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) Predictable Related to pharmacologic actions of the drug 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 (IgE-mediated) 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, thrombo- cytopenia/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 cross-react 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!!! scho2@health.usf.edu