIUA
Recent Example
• 838 consecutive CIUA patients
• Results:
R
l
– DBPC mixed additive (#6): 116 + (13
(13.8%)
8%)
– Only 24 (or 31) were + when repeated as single
additives
dditi
((~ 3%)
Di Lorenzo G et al Int Arch Allergy Imunol 2005;138:2352005;138:235-242.
Additive Challenges in CIUA/AD
Most Recent Example
• 54 Korean patients; CIUA or AD
• Challenge: mixture of 6 additives
• Results:
– 44 (81.5%) no reactions (additives or placebos)
– 5 (9.3%) reacted only to additive
– 2 (3.3%) reacted to both additives and placebo
– 3 (5.5%)
(5 5%) reacted
t d only
l tto placebo
l
b
Park, WH et al J Allergy Clin Immunol 2008;121:10562008;121:1056-1061. (letter)
Prevalence of Sensitivity to Food/Drug
Additives in Patients with Chronic
Idiopathic Urticaria and Angioedema
(CIUA)
CIUA
Definition
•
Subjects (n = 110) with hives (with or without swelling) persisting for
more than 6 weeks without cause)
•
Excluded causes
– Cutaneous Vasculitis
• Hx, exam
• Esr, complement activation
• Biopsy (n = 40)
– Autoimmune
• Various
V i
serum autoantibodies
ib di (n
( = 35)
– Physical Urticaria
• Hx
• Challenges
Ch ll
(MCH,
(MCH cold
ld vibration,
ib ti pressure)) (n
( = 40)
Demographic Data
•
•
•
100 subjects, 64 females, 36 male
A
Ages:
14-67
14 67
Average duration of hives (mos.)
– Mean: 9
– Range: 3-52
•
Hx adverse reactions food/drug additives
((n = 43))
–
–
–
–
–
–
–
Sulfite (n = 5)
FD&C yellow #5 (n = 14)
Sulfite + FD&C yyellow #5 ((n = 8))
MSG (n = 10)
FD&C red #40 (n = 2)
FD&C blue #1 ((n = 1))
“Preservatives/chemicals” (n = 15)
Additives Tested/Dose (mg)
FD&C yyellow #5
50
FD&C yellow #6
50
K+ metabisulfite
100
MSG
2500
Aspartame
150
S di
Sodium
benzoate
b
100
Methyl paraben
100
BHT
250
BHA
250
Sodium nitrate
50
Sodium nitrite
50
Results
Positive Challenges
• Single blind placebo controlled: N = 2
• Double blind placebo controlled: N = 0
Conclusions
• With 99% confidence we conclude that sensitivity
to any of the 11 food drug additives in patients
with CIUA is < 1%
• Food/drug additives appear to be a rare
cause/exacerbant of CIUA
• Therefore,
Therefore avoidance is not recommended
Additives and Asthma
Asthma and Sensitivity to Tartrazine
•
Speer The management of childhood asthma.
Speer,
asthma Springfield,
Springfield Ill:
Charles C. Thomas, 1958, 23.
– Simple statement in monograph: No data presented
•
Chafee and Stettipane, J. Allergy 40:65, 1967.
– One patient
– Double-blind placebo controlled challenges, symptoms, no PFT’s
• Samter and Beers, J. Allergy 40:281, 1967.
• 80 asthmatics
h i (1/2 ASA sensitive)
ii
• Open solution challenge reaction + “Rhinorrhea and
Bronchoconstriction”
• Samter and Beers, Ann Int. Med. 68:975, 1968.
• ASA sensitive asthmatics, history positive, no challenges
Asthma and Sensitivity to Tartrazine
• Weber, et al., J. Allergy Clin. Immunol. 64:32, 1979
– 45 moderately severe asthmatics
• 50% ASA sensitive
– 7/45 “reacted” to tartrazine open challenge 20 mg.
– 0/45 double
double-blind
blind placebo controlled
• Vedanthan, et al., J. Allergy Clin. Immunol. 60; 1977
– 54 chronic asthmatic children
– 50 ASA
– Double-blind placebo controlled tartrazine challenges
– none reacted
Asthma and Sensitivity to Tartrazine
• Tarlo and Broder, Clin. Allergy 12:3030, 1982
– 28 chronic asthmatics
– 10 ASA sensitive
• 8 Hx
• 2 challenge
– Double-blind pplacebo controlled
– 1/28 positive (20.4% decreased FEV1)
• Not ASA sensitive
• No response to dietary elimination
Results of Tartrazine Challenges in Known
ASA-Sensitive Asthmatics (SCRF)
No ASA
Sensitive
No. of Tartrazine
Challenges (Single Blind)
No of Positive
(Single Blind)
No. of Positive
Double Blind
Group I
(1970-1980)
80
3
0
Group II
(1981 1985)
(1981-1985)
70
3
0
Group III
(1986-1991)
44
1
0
194
7 (3.6%)
0
Food Dye and Coloring Act
(FD&C) Approved Dyes
• AZO Dyes
– Tartrazine (FD&C Yellow #5)
– Ponceau (FD&C Red #4)
– Sunset Yellow #6)
– Amaranth (FD&C Red #5)
• Non AZO Dyes
y
– Brilliant Blue (FD&C Blue #1)
– Erythrosine (FD&C Red #3)
– Indigotin (FD&C Blue #2)
Commonly Used Sulfiting Agents
• Sulfur Dioxide
• Sodium
S di
or Potassium
i
– Sulfite
– Bisulfite
– Metabisulfite
Possible Mechanisms of Sulfite Sensitivity
• SO2 Inhalation
– Generated by sulfite
in solution
• Temperature
• pH
– Stimulation of
cholinergic/irritant receptors
• IgE Mediated
– Anaphylaxis
A h l i
– Asthma
• Sulfite Oxidase
Deficiency
• Other
Relationship of Sulfite Form Ingested and
Reactions
Approx. Sulfite
Potential for
Concentration
Reaction
(ppm SO2)
Food/Beverage
(Free Sulfite Available)
500-700
Salad
High
1,000-3,000
Dried Fruit
High
100-1,500
Potatoes
Low (but severe)
<10 1 000
P
Processed/Pkg.
d/Pk Food
F d <10-1,000
L
Low
((with
ith a ffew
exceptions)
50-150
50
150
Wine
Moderate
Monosodium Glutamate (MSG)
Non-essential Dicarboxylic Amino Acid
Purpose:
Flavor Enhancement
Dosage:
Up to 5 grams: Chinese meal
Reactions:
Chinese Restaurant Syndrome
Vascular headache
Monosodium Glutamate (MSG) and Asthma
• Scripps Experience
– 65 subjects
– High risk:
• 50 ASA sensitive asthmatics
• 15 asthmatics avoiding all MSG
– Double blind placebo controlled challenges
– No reactions
– >95% confidence no association
Woessner et al; J Allergy Clin Immunol. 1999; 104: 305.
Monosodium Glutamate (MSG)
Angioedema
Squire; Lancet 1;988
1;988, 1987 (letter)
Single-blind placebo controlled challenges (2)
Angiodema 16 hours after ingestion MSG
Aspartame (NutrasweetR)
Dipeptide
p p
(aspartic
( p
acid + methyl
y ester of phenylalanine)
p
y
)
Urticaria
Kulczycki, Ann. Int. Med 104:207, 1986
2 subjects
bj t
Double-blind placebo controlled
25-75 mg Aspartame (6 oz. Diet soft drink)
Headache
Schiffman et al. N. Engl. J. Med. 317:1181, 1987
40 subjects positive history
One day treatment in hospital
Negative results
Koehler and Glaros, Headache 28:10, 1988
11 subjects positive history
Four weeks of treatment at home
Positive results
BHA / BHT
Butylated Hydroxy Anisole / Butylated Hydroxy Toluene
Action:
Antioxidant
Uses:
Breakfast cereals
cake mixes
chewing gum
Toxicity:
Nausea, vomiting, cramps,
dizziness, confusion
NEJM 312
312:648,
648 1986
Sensitivity:
Chronic Idiopathic Urticaria
JACI 86:570, 1990.
Commonly Used Parabens/Benzoates
and Related Chemicals
Methyl Paraben
Sodium Benzoate
Propyl Paraben
Hydroxybenzoic Acid
Benzocaine
Para Amino Benzoic Acid (PABA)
Procaine
Reaction to Parabens/Benzoates in
Asthmatics



SCRIPPS
CLINIC
Samter and Beer, Ann. Int. Med. 68:975, 1968

ASA sensitive asthmatics

History positive - no challenges
Freedman, clin. Allergy 7:407, 1979

14 p
patients,, positive
p
history
y

4 positive challenges - no placebos
Weber et al., J. Allergy Clin. Immunol. 64:32, 1979:

43 mod
mod. Severe asthma

Double-blind placebo controlled

1/42 reacted - 250 mg. Sodium benzoate

2 years later - negative
RS717
39
Paraben Provoked Anaphylaxis
Local Anesthetics
Aldrete and Johnson, JAMA 207:356, 1969
Latronica et al. Oral Surg 28:439, 1969
Corticosteroids
Nagel et al. JAMA 237:1594, 1977
Subjects:
Reactions:
Positive Skin Test:
Otherwise normal
Only to injected paraben
Parabens
Drug with paraben
Passively transferred
Nitrates and Nitrites
Preservatives
Coloring
Flavor
Processed meat
No well documented reports of hypersensitivity reactions
Can provoke vascular headache
Metabolites ((Nitrososamines)) carcinogenic
g
Nitrates and Benzoates
• Chronic Pruritis
– Case Reports: Nitrates 1,2 or Benzoates 3
• All same author
– Improvement with avoidance
– Return with reintroduction &/or + challenge
• pruritis within 24 hours
• single placebo given first
• meds withheld
1. Asero, R J Allergy Clin Immunol 1999;104:1110-1111.
2. Asero, R Clin Exp Derm 2005;30:719-720.
3 Asero
3.
Asero, R Allergy 2006;61:1240
2006;61:1240-1241.
1241
Anaphylaxis From Natural
Additives
Annato, Carmine
Annato
Erythritol
Spearmint, peppermint,
menthol
Guar gum
Psyllium
C
Carrageenan
Lupine
p
Pectin
Gelatin
Mycoprotein
Celery-Mugwort-Spice
L
Lysozyme
Annatto Dye
• Yellow-orange food coloring
• Extracted from seeds of Bixa Orellana tree
(South America)
• Common in cheeses
• Anaphylaxis following “Fiber-One” cereal
• + Skin test - no challenge
Nish
i h WA
A et al.
l Ann
A Allergy
All
1991
1991; 66
66:129-131.
129 131
Carmine
• Red food dye
y
•
Extracted from dried female cochineal insects (coccus cacti)
•
Anaphylaxis following yogurt, delicatessen meats*,
popsicles**,
popsicles** candy
candy, ice cream,
cream pastry
pastry, jam
jam, tablets
tablets, capsules
•
Single case report; + Skin test, leukocyte histamine release no challenge*
•
Single case report; + Skin test, PK test - no challenge **
•
3 patients + skin test; 2 with + blinded placebo controlled
challenges
* Beaudouin E et al Ann Allergy
gy Asthma Immunol 1995;; 74:427-430.
** Baldwin, JL et al Ann Allergy Asthma Immunol 1997;79:415-419.
*** Chung, K et al Allergy 2001;56:73-77.
Anaphylaxis
p y
From Natural Additives
• Erythritol
– 4-carbon sugar alcohol
• prepared from glucose by fermentation
• U
Used
d as a sweetener
t
• May occur naturally in foods such as
wine beer
wine,
beer, soy
soy, cheese
cheese, mushroom
mushroom,
grape, and watermelon.
Yunginger, J et al. J Allergy Clin Immunol 2001; 108:650.
Anaphylaxis
p y
From Natural Additives
•
•
•
•
•
Spearmint
p
((Mentha spicata)
p
)
Peppermint (Mentha piperita)
e t o (Mentha
( e t a labiateae)
ab ateae)
Menthol
Flavorings used in chewing gum and toothpaste
Have been confirmed by challenges to have
triggered asthma in two cases
Spurlock, BW, Dailey, TM. N Engl J Med 1990; 323:1845.
Subiza J et al
Subiza,
al. J Allergy Clin Immunol 1992; 90:1004
90:1004.
Anaphylaxis
p y
From Natural Additives
• Guar gum
• A galactomannan derived from the guar bean
• Used as an emulsifier and binder in foods and
pharmaceuticals.
• Severe anaphylaxis and occupational
rhinitis/asthma
• + RAST/PST,, no oral challenge
g
Papanikolaou, I, Allergy 2007;62:822.
Anaphylaxis
p y
From Natural Additives
• Psyllium
y
– Soluble dietary fiber derived from the husks of
Plantago ovata seeds.
– Commonly used in bulk laxatives, and fiber-enriched
breakfast cereals.
anaphylaxis, occupational asthma/rhinitis
– Severe anaphylaxis
– Healthcare workers who have prepared and handled
psyllium-containing bulk laxatives appear to be at
particular risk
– + RAST tests; no PST, no oral challenges
James JM, et al J Allergy Clin Immunol. 1991;88:402-8.
Anaphylaxis
p y
From Natural Additives
• Carrageenan
– A gelatinous polysaccharide
– Derived
e ved from
o seaweed
– Used as a stabilizer and thickener.
– Anaphylaxis during barium enema
• Not latex
• + RAST & PST
• Pts. abdominal pain resolved on a carageenan free diet
Tarlo
a oS
SM;; Dolovich
o ov c J; Listgarten
stga te C J Allergy
e gy C
Clin Immunol.
u o . 1995;
995;
95:933-6.
Anaphylaxis
p y
From Natural Additives
• Lupine
– inexpensive flour extender
•
•
•
•
Lupine may have some cross
cross-reactivity
reactivity with peanut.
peanut
Anaphylaxis from a bun with traces of lupine flour
- RAST & PST; + basophil histamine release
No oral challenge
De las, Marinas D J Investig Allergol Clin Immunol 2007; 17:283.
Anaphylaxis
p y
From Natural Additives
• Pectin
• Jelling agent and thickener,
Cashews,
ews, pistachios,
p stac os, citrus
c t us (seeds)
• Cas
• Occupational asthma upon inhalation
• Anaphylaxis upon ingestion
– 3 ½ yo “cashew allergy”, anaphylaxis to “fruit
smoothie”
– + RAST, PST, no oral challenge
Ferdman RM et al. Allergy Asthma Immunol. 2006; 97:759-60.
Anaphylaxis
p y
From Natural Additives
• Gelatin
• Anaphylaxis
– Vaccines
– Measles, mumps and rubella (MMR), varicella,
Japanese encephalitis, influenza (1) has been reported
(2)
– Gummy
G
candies
di andd ffruit
i chews
h
1. Wang
1
Wang, J,
J Sicherer,
Sicherer SH
SH. Ann Allergy Asthma Immunol 2005; 94:530
94:530.
2. Scurlock, AM et al J Allergy Clin Immunol 2002; 110:936.
Anaphylaxis
p y
From Natural Additives
• Mycoprotein
– Fermented fungus (Fusarium venenatum) bound with egg
albumin.
– Shares common allergenic
g
determinants with other molds.
• Alternaria, Aspergillus & Cladosporium
– Used as a meat substitute (marketed as Quorn® in the United
States).
)
– Allergic reactions mainly in patients with inhalant mold allergy
Hoff, M et al J Allergy Clin Immunol. 2003; 111:1106-10.
Sandhu, MS, Hopp, RJ Ped Asthma Allergy and Immunol 2009; 22:5.
Tee RD; et al Clin Exp Allergy. 1993 Apr;23(4):257-60.
Anaphylaxis
p y
From Natural Additives
•
Celery-Mugwort-Spice Syndrome
– Potentially severe form of celery allergy
– Patients sensitized to both birch and mugwort.
– React
R t to
t the
th A
Apiaceae
i
ffamily
il ((carrot,
t caraway, parsley,
l
fennel, coriander, and aniseed), paprika, pepper,
mango, garlic, leek, and onion
– Due to celery profilin (Api g 4), which is highly crossreactive with profilins from both mugwort (Art v 4)
and birch (Bet v 2).
– Differs from OAS: reactions to cooked celery
Wuthrich B et al Allergy. 1990;45:566-71.
Angioedema
g
From Natural Additives
• Lysozyme
yso y e
– In raw egg, aged cheeses and pharmaceuticals
– Single case report
– Positive RAST, prick skin test
– Negative
N ti skin
ki tests
t t andd challenges
h ll
to
t other
th
ingestants
– No
N llysozyme challenge
h ll
Perez-Calderon R et al J Investig Allergol Clin Immunol. 2007;17(4):264-6.