6/13/2014
Drug Allergy Update
Disclosures
Gap in Knowledge
• None.
• Fill a gap in knowledge regarding the evaluation and
management of adverse drug reactions and drug allergies.
• No discussion of off-label uses of medications.
• No commercial support provided for this activity.
Thanai Pongdee, MD, FAAAAI
Division of Allergy and Pulmonary Medicine
Mayo Clinic, Jacksonville ,FL
SOWEGA-AHEC
CURE Activity
06.17.14
©2011 MFMER | slide-2
©2011 MFMER | slide-3
©2011 MFMER | slide-4
Adverse Drug Reactions (ADRs):
Why is this important?
Adverse Drug Reactions (ADRs): Definition
Objectives
• Most useful components of history in drug allergy
evaluation
• ADR- “Any noxious, unintended and undesirable
effect of a drug, which occurs at standard doses
when administer by proper route in humans for
prevention, diagnosis, or treatment.”
• How to manage beta-lactam allergies
• For sulfa allergy, should all sulfa medications be
avoided?
• Adverse drug reactions are a major health
problem in the United States1
• Over 2 MILLION serious ADRs yearly2
• 100,000 DEATHS yearly2
• Fourth-leading cause of death after heart disease,
cancer, and stroke2
• Approximately 24% of hospitalized
patients report reactions to antibiotics1
• Aspirin/NSAID allergy – do all NSAIDs have to be
avoided?
WHO. 1966. Technical Report Series No. 425
• What is drug desensitization and who is eligible?
• Penicillin most frequently reported allergy1
•
1. Lee CE et al. Arch Inter Med 160:2819, 2000
•
2. Lazarou J, Pomeranz BH, Corey PN. JAMA. 1998;279:1200-1205.
©2011 MFMER | slide-5
Classification of adverse drug reactions
Nomenclature
Nomenclature
Drug hypersensitivity
• Immune mediated drug hypersensitivity (drug allergy)
• Type A: predictable; strictly dose dependent
• 80% of all side effects
• Pharmacological side effects (e.g. gastrointestinal bleeding under
treatment with NSAID)
• Type B: not predictable; usually not dose dependent,
and sometimes reactions to very small amounts
•
•
•
•
15-20% of all side effects
Immunologic/allergic
Non-immune mediated, “pseudoallergic”
Idiosyncratic
• Clinical symptoms due to different types of specific immune reactions
(T-cell & B-cell/Ig mediated)
Drug allergy
Non-allergic hypersensitivity
eg: Non-specific histamine release,
Arachidonic acid pathway activation,
Bradykinin pathway alteration,
Complement activation
• Non immune mediated drug hypersensitivity (non-allergic
drug hypersensitivity)
• Symptoms and signs similar to immune mediated hypersensitivity, but
failure to demonstrate a specific immune process to the drug
• Older term: “pseudoallergy”
IgE-mediated
Non IgE mediated
drug allergy
drug allergy
• Idiosyncrasy
• symptoms and signs due to some genetic alterations, e.g. an enzyme
deficiency: e.g. hemolytic anaemia due to certain drugs in patients
with G-6-P-deficiency
Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature
for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization,
October 2003. J Allergy Clin Immunol 2004;113:832-6
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Allergic Drug Reactions
Patient’s history is an important component of
the evaluation of drug allergies
Gell and Coombs Classification
• Type I - IgE Mediated
• Example: Penicillin induced anaphylaxis
• Type II – IgG or IgM cytotoxic mediated
• Example: Penicillin-induced hemolytic anemia/ heparin
induced thrombocytopenia
• Type III - Immune Complex-Dependent
• Example: Penicillin causing serum sickness
• Type IV - Delayed Hypersensitivity
• Example: Penicillin used topically causing contact
dermatitis
• What is the name of the medication and route?
• How long ago did the reaction occur?*
• Which systems were involved in the reaction?*
• What were the characteristics of the reaction?*
• When during the course did the reaction occur?*
Patient’s history is an important component of
the evaluation of drug allergies
• Had the patient taken the same or a cross-reacting
medication before the reaction?
• Has the patient been exposed to the same or similar
medication since the reaction?*
• Has the patient experienced similar reactions in the
absence of drug treatment?*
• Why was the medication prescribed?
• Does the patient have an underlying condition that
favors reactions to certain medications?
• What other medications was the patient taking
concurrently at the time of the reaction?*
• How long did it take for the reaction to resolve?
• How was the reaction treated?
• Review the medical record*
Khan D et.al. J Allergy Clin Immunol. 2010;125:S126-137.
Khan D et.al. J Allergy Clin Immunol. 2010;125:S126-137.
Drug Allergy Testing
• Is there a safe validated diagnostic test
available?
• If not, are there alternative medications
available?
• Drug challenge vs. desensitization
Khan D et.al. J Allergy Clin Immunol. 2010;125:S126-137.
Penicillin Allergy
Penicillin Allergy
• 63-year-old female
• 85-year-old male
• Adverse reaction to penicillin when she was a teenager
• Adverse reaction to penicillin in the 1940s
• Received oral penicillin and subsequently developed
hives on her arms, facial swelling as well as the
sensation of throat swelling and dyspnea
• Recalls receiving an injection of penicillin into his finger
and subsequently developing generalized hives and
angioedema. He does not recall any respiratory distress
or gastrointestinal distress. He was not hospitalized and
did not seek emergency care.
• Treated at ER
• She was told she was allergic to penicillin and has
avoided its use since that time.
• Symptoms resolved after two to three days.
• He was told he was allergic to penicillin and has
avoided penicillin use since that time.
Penicillin Allergy
• 36-year-old female
• States her mother told her she had an adverse reaction
to penicillin when she was three years old.
Recommendations for these patients?
• Developed some type of rash after taking penicillin. No
other specific details are known.
A) Continue avoidance of penicillin and
find an alternative antibiotic
• She was told she was allergic to penicillin and has
avoided its use since that time.
B) Penicillin allergy skin testing
What is the negative predictive value (NPV) and
positive predictive value (PPV) of penicillin skin
testing?
A)
NPV = ~80% PPV = ~80%
B)
NPV = ~50% PPV = almost 100%
C)
NPV = almost 98% PPV = ~50%
C) These reactions happened so long
ago, penicillin should be safe to give.
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Penicillin Allergy - Epidemiology
Structures of Penicillin
Allergenic Determinants
Penicillin Allergenic Determinants
• About 10% of the population self-reports “penicillin allergy”
• ~90% are NOT allergic and able to tolerate penicillin
Penicillin
• Mayo Experience: ~97% of the patients who have a history of penicillin
allergy are pcn skin test negative1,2,3,4,5
95%
• Why the discrepancy between “claimed” and “real” penicillin
allergy?
• Previous reaction predictable, not truly allergic
• Previous reaction due to underlying illness
• Previous reaction due to interaction between illness/antibiotic
• Penicillin allergy wanes and may resolve over time
1.Park MA et al. Ann Allergy Asthma Immunol 97 (2006): 681-87.
2.Frigas E. et al. Mayo Clinic Proceedings. 2008; 83(6): 651-657.
3.Park MA et al. Ann Allergy Asthma Immunol 99 (2007): 54-58.
4.Park MA, et al. International Archives of Allergy and Immunology 2010; 153(3):268-273.
5.Park MA, et al. International Archives of Allergy and Immunology 2011; 154:57-62.
PrePen (penicilloyI-polylysine)
1. Sogn et al. demonstrated that among 167 patients with a positive PCN
skin test, 140 (84%) of the patients were skin test positive to the PPL.
Major determinant
(Penicilloyl)
5%
Penicilloyl
Penicilloate
Penilloate
Minor determinants
(Penicilloate, Penilloate)
*Gadde J, Spence M, Wheeler B, Adkinson NF, Jr. Clinical experience with penicillin skin testing in a large inner-city STD clinic. Jama 1993; 270:2456-63.
Sogn DD, Evans R, 3rd, Shepherd GM, et al. Results of the National Institute of Allergy and Infectious Diseases Collaborative Clinical Trial to test the predictive
value of skin testing with major and minor penicillin derivatives in hospitalized adults. Arch Intern Med 1992; 152:1025-32.
Penicillin skin test
• Penicillin skin test is designed to detect IgE
antibodies to the components of penicillin
2. Gadde et al. reported that 115 (89.8%) of 128 patients with a positive
PCN test were positive to the PPL.
3. However, several recent studies have shown a less robust detection of
PCN allergy by PPL (64%-69%).*
Penicillin
• Penicillin skin test has been validated for IgE
mediated reactions to PCN*
Penicillin Skin Testing
Predictive Value
• Negative predictive value (using both major and minor
determinants) approaches 100%
• Gadde et al. studied a total of 5,063 outpatients with and
without a history of PCN allergy.
• 3% h/o PCN allergy/negative ST/challenged w/ PCN had
an IgE mediated reaction to PCN
• vs. 0.2% w/o h/o PCN allergy/negative ST/challenged w/
PCN
• Sogn et al.
*Blanca M, Romano A, Torres MJ, et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy 2009; 64:183-93.
Wong BB, Keith PK, Waserman S. Clinical history as a predictor of penicillin skin test outcome. Ann Allergy Asthma Immunol 2006;
97:169-74.
Goldberg A, Confino-Cohen R. Skin testing and oral penicillin challenge in patients with a history of remote penicillin allergy. Ann Allergy
Asthma Immunol 2008; 100:37-43.
Jost BC, Wedner HJ, Bloomberg GR. Elective penicillin skin testing in a pediatric outpatient setting. Ann Allergy Asthma Immunol 2006;
97:807-12.
*Gadde J, Spence M, Wheeler B, Adkinson NF, Jr. Clinical experience with penicillin skin testing in a
large inner-city STD clinic. Jama 1993; 270:2456-63.
Sogn DD, Evans R, 3rd, Shepherd GM, et al. Results of the National Institute of Allergy and Infectious
Diseases Collaborative Clinical Trial to test the predictive value of skin testing with major and minor
penicillin derivatives in hospitalized adults. Arch Intern Med 1992; 152:1025-32.
• 1.2% (726 h/o pcn allergy/negative ST)
• vs. 0% (568 negative h/o pcn allergy/negative ST) had an
IgE mediated ADR to challenge with PCN
Gadde et al. JAMA 1993; 270 (20); 2456-2463
Sogn et al. Arch Intern Med. 1992;152:1025-1032
Penicillin Skin Testing
Predictive Value
Penicillin Skin Testing
Whom to Skin Test
After the Skin Test
•
• Any patient with a history of a reaction to a penicillin class
antibiotic that may have been IgE-mediated
Skin test positive patients
1-3% of skin test-negative patients develop
a mild reaction upon being challenged
with penicillin
•
Rank MA, Park MA*. Anaphylaxis to piperacillin-tazobactam despite negative skin tests.
Allergy. August 2007; 62(8): 964-5
• Patient’s reaction history is known to be a poor predictor of
skin test reactivity
• Many patients cannot recall specifics of their reaction
•
Penicillin skin testing is not predictive of
non-IgE-mediated reactions (Stevens-Johnson
syndrome, interstitial nephritis, hemolytic anemia,
etc.)
• Patients with convincing histories (i.e., anaphylaxis) lose
penicillin-specific IgE antibodies over time
Penicillin Skin Testing
• Avoid all penicillins
• Consider reevaluation in 3-5 years
• If develop absolute need for penicillin –
desensitize
• Patients with vague histories could be allergic
• Review of published studies revealed that among history-positive/skin
test-positive patients, 1/3 had a vague reaction history*
Solensky R et al: Ann Allergy Asthma Immunol 85:195, 2000
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Penicillin Skin Testing
After the Skin Test
Skin test negative patients
What is the negative predictive value (NPV) and
positive predictive value (PPV) of penicillin skin
testing?
• Low likelihood of an IgE mediated adverse reaction to PCN
A)
NPV = ~80% PPV = ~80%
• In children and those with a history of anaphylaxis that is recent,
consider oral challenge
B)
NPV = ~50% PPV = almost 100%
C)
NPV = almost 98% PPV = ~50%
First principal of drug allergy
• If an alternative medication that is equally efficacious, then
give alternative medication
• However, if no alternative medication is available, then
testing or drug challenge or desensitization is warranted.
Which penicillin skin test reagent do patients
with a history of an IgE mediated reaction to
penicillin react to most often?
A) PrePen (penicilloyI-polylysine)
B) Penicillin G
C) Penicilloate
D) Amoxicillin
60 year old female had hives 20 years ago after
taking penicillin and has avoided penicillin since
the original reaction. She has a proven Strep
throat infection. What would be the next best
step?
•
A) Give azithromycin
•
B) Give penicillin VK
•
C) Penicillin skin test: if negative give penicillin
VK
•
D) Give cephalexin
60 year old female had hives 20 years ago after
taking penicillin and has avoided penicillin since
the original reaction. She has a proven Strep
throat infection. What is the probability that she
is still allergic to penicillin?
A) About 20%
B) About 30%
C) About 50%
D) About 90%
Waning penicillin allergy
• After one year:
• 67 to 82% still will be positive to skin testing
• After 5 years:
• ~40% still will be positive to skin testing
Penicillin skin testing is not predictive for which
type of allergic drug reaction?
Allergic cross-reactivity between beta-lactam
antibiotics may be due to:
A) Anaphylaxis
A) beta-lactam portion of the molecule
B) Urticaria
B) R-group side chains
C) Interstitial nephritis
C) Either A or B
D) Bronchospasm
• After 10 years:
• ~20% still will be positive to skin testing
Blanca et al. JACI 1999; 103:918-24
Chandra et al. Arch Dis Child 1980; 55:857-860
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Beta-lactam Structures
R-side chains
Beta-lactam ring
What is the cross-reactivity between penicillins
and cephalosporins?
Cephalosporin Challenges in Patients with History
of Penicillin Allergy
Reference (Year)
A) Approximately 3%
Dash CH (1975)
B) Approximately 15%
Petz LD (1978) C) Approximately 50%
Goodman EJ (2001)
Dalat SB (2004)
Cephalosporin Reaction Rate
+ History Pcn ‐ History Pcn Allergy
Allergy
7.7% (25/324)
0.8%
(140/17,216)
8.1% (57/701)
1.9%
(285/15,007)
0.33% (1/300)
0.04% (1/2,431)
0.17% (1/606)
Fonacier L (2005)
8.4% (7/83)
0.06%
(15/22,664)
N/A
MacPherson RD (2006)
0% (0/84)
N/A
Comments
No reaction details
No reaction details
Reaction questionable
Reaction = eczema
Reactions convincing
Khan et al. J Allergy Clin Immunol 2010;125:S126-37.
Cephalosporin Challenges in Penicillin ST+ Patients
Reference (Year)
# of
Patients
# (%) of
Reactions
Girard (1968)
Assem (1974)
Warrington (1978)
Solley (1982)
Saxon (1987)
Blanca (1989)
Shepherd (1993)
Audicana (1994)
Pichichero (1998)
Novalbos (2001)
Macy (2002)
Romano (2004)
Greenberger (2005)
Park (2010)
Ahmed (2012)
23
3
3
27
62
16
9
12
39
23
42
75
6
85
21
2 (8.7)
3 (100)
0
0
1 (1.6)
2 (12.5)
0
0
2 (5.1)
0
1 (2.4)
0
0
5 (6%)
0
446
16 (3.6%)
TOTAL
Cephalosporin Challenges in Penicillin STPatients
Reference (Year)
# of patients
# (%) reactions
Sullivan (1981)
23
0
Solley (1982)
151
2 (1.3)
Cephalosporin
challenges0 in Penicillin
Shepherd and 159
Burton (1993)
ST
+ 3.6% vs Penicillin ST – 0.7%
Audicana (1994)
18
0
patients 5 (0.7%)
Park (2010)
726
Ahmed (2012)
152
1 (0.7%)
Total
1229
0.7%
What is the cross-reactivity between penicillins
and cephalosporins?
A) Approximately 3%
B) Approximately 15%
C) Approximately 50%
Khan et al. J Allergy Clin Immunol 2010;125:S126-37.
Cephalosporin Administration to Patients with History of
Penicillin Allergy
Penicillin Administration to Patients with History of
Cephalosporin Allergy
Penicillin Allergy/Cephalosporins
• Early reports of relatively high reaction rates to
cephalosporin's in penicillin-allergic patients were
likely due to:
• Trace contamination of cephalosporin's with
penicillin
• Similarity of R-group side chains between
benzylpenicillin and early 1st generation
cephalosporins (cephalothin, cephaloridine,
cefamandole)
Solensky R, et al. Ann Allergy Asthma Immunol 2010; 105:259.
Solensky R, et al. Ann Allergy Asthma Immunol 2010; 105:259.
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35 yo with a history of anaphylaxis to amoxicillin
and positive to the penicillin skin test needs a
carbapenem. The carbapenem is the best
antibiotic for the patient and no equivalent
antibiotic is available for the type of infection.
What is the best next step:
Beta-lactam Structures
Carbapenem Challenges in Patients with History of
Penicillin Allergy
Beta-lactam ring
Reference (Year)
A) Give full dose
Beta-lactam ring
B) Give as a graded challenge
McConnell SA (2000)
Prescott WA (2004) Carbapenem Reaction Rate
+ History Penicillin ‐ History Penicillin Allergy
Allergy
6.3% (4/63)
N/A
P Value
N/A
11% (11/100)
2.7% (3/111)
0.024
Sodhi M (2004)
9.2% (15/163)
3.9% (4/103)
0.164
Cunha BS (2008)
0% (0/110)
N/A
N/A
Khan D et.al. J Allergy Clin Immunol. 2010;125:S126-137.
Carbapenem Challenges in Penicillin ST+ Patients
Carbapenem Administration to Patients with a
History of Penicillin Allergy
Reference (Year)
Negative
Romano A (2006)
Romano A (2007) # of Patients
110
103
# of Reactions
Carbapenem Given
0
Imipenem
0
Meropenem
Atanaskovic (2008)
107
0
Meropenem
Atanaskovic (2009)
123
0
Imipenem
Comment
Skin test to penicillin
Positive
One patient imipenem ST+
35 yo with a history of anaphylaxis to amoxicillin
and positive to the penicillin skin test needs a
carbapenem. The carbapenem is the best
antibiotic for the patient and no equivalent
antibiotic is available for the type of infection.
What is the best next step:
One patient meropenem ST+
One patient meropenem ST+
One patient imipenem ST+
• All challenged patients also skin test‐negative to carbapenems
Khan D et.al. J Allergy Clin Immunol. 2010;125:S126-137.
May safely administer
carbapenem
1. Give alternate
drug
2. Give
carbapenem
via graded
challenge
3. Desensitize to
carbapenem
A) Give full dose
B) Give as a graded challenge
Aztreonam (Monobactams)
Aztreonam (a monobactam beta-lactam
antibiotic) does not cross react with other betalactams with the exception of:
• Share common beta-lactam ring with penicillin
Aztreonam
• There is NO in vitro immunologic cross-reactivity
between aztreonam and penicillins/cephalosporins
with the exception of ceftazidime (which has the
identical R-group side chain as aztreonam)
A) Ceftazidime
B) Cefazolin
• All penicillin skin test-positive patients challenged with
aztreonam tolerated the medication
C) Cefuroxime
Ceftazidime
• Case reports of patients allergic to aztreonam being
able to tolerate all other beta-lactams except
ceftazidime
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60 year old female with a history of anaphylaxis
to a cephalexin 10 years ago needs ceftriaxone.
What is the next best step assuming no better
alternative medication is available?
•
A. Give ceftriaxone because cephalosporins do
not cross-react
•
B. Desensitize to ceftriaxone
•
C. Give ceftriaxone as a graded challenge
•
D. Cephalosporin skin test because
cephalosporin skin test has been standardized
Not a lot of data!
Beta-lactam Structures
R-side chains
Beta-lactam ring
• Themes:
• Speculation that side chains of cephalosporins play a
bigger role
• Similar side chains more likely to be “allergic”
• Dissimilar side chains less likely to be “allergic”
Romano et al. Allergy 2002
Cross-reactivity among cephalosporins by
skin test and in vitro testing
Cephalosporin Administration to Patients with
History of Cephalosporin Allergy
The most common class of antibiotic to cause
allergic reactions aside from penicillin is:
• Cross-reactivity with similar side chains:
• ~68% (67-69%)
• Cross-reactivity with dissimilar side chains:
A) Macrolides
• ~30% (28.6-38%)
B) Sulfonamides
• However, data is very limited and need caution.
C) Quinolones
Solensky R KD, Bernstein IL, Bloomberg GR, Castells MC, Mendelson LM, Weiss ME, et al. Drug Allergy: An
Updated Parameter. Ann Allergy 2010; 105:273e1-e78.
Antunez C, Blanca-Lopez N, Torres MJ, Mayorga C, Perez-Inestrosa E, Montanez MI, et al. Immediate
allergic reactions to cephalosporins: evaluation of cross-reactivity with a panel of penicillins and
cephalosporins. J Allergy Clin Immunol 2006; 117:404-10.
Atanaskovic-Markovic M, Velickovic TC, Gavrovic-Jankulovic M, Vuckovic O, Nestorovic B. Immediate
allergic reactions to cephalosporins and penicillins and their cross-reactivity in children. Pediatr Allergy
Immunol 2005; 16:341-7.
Somech R, Weber EA, Lavi S. Evaluation of immediate allergic reactions to cephalosporins in non-penicillinallergic patients. Int Arch Allergy Immunol 2009; 150:205-9.
Solensky R, et al. Ann Allergy Asthma Immunol 2010; 105:259.
Boston Collaborative Drug Surveillance Program – Skin
reaction rates* due to antibiotics
• Amoxicillin – 51.4
• TMP-SMX – 33.8
• Ampicillin – 33.2
• Cephalosporins – 21.1
• Erythromycin – 20.4
• Penicillin G – 18.5
The most common type of allergic reaction
caused by sulfonamide antibiotics is:
A) Anaphylaxis
* Reaction rate per 1000 recipients
B) Serum sickness-like reaction
C) Maculopapular eruption
D) Drug fever
Patients with a history of allergy to trimethoprimsulfamethoxazole (Septra) should avoid the
following non-antibiotic sulfonamides:
A) Celecoxib (Celebrex)
B) Sumatriptan (Imitrex)
C) Furosemide (Lasix)
D) All of these
E) None of these
Bigby M, et al. JAMA 1986; 256:3358‐63.
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Sulfonamides Definitions
• Sulfonamides = drugs containing an SO2-NH2 moiety
• Sulfonamide antibiotics
• Aromatic amine (arylamine) at N4 position
• Substituted ring at N1 position
Sulfonamide Antibiotics
Sulfamethoxazole
N4 Aromatic Amine
• Non-antibiotic sulfonamides
• No aromatic amine at N4 position
• No substituted ring at N1 position
• Examples
• Diuretics: Furosemide, thiazide
• Oral hypoglycemics: Glyburide, chlorpropamide
• Carbonic anhydrase inhibitors: Acetazolamide,
dorzolamide
• Other: Celecoxib, sumatriptan
Glyburide
N1 Substituted Ring
Furosemide
Acetazolamide
Sulfonamide Moiety
Celecoxib
Sulfonamides Cross-Reactivity
Aspirin and NSAIDS
Adverse Reaction Types
• N4 aromatic amine – essential for non-IgE
mediated reactions to sulfonamide antibiotics
• N1 substituted ring – appears important for
IgE-mediated reactions to sulfonamide antibiotics
• Growing body of evidence showing no increased
risk of allergic reactions to non-antibiotic
sulfonamides in patients with history of allergy to
sulfonamide antibiotics
Patterson R et al: Clin Ther 21:2065, 1999; Storm BL et al: N Eng J Med 349:1628, 2003; Shapiro LE et al: Drug Safety
26:187, 2003; Morgan M et al: J Allergy Clin Immunol 113:S180, 2004; Khan et al. J Allergy Clin Immunol 2010;125:S126-37.
Which of the following NSAIDs will patients with AERD
(aspirin exacerbated respiratory disease) not react to?
A) ibuprofen
B) naproxen
C) celecoxib
D) ketorolac
Hydrochlorothiazide
Reaction Type
Underlying
disease
Crossreactions
NSAID-induced rhinitis and
asthma
(AERD – aspirin exacerbated
Respiratory disease)
Asthma, nasal
polyps, sinusitis
Yes
NSAID-induced
urticaria/angioedema
Chronic idiopathic
urticaria
Yes
Single drug-induced
urticaria/angioedema
None
No
Multiple drug-induced
urticaria/angioedema
None
Yes
Single drug-induced
anaphylaxis
None
No
Skin testing for allergic reactions to
aspirin/NSAIDs is highly valuable.
A) True
AERD (aspirin exacerbated
respiratory disease) prevalence
B) False
AERD Natural History
• Rare in children less than 10 years old
• Questionnaires
• 0.6% to 2.5% in general population
• 3.8% to 11% in asthmatics
• Oral challenges
• all asthmatics, 10-20%
• asthma, rhinosinusitis, polyps, 30-40%
• hx of ASA/NSAID resp rxns, 60-100%
• Acquired disorder with onset of symptoms
beginning between teenage years and age 40
years
• Average ages of onset were 29 and 34 years in two
large studies
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AERD Natural History
AERD Natural History
• First clinical manifestation is usually nasal
congestion
• ASA/NSAID- induced respiratory reactions can
occur at any time
• URI may be an inciting event
• Despite avoidance of aspirin and NSAIDs, mucosal
inflammation of the upper and lower respiratory
tracts persists and progresses
• Chronic rhinitis progresses to chronic hyperplastic
eosinophilic sinusitis with nasal polyposis
Respiratory Reactions to Aspirin and NSAIDs
• Asthma either previously present or begins de novo
between 3 months to 5 years after onset of nasal
congestion and polyposis
Respiratory Reactions to Aspirin and NSAIDs
• Reactions usually occur within 30 to 60 minutes
after ingesting full therapeutic doses, but can occur
up to 3 hours later
• Cross-reactivity among NSAIDs that inhibit COX-1
is 100%
• Most common eliciting agents
• Aspirin (80%)
• Ibuprofen (41%)
COX-1-Inhibiting NSAIDs that Cross-react with ASA
Generic name
Generic name
Brand name
Mefenamic acid
Ponstel
Indomethacin
Sulindac
Indocin
Clinoril
Flurbiprofen
Diflunisal
Ansaid
Dolbid
Tolmetin
Tolectin
Ketoprofen
Orudis, Oruval
Ibuprofen
Motrin, Advil, Rufen
Diclofenac
Voltaren, Cataflam
Naproxen
Naproxen sodium
Naprosyn
Anaprox, Aleve
Ketoralac
Etodolac
Toradol
Lodine
Fenoprofen
Nalfon
Nabumetone
Relafen
Meclofenamate
Meclomen
Oxaprozin
Daypro
• Partial cross-reactivity with partially selective COX2 inhibitors
• Salsalate tolerated up to 2000mg
COX-1-Inhibiting NSAIDs that Cross-react with ASA (cont.)
Feldene
Respiratory Reactions to Aspirin and NSAIDs
• 28% with mild rxns to 1000mg
• 6% with rxns at doses of 1500mg
• Reactions include rhinorrhea, nasal congestion,
ocular itching/tearing, laryngeal spasm, and asthma
exacerbations
Piroxicam
• Partial cross-reactivity with poor inhibitors of COX-1
• Most patients can safely tolerate up to 500mg
acetaminophen
• Reactions occur to ASA and all NSAIDs that
preferentially inhibit cyclooygenase (COX)-1
Brand name
Respiratory Reactions to Aspirin and NSAIDs
• acetaminophen
• salsalate
• Only occurs in patients with AERD
• meloxicam
• nimesulide
• Lack of cross-reactivity with selective COX-2
inhibitors
• celecoxib
Diagnosis of AERD
• Diagnosis can be definitively established only
through provocative aspirin challenges
• No reliable in vitro test
• 4 types of provocation challenges
•
•
•
•
Oral
Inhalation
Nasal
Intravenous
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6/13/2014
Aspirin Desensitization
AERD Treatment
Aspirin Desensitization
• Avoiding ASA/NSAIDs
• Discovered in 1979
• ASA must be continued to maintain refractory state
• Add-on treatment for underlying AERD
• Indications:
• Poorly controlled AERD • ASA/NSAID needed for CV disease, osteoarthritis, etc.
• Does not prevent AERD from starting, continuing, and
progressing
• Eliminates acute respiratory reactions
• Cross-desensitization with other NSAIDs
• Treat underlying respiratory disease
• Progressive administration of ASA leading to respiratory reac on → refractory state of tolerance
• Treat underlying allergic inflammation
Changes in clinical markers after
aspirin desensitization
Baseline
≥ 1 year after therapy
Aspirin desensitization as add on therapy:
•
Clinical measures
Median
Range
Median
Range
P values
# sinus infections/yr
5.0
0-12
2.0
0-12
<0.0001
Olfactory scores
0.0
0-5
3.0
0-5
<0.0001
Nasal symptom scores
2.0
0-4
4.0
0-4
<0.0001
Asthma symptom scores
3.0
0-4
4.0
0-4
<0.0001
Sinus operations/yr
Hospitalizations/yr
ER visits/yr
0.22
0-3
0.0
0.0
0- 5
0.0
0-2
0-3
0.15
0-15
0.0
0-5
Effects of daily aspirin treatment
<0.0001
<0.0001
<0.0001
Which of the following NSAIDs will patients with AERD
(aspirin exacerbated respiratory disease) not react to?
1.
2.
3.
4.
5.
6.
7.
8.
Decreases nasal congestion
Decreases need for additional sinus/polyp surgery
Decreases infectious sinusitis (from 5 to 2/year)
Improves sense of smell
Improves asthma control
Reduces need for nasal corticosteroids
Reduces need for bursts of systemic steroids
Reduces daily systemic steroids (10.8 to 3.6 mg.)
Most patients with a severe anaphylactic allergy
to a specific NSAIDs are able to tolerate:
A) ibuprofen
A) Other NSAIDs
B) naproxen
B) No other NSAIDs
C) celecoxib
C) Only selective COX-2 inhibitors (like
celecoxib)
D) ketorolac
Skin testing for allergic reactions to
aspirins/NSAIDs is highly valuable.
A) True
B) False
Drug tolerance induction (Desensitization)
• Drug tolerance is defined as a state in which a
patient with a drug allergy will tolerate a drug
without an adverse reaction.
• Drug tolerance does not indicate a permanent state
of tolerance
• Induction of drug tolerance procedures modify a
patient’s response to a drug to temporarily allow
treatment with it safely.
Solensky R , et al. Drug Allergy: An Updated Parameter. Ann Allergy 2010; 105:273e1 - 273e78 .
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6/13/2014
Drug tolerance induction (Desensitization)
• They are indicated only in situations where an
alternate non–cross-reacting medication cannot be
used.
• Induction of drug tolerance can involve IgE immune
mechanisms, non-IgE immune mechanisms,
pharmacologic mechanisms, and undefined
mechanisms
• All procedures to induce drug tolerance involve
administration of incremental doses of the drug.
65 yo with a history of penicillin allergy
(anaphylaxis) 20 years ago underwent penicillin
skin testing. The penicillin skin test is positive
and penicillin is the best medication. What
percentage of patient’s will have a reaction to
penicillin while undergoing penicillin
desensitization?
1.
5%
2.
10%
3.
30%
4.
60%
Solensky R , et al. Drug Allergy: An Updated Parameter. Ann Allergy 2010; 105:273e1 - 273e78
64 yo male underwent a successful
“desensitization” to trimethoprim and
sulfamethoxazole (Bactrim). After three weeks of
consistently taking trimethoprim and
sulfamethoxazole, the patient forgets to take it
for three days. What is the best next step?
A) Resume full dose trimethoprim and
sulfamethoxazole since he is desensitized
B) Proceed with a drug challenge to trimethoprim and
sulfamethoxazole before being able to take the full
dose
C) Undergo a desensitization to trimethoprim and
sulfamethoxazole
Desensitization
Take away points:
Take away points:
•
Many medications can undergo successful
desensitization
• Penicillin skin test is only validated skin test for
medications with high NPV
• Drug desensitization may be considered if a
medication is absolutely indicated.
• Many have not been standardized
Sulfonamide antibiotic desensitization is 80 to
90% successful in the short-term but decreases
to 72% in the long-term1,2,3,4
• Growing body of evidence showing no increased
risk of allergic reactions to non-antibiotic
sulfonamides in patients with history of allergy to
sulfonamide antibiotics
• Patients with aspirin allergy and sulfonamide allergy
can be desensitized as an outpatient in most cases
•
ASA desensitization for AERD can be done
successfully as an outpatient
• Aspirin desensitization should be considered for
treatment of AERD
•
Contraindication: Severe non-IgE mediated ADR
such as Stevens Johnson Syndrome, Toxic
epidermal necrolysis, DRESS syndrome etc.
• Not all patients with NSAID allergy need to avoid all
NSAIDs
•
• Don’t challenge, test, or desensitize to patients with
SJS, TEN, Serum Sickness, DRESS due to a
medication
1.Bonfanti P, et al. Biomed Pharmacother. 2000 Feb;54(1):45‐9.
2.Kalanadhabhatta V, et al. Ann Allergy Asthma Immunol. 1996 Nov;77(5):394‐400.
3.Palusci VJ, et al. Pediatr Infect Dis J. 1996 May;15(5):456‐60. 4. Nguyen MT, Weiss PJ, Wallace MR. AIDS. 1995 Jun;9(6):573‐5.
Thank you
• Allergy Section
• Thanai Pongdee, MD
• Arveen Thethi, MD
• Special thanks
• Miguel Park, MD
Evaluation
Attended Live Activity on 06.17.14
• Allergy
•
•
•
•
•
•
Allergic rhinitis
Anaphylaxis
Drugs
Immunotherapy
Foods
Stinging insect
http://www.surveymonkey.com/s/CURE53
Attended Archived Activity 06.18.14 or later
http://www.surveymonkey.com/s/CURE53Archived
• Asthma
• Allergic and nonallergic
• Exercise-induced
• Refractory
©2011 MFMER | slide-98
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