Download What To Know About Drug Allergy

Drug Allergy
Seong H. Cho, MD
Assistant Professor of Medicine
Division of Allergy and Immunology
Northwestern University Feinberg School of Medicine
경희의대 내과 전임 IS 교수
Allergy-Immunology
 Primary immunodeficiency
(ex. CVID)
 Angioedema and urticaria
 Immunologic lung disease
(ex. ABPA, hypersensitivity
pneumonitis)
 Eosinophilc GI disorders
(ex.EoE)
 Hypereosinophilc syndrome
 Mastocytosis
Classification of Drug Reactions
• Type A reactions (Most common)
1. Predictable
2. Related to pharmacologic actions of the drug
3. No specific host factors
Type A Reactions
•
•
•
•
Toxicity - Renal failure from aminoglycosides
Side effect - Sedation from antihistamines
Secondary effect - Diarrhea from antibiotics
Drug Interaction - Theophylline toxicity from
concomitant erythromycin
Type B Reactions
• Unpredictable
• Less Common
• Occur in susceptible individuals
Type B Reactions
• Intolerance - Tinnitus with aspirin
• Idiosyncratic reaction - Hemolysis with
dapsone in G6PD deficiency
• Hypersensitivity (Specific immunologic) Anaphylaxis after penicillin
• Pseudoallergic (non-immunologic) Anaphylactoid reaction to radiocontrast media
Gell & Coombs Classification
• Type I - Immediate hypersensitivity (IgEmediated)
• Type II - Cytotoxic reactions
• Type III - Immune complex (e.g. serum
sickness, drug fever)
• Type IV - Delayed hypersensitivity
Sub classification of Type IV Reactions
Pichler W. Ann Intern Med 2003;139:683-9.
Other Immunopathology of Drug
Reactions
• Pseudoallergic reactions
- Resemble type I reactions
- Due to non-IgE-mediated mast cell activation
- Examples: Opiates, vancomycin, radiocontrast
media, NSAID-urticaria
- Clinical importance: can be prevented by steroid
• Innate Immune Reactions
- Complement activation
- Bradykinin release
• Others (TEN/SJS/DRESS)
Hapten Hypothesis
• Haptens are chemically reactive small
molecules
• Undergo stable covalent binding to a larger
protein or peptide
• Covalent binding of small hapten drugs to selfproteins leads to immunogenic compounds
• Penicillin classic example
Prohapten Hypothesis
• Drug that is not chemically reactive becomes
reactive after metabolism
• Chemically reactive drug metabolite can then
bind covalently to proteins/peptides and
become immunogenic
• Sulfamethoxazole example: Metabolized to
sulfamethoxazole-nitroso (highly reactive)
• Others: Acetaminophen, phenytoin,
procainamide, halothane
Drug Presentation to T cells
Posadas SJ et al. Clin Exp Allergy 2007;37:989–999
Risk Factors for Drug Allergy
• Drug Related
- Higher dose
- Parenteral administration
- Large molecular weight agents
• Host Factors
- Female gender
- Age (less frequent in infants and elderly)
- Diseases requiring repeated courses of therapy
- Genetics
Risk Factors for Drug Allergy
• Atopy (allergy)
- Atopy NOT a risk factor for small MW agents
(e.g. beta-lactam allergy)
- Atopy is a risk factor for:
 Latex allergy
 Radiocontrast media reactions
 Severe iv penicillin anaphylaxis
Clinical Manifestation: Exanthems
• Most common cutaneous drug eruption
• Usually develops days after new medicine
• Typically described as morbilliform
“maculopapular”
• Immunopathogenesis
:Many T cell mediated
Fixed Drug Eruptions
• Mechanism unknown
• Typically develops 1-2 weeks for initial reaction but
sooner with later exposures
• Occur in same location
with each subsequent
exposure to drug
• Pleomorphic: Eczema,
erythematous papules,
hyperpigmented areas,
bullous, urticarial
• Examples: Tetracycline, NSAIDs, carbamazepime
Photoallergic Reactions
• Immune mediated: DTH reactions
• UV light alters drug: Conjugation to selfprotein
• Acute reactions usually 24-72 hrs
• Medications: Quinidine, dapsone, HCTZ
Phototoxic Reactions
• Non-immunologic
• No drug alteration by UV light
• Erythroderma minutes to hrs after light
exposure
: Vesicles with severe reactions
• Often with first exposure to drug
• Medications: Sulfonamides, tetracycline,
furosemide, HCTZ, fluoroquinolones
Drug-Induced Blistering Disorders
• Drug-Induced Pemphigus
- 80% due to thiol group-containing medication
: Captopril, penicillamine
- Flaccid blisters
• Drug-Induced Bullous Pemphigoid
- Tense bullae on extremities, trunk, and
sometime mucous membranes
- ACE-I, furosemide, penicillin, sulfasalazine
Linear IgA Bullous Dermatosis
• Most commonly with vancomycin
• Other medications
: Captopril, furosemide, lithium, TMP/SMX
• Tense blisters that mimic bullous pemphigoid
• Generally occurs within 24 hours to 15 days
following administration of the offending drug
• Vancomycin-induced LAD is not dose dependent
and the severity of the reaction does not
correlate with serum vancomycin levels
Systemic vs. Cutaneous Drug-Induced
Lupus Erythematosis (DILE)
Solensky R et al. Ann Allergy Asthma Immunol 2010;105:273e1-78.
Serum Sickness
• Mediated by immune complexes:
Heterologous antisera, snake antivenom,
Rabbit antithymocyte globulin (ATG) and
rituximab
• Clinical features: Fever, lymphadenopathy,
arthralgias, rashes, gastrointestinal symptoms,
proteinuria (some cases)
• Typically occurs after 1-3 weeks: More rapidly
in previously sensitized
Serum Sickness-Like Reactions
• Small molecular weight agents: Penicillin,
sulfonamides, thiouracils, phenytoin
• May lack features of immune complexes,
hypocomplementemia, vasculitis, renal
disease
• Cefaclor most common cause in children
- Altered metabolism leading to toxic reactive
intermediates
Drug Fever
• Caused by release of pyrogens from
phagocytes :
- can be immune complex or T cell-mediated.
• Typically 7-10 days after therapy
• Fever pattern variable
• Relieved within 48 hrs of stopping drug
Pulmonary Drug Hypersensitivity
• Pulmonary infiltrate with eosinophilia (PIE)
- Cough within 10 days of starting drug
- Migratory infiltrates
- Peripheral eosinophilia
- Antibiotics, NSAIDs most common cause of
PIE
- Nitrofurantoin most common antibiotic
Pulmonary Drug Hypersensitivity
• Amiodarone
- Pneumonitis, bronchioloitis obliterans, ARDS
- Some reactions may be immunologic
• Methotrexate: Acute granulomatous ILD
• Chemotherapeutics
- ILD from bleomycin, mitomycin-C, busulfan,
cyclophosphamide, nirosourea
• Nitrofurantoin: Pleural effusion, pneumonitis,
fibrosis
Misc. Drug Allergy Syndromes
• Immunologic nephropathy
- Interstitial nephritis: +Urine eosinophils, benzyl
penicillin, methicillin or sulfonamides
- Membranous glomerulonephritis: gold, penicillamine,
allopurinol
• Aseptic meningitis: NSAID’s, IVIG, antibiotics
• Immunologic hepatitis: Halothane, para-aminosalacylic
acid, sulfonamides and phenothiazines
Severe Cutaneous Adverse Reactions
(SCAR)
• AGEP
• DRESS
• SJS/TEN
Acute Generalized Eczematous Pustulosis
(AGEP)
• Characterized by fine
pustules, fever, and neutrophilia
• Rash begins in intertriginous
areas or face as edema and
erythema
 Nonfollicular sterile pustules
develop afterwards
• Atypical target lesions, blisters and oral mucosal
involvement uncommon but may confuse with
SJS or TEN
• Lesional T cells secrete high amounts of IL-8
(CXCL8)
DRESS
• Drug Rash Eosinophilia Systemic Symptoms
• Causative Drugs
: Anticonvulsants, sulfonamides, allopurinol,
minocycline, dapsone, sulfasalazine,
abacavir, nevirapine, hydroxychloroquine,
vancomycin, etc.
Clinical Features of DRESS (I)
• Rash
: Exanthem, erythroderma, erythema multiforme,
purpura
• Facial edema is diffuse and may be mistaken for
angioedema
- Genital & extremity edema
• Fever
: Vast majority of cases
• Hypotension
: Up to 40% cases
Clinical Features of DRESS (II)
• Hematologic abnormalities
- Eosinophilia in > 50%
- Anemia, neutropenia, thrombocytopenia/cytosis less common
• Hypogammaglobulinemia in some cases
Organ Involvement in DRESS
• Lymphadenopathy <30% cases
• Liver involvement in >60% cases
• Renal dysfunction < 30% cases
: 40-80% with allopurinol
• Respiratory & Cardiac less common
: Eosinophilic pneumonitis, cough, dyspnea,
pharyngitis, Pericarditis, myocarditis
Unique Aspects of DRESS
• Reaction occurs after 2-8 weeks of therapy
• Symptoms may worsen after drug
discontinued
• Symptoms may last weeks to even months
after drug discontinued
Stevens-Johnson Syndrome (SJS) and
Toxic Epidermal Necrolysis (TEN)
• SJS/TEN thought to represent a spectrum of a
single reaction
• SJS: < 10% total body surface area
Overlap SJS/TEN: 10-30% body surface area
TEN: >30% surface area involvement
SJS vs TEN
*Nikolsky’s sign
Clinical Features of SJS/TEN
• Triad
1. Mucous membrane erosions: lip, oral cavity,
conjunctiva, nasal cavity, urethra, and vagina
2. Target lesions
3. Epidermal necrosis with detachment
• Multi-organ involvement
- Gastrointestinal, hepatic, pulmonary, renal
• Mortality: SJS: < 5%; TEN: 10-50% or higher
SJS/TEN
• Higher Risk Patients
: HIV, SLE, Bone marrow transplant
• High risk agents (*newer agents)
: *Nevirapine, *lamotrigine, *sertraline,
*pantoprazole, *tramadol, carbamazepime,
phenytoin, phenobarbitol, sulfasalazine,
allopurinol, sulfonamide antibiotics, oxicamNSAID’s
• TEN usually drug-induced and glucocorticoids are
contraindicated
Penicillin Allergy (Antigens)
• Major determinant (BPO)
: 95% PCN reacts with self-proteins via
beta-lactam ring to form benzylpenicilloyl
(BPO)
• Minor determinants
- penicilloate
- penilloate
- penicillin G
Penicillin Allergy
• 90% patients with a Hx of PCN allergy will
tolerate PCN
• ~ 80% PCN allergic patients lose PCN IgE after
10 years
• 1/3 patients with vague Hx of PCN allergy are
PCN skin test positive
PCN Skin Tests
• Negative predictive value for anaphylaxis is
close to 100% if skin test negative to
penicilloylpolylysine (Pre Pen) and minor
determinants
• 10-20% of PCN-allergic patients show skin test
reactivity only to penicilloate or penilloate
: Clinical significance is unknown
Ampicillin/Amoxicillin
• Some patients have IgE antibodies directed at the Rgroup side chain (not core penicillin determinants) and
are able to tolerate other penicillin class compounds
- Frequent in Europe, rare in U.S.
- PCN skin tests negative
• Amoxicillin and ampicillin are associated with the
development of a delayed maculopapular rash in about
5-10% of patients
- not IgE-mediated
- Concomitant conditions
: EBV (infectious mono; ~100% children develop rash)
Penicillin and Cephalosporins
Share a common beta-lactam ring
Cephalosporin & PCN Allergy
• Only 2% of penicillin skin test-positive patients
react to treatment with cephalosporins: Some
fatal
• If penicillin skin testing is unavailable, and
cephalosporin needed, it may be given via graded
challenge
: Negative cephalosporin skin test appears to
predict tolerance (Romano 2004)
• Patients with a history of non-severe reaction to
penicillin rarely react to cephalosporins
Cephalosporin Allergy
• Most hypersensitivity reactions to
cephalosporins are directed at the R group
side chains rather than the beta-lactam group
• Cephalosporin allergic patients should avoid
cephalosporins with similar R-group side
chains
PCN Allergy and Monobactams
• Aztreonam (monobactam) does not crossreact with other beta-lactams
: except for ceftazidime
shares an identical R-group side chain
PCN Allergy and Carbapenems
• Moderate allergic cross-reactivity between
penicillin and carbapenems based on skin tests
: 50% PCN-allergic patients skin test positive to
imipenem (Saxon 1988)
• Clinical cross-reactivity variable but much lower
- Recent studies suggest 0-11% react
NEJM 2006;354:2835-7,
Ann Intern Med 2007;146:266-69,
JACI 2009;124:167-9.
Skin testing for Non-PCN Antibiotics
• There are no validated diagnostic tests for
evaluation of IgE-mediated allergy to
nonpenicillin antibiotics
• A negative skin test result does not rule out
the possibility of an immediate-type allergy
• Positive skin test results to a drug
concentration known to be non-irritating
suggests the presence of drug-specific IgE
Sulfonamide Allergy
• A sulfonamide is any compound that contains
a sulfonamide (SO2NH2) moiety
• Sulfonamide antimicrobial drugs are different
from other sulfonamide-containing
medications (furosemide, thiazide diuretics
and celecoxib) by virtue of an aromatic amine
at the N4 position and a substituted ring at
the N1 position
Sulfonamide Allergy
• Delayed maculopapular eruption most typical
reaction: Mechanism unclear
• Very frequent in HIV infected patients
: (44-70%)
Cross-Reactivity between
Sulfonamide Antibiotics and Nonantibiotics
• Myth about cross-reactivity between
sulfonamide antibiotics and nonantibiotic
drugs (lasix, HCTZ, sulfasalazine etc)
• Patients with sulfonamide antibiotic allergy
were more likely to react to penicillin than a
sulfonamide non-antibiotic
Strom BL et al. NEJM 2003;349:1628-35
Vancomycin: Red Man Syndrome
• Constellation of symptoms
- Pruritus, flushing, erythroderma common
- Hypotension uncommon
• Due to nonspecific histamine release that is rate
related (rare reports of IgE-anaphylaxis)
• Severity correlates with amount of histamine
released into plasma
• Severity reduced by
- reducing rate to < 500 mg/hr
- premedication with H1-antagonists
Perioperative Drug Reactions
• Neuromuscular blocking agents are most
common (succinylcholine, rocuronium,
atracurium, vecuronium, etc)
- IgE mediated or direct mast cell activation
• Other causes of IgE mediated perioperative
reactions
- Latex, barbiturates (thiopental), antibiotics
Perioperative Drug Reactions
• Dextran and hydroxyethyl starch
: Anaphylactoid reactions
• Propofol
- Rare reports including those with egg allergy
- Propofol contains egg lecithin (from egg yolk)
which contains minimal contaminant egg
protein
- One study showed 98% egg allergic children
tolerated propofol
Chemotherapeutics
• Taxanes (paclitaxel, docetaxel)
- Anaphylactoid reactions
- Pretreatment with systemic corticosteroids and
antihistamines prevents most reactions
• Platinum compounds (cisplatin, carboplatin, oxiplatin)
- IgE mediated
- typically cause hypersensitivity reactions after
completion of several treatment courses
• Asparaginase may cause anaphylactic or anaphylactoid
reactions
Local Anesthetic Allergy
• Most adverse reactions to local anesthetics are due to
nonallergic factors
- Vasovagal, anxiety
- Toxic or idiosyncratic reactions due to intravenous
epinephrine
• Local anesthetic groups
- group 1 benzoic acid esters: procaine, benzocaine
- group 2 amides: lidocaine, bupivicaine, mepivacaine
• Based on patch testing, benzoic acid esters cross-react
with each other, but not group 2 amide drugs
Local Anesthetic Allergy
• Skin tests are not adequate to diagnose
lidocaine allergy
: false positives
• Graded challenge test of choice for evaluating
potential local anesthetic allergy
Radiocontrast Media Reactions
• Mechanisms
- Anaphylactoid
: Direct mast cell activation
? IgE mediated (Allergy. 2009 Feb;64(2):234-41.)
- Delayed reactions due to type IV hypersensitivity
• Reaction rate from ionic contrast > non-ionic contrast
• No evidence that sensitivity to seafood or iodine
predisposes or is cross-reactive with RCM reactions
Radiocontrast Anaphylactoid Reactions
• Risk Factors
- Female
- Asthma
- Cardiovascular disease
- Prior reaction to RCM
• Management
- Non-ionic RCM
- *Pre-treatment
1. Prednisone 50 mg
: 13, 7, 1 hr prior
2. Diphenhydramine 50 mg
: 1 hr prior
3. Ephedrine/albuterol
4. H2-antagonists
: controversial
*Pre-treatment does not completely prevent RCM reactions
Aspirin-Exacerbated Respiratory Disease
(AERD)
• Associated with asthma, rhinitis, sinusitis,
nasal polyposis
• Symptoms with NSAIDs
: Rhinorrhea, conjunctivitis, bronchospasm
- Rarely flushing, urticaria, GI symptoms,
laryngospasm, hypotension
• Dependent on COX-1 inhibition
• COX-2 inhibitors generally safe
Pathophysiology of AERD
- Inhibition of COX-1 results in
: Inhibits PGE2 leading to ↑ leukotrienes
- ↑ urinary LTE4
↑ LTE4 and TXB2 in BAL
↑ LTC4 synthase expression in bronchial mucosa
↓ lipoxin generation
↑ cysLTR1 & cysLTR2 receptor expression
↑ response to inhaled LTD4
AERD
• Diagnosis
: Oral challenge
Inhalation of lysine-ASA
• Aspirin Desensitization
- Improvement in upper and lower airway
symptoms
- After ASA desensitization
↓ uLTE4, ↓ BHR to LTE4
↓ serum tryptase/histamine
↓ nasal expression of cysLT1 receptor
Angiotensin Converting Enzyme (ACE)
Inhibitors
• Cough
- Incidence up to 20%
- Mechanism unknown
- Angiotensin II receptor blockers (ARBs) tolerated
• Angioedema
- 0.1-0.7%, more common in African-Americans
- Usually delayed in onset: mean 1.8 yrs (Malde 2007)
- Likely des-Arg bradykinin induced
- Usually tolerate ARBs but case reports of AE with
ARBs too
Insulin
• Local Reactions
- IgE mediated
- Resolve with continued administration
• Systemic Reactions
- Usually occur after gap in insulin therapy
(ex. Gestational diabetes)
- Skin tests and desensitization may be required if
insulin therapy interrupted > 24-48 hrs
Adverse Reactions to Biologics
• Cytokine release syndrome
- Fever, rash, bronchospasm, capillary leak
syndrome, GI sxs, aseptic meningitis,
encephalopathy
- ↑ LFTs, uric acid, LDH
- Associated with rituximab (anti-CD20) &
muromunab (anti-CD3)
Adverse Reactions to Biologics
• IL-2 (aldesleukin)
- Capillary (vascular) leak syndrome
- Uncommon but potentially fatal
- Hypotension and edema due to
extravascular fluid and protein
extravasation
Monoclonal Antibody Reactions
• Anaphylaxis
- Basiliximab (chimeric anti-IL2 receptor antagonist)
- Muromonab (murine anti-CD3 mAb)
- Cetuximab (anti-EGFR)
: Due to pre-existing antibodies to an oligosaccharide,
galactose-α-1,3-galactose present on the Fab portion
of cetuximab (Chung NEJM 2008)
: most had specific IgE to cetuximab before therapy
Management of the Drug Allergic
Patient
• For most drugs no validated in vivo or in vitro
diagnostic tests are available
• If a patient requires a medication they are
allergic to options include:
1) finding an alternative medication
2) performing a graded drug challenge
3) performing drug desensitization
Drug Desensitization
• Benefit
- Established protocols for many drugs
- Relatively safe
: May be done in an office setting
: Reactions during desensitization variable depending on
drug but rarely severe
• Disadvantages
- Temporary effect (not tolerance induction)
- Need to take medicine continuously to maintain
desensitized state
- Need to repeat for every subsequent courses
Graded Challenge (Test Dose)
• A graded challenge is a procedure to
determine if a drug is safe to administer
• Intended for patients who are unlikely to be
allergic to the given drug
• In contrast to a desensitization, a graded
challenge does not modify the patient’s
response to a drug
Graded Challenge (Test Dose)
• Benefit
- Easy to perform
- Typically start with 1/100th of final dose, then
1/10th and full dose
- usually given every 30-60 minutes
- confirms or negates drug allergy history
• Disadvantages
- Potentially higher risk
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