Download What To Know About Drug Allergy

Drug Allergy, Diagnosis and
Treatment
Seong H. Cho, MD
Division of Allergy and Immunology
University of South Florida Morsani College of Medicine
경희의대 류마티스내과 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
Immunopathobiology of Other Drug
Reactions
• Pseudoallergic reactions
: Due to non-IgE-mediated mast cell activation
Examples - Opiates, vancomycin,
radiocontrast media
NSAID-urticaria
• Innate Immune Reactions
: Complement activation
Bradykinin release
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, carbamazepine
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
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
• High risk patients: HIV, SLE, BM transplant
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
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
• No reactions in patients with negative skin test to
imipenem or meropenem
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
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
and premedication with H1-antagonists
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
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
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
Journey in the US
NU
UCLA
UT
USF
UCLA School of Medicine
University of Tennessee College of
Medicine
Northwestern University School of Medicine
University of South Florida College of
Medicine
University of South Florida, Tampa, FL
USF Health North Campus
USF-Affiliated Tampa VA Hospital
Tampa Bay Area
USF Health South Campus
Thank You!!!
[email protected]