Drug Allergy Classifications

Gell & Coombs

• Type I:  Immediate Hypersensitivity (IgE mediated)
• Type II:  Cytotoxic
• Type III:  Immune complex (ie serum sickness)
• Type IV:  Delayed type hypersensitivity

Sub Classification of Type IV  Exanthematous Drug Reactions

• Type IVa: Th1, IFNg /Monocytic infiltrate/ Eczematous
• Type IVb: Th2, IL-4&5 /Eos infiltrate/ Maculopap, bullous
  
• Type IVc: CTL, perforin, granzyme /CD4 & 8/ Maculopap, bullous (w CD8),  pustular
• Type IVd: T cells, IL-8 /Neutrophilic infiltrate/ Pustular

Hapten Hypothesis

• Haptens: small molecules, chemically reactive
• Can covalently bind to larger proteins or peptides
• Small hapten DRUGs  covalently bind to SELF proteins forming immunogenic cpmnds
• EXAMPLE:  PCN

Prohapten Hypothesis

• PRODRUG not reactive, but after reactive metabolite binds covalently to self proteins/peptides and becomes immunogenic
• EXAMPLE:  Sulfmethoxizole metabolized to Sulfmethoxizole-nitroso which is highly reactive

p-i Concept

(Pharmacologic interaction with immune receptors)

• Drug binds directly to Tcell receptor
• Interacts w MHC molecules leading to Tcell stim
• Examples: Sulfamethoxazole, Cipro, Lidocaine, Carbamazepine, PPheylendiamine, Lamotrigine

Risk Factors for Drug Allergy

• High Dose
• IV
• Large MW agents
• Frequent repetative courses
• Female>male
• Less frequent in infants and elderly
• HLA-DR-3:  Nephropathy w gold,penicillamine, insulin
  
• HLA_B*5701:  Abacavir
  

Atopy as risk factor in Drug Allergy

• NO:  not w small MW agents ie beta lactam
• YES:  RCM, Latex allergy

Fixed Drug Eruption

• Same location w each drug exposure
• Pleomorphic (eczema, bullous, papular, urticarial...)
• EXAMPLES:  Tetracycline, sulfa, barbiturates, NSAIDs, Carbamazepine
• Predelection to breasts, genitalia

Phototoxic/Photoallergic reactions

• Face, V area of neck, hands,arms
• Spares scalp, submental and periorbital ('sun distribution')
• UV-A light (can go through glass, sunscreen doesn't prevent)
• Photopatch test can diagnose

Photoallergic reactions

• Immune mediated (T cell)
• UV light alters drug and allows conjugation to self protein
• Eczematous
• Days to months to develop

Phototoxic reactions

• Non immunologic
• No drug alteration w UV light
• Erythroderma 4-8 hours p light exposure
• Often w first exposure to drug (no sensitization needed)

Drug Induced Cytopenias

• Immunohemolytic anemia:  Quinidine, methyldopa, pcn  (+direct and indirect Coombs)
• Immune induced thrombocytopenia:Quinidine, PTU, gold, sulfa, Vancomycin, Heparin (IgG to heparin-plt factor 4 forms immune complex)

Pulmonary Drug Hypersenstivity

• Cough within 10 d of drug initiation, migratory infiltrates, peripheral eosinophilia
• Pulmonary fibrosis: usually non immune (toxic) mechanisms
• Many drugs can cause: Unique: Nitrofurantoin  also causes pleural effusion

DRESS

Drug Rash Eosinophilia Systemic Syndrome

aka

Drug hypesensitivity syndrome

Anti-epilepetic Drug hypesensitivity syndrome

Phenytoin  hypesensitivity syndrome

• Associated w HumanHerpes (HHV-6)
• Anticonvulsants, sulfa, allopurinol, minocycline, dapsone, abacavir

DRESS

Drug Rash Eosinophilia Systemic Syndrome

aka

• Fever, rash, Eosinophilia, LAN, hepatitis
• Characteristic facial edema (not angioedema),
• Multisystem incl renal, cardiac
• Reactions can occur p2-3 weeks on drugs and develop over several days
• May last weeks or months p drug d/c'd

SJS and TEN

• Spectrum of same disease
• SJS: epidermal detachment <10%, confluent purpuric macules, mucosal lesions, ocular, liver , kidney or lung involvement; steroids controversial
• TEN: >30% epidermal detachment; drug induced. NO steroids (contraindicated)
• Hi risk:  Sulfa, cephalosporins, NSAIDs, anticonvuls

SJS and TEN

Mechanisms

• Reactive metabolites
• Cytotoxic T lymphocytes
• Apoptosis vis Fas/FasL

Drug induced Blistering disorders

• Drug-induced Pemphigus: FLACCID blisters, 80% to thiol group containing meds ie Captopril, penicillamine
• Drug induced Bullous Pemphigoid: TENSE bullae on extr, trunk, occ mucous membranes:  ACE-1, furosemide, penicillium, sulfa
• GUS IS FLACCID

Linear IgA Bullous Disease

• Most commonly assoc with vancomycin, furosemide, lithium, SMX/TMP
• Tense bullae that mimic pemphigoid
• Vanc induced is NOT dose dependant, does NOT correlate with serum levels

Drug Induced Lupus Erythematosis

Systemic vs Cuntaneous

Systemic

Systemic DILE                          Cutaneous  DILE

Purpura/E Nodosum     Photosens erythema,scaly plaques

Arthralgias, myalgias 

Anti-histone abs                      Anti-Ro/SSA, Anti-La/SSB

Develops over months                Develops over weeks

Hydralazine, procainamide,         HCTZ, CCB, ACE inhibs

INH

Misc Drug Allergy Syndromes

Immunologic nephritis: 

   -Interstitial nephritis (urine eos): benzyl pcn, methicillin, sulfonamides

   -Membranous GN:  Gold, penicillamine, allopurinol

Aseptic Menigitis:  NSAIDS, IVIG, antibiotics

Immunologic hepatitis:  Para-aminosalacylic acid (PAS for TB), sulfa, phenothiazines

 Penicillin Allergy

Major Determinants

95% of PCN  reacts w self proteins via

beta lactam ring  to form

Benzylpnicilloyl (BPO)

 Penicillin Allergy

Minor Determinants

• Penicilloate
• Penilloate
• Penicillin G

Penicillin Allergy

Incidence/tolerance

• 90% of pts w/ + history will tolerate
• 80% PCN allergic pts lose PCN IgE after 10 yrs (transient?)
• BUT: 1/3 of pts w vague Hx of PCN are ST +

PCN Skin Tests

• NPV for anaphylaxis is close to 100% if ST neg to both Pre Pen (Penicilloyl-polylysine) and MDM
• 10-20% of PCN allergic pts show ST + only to peniclloate or penilloate (MDM)
• "Aged" Penn-G of no value (does not form MDM)

PCN Resensitization

• Risk after subsequent oral treatment w PCN is rare in both pediatric and adults pts
• More likely after high dose IV but little data

Ampicillin/Amox Allergy

• Some pts w IgE directed at R-group side chain (not core PCN determinants), therefore able to tolerate other pencillin class compounds (PCN ST negative)
• Non-IgE mediated delayed maculopapular rash in 5-10% of pts: EBV (100% will develop rash), CLL, Allopurinol or high uric acid

Cross reactivity PCN vs Cephalosporins

• 2% PCN ST+pts react to cephalosporins (some fatal)
• PCN ST- pts may receive cephalosporins safely
• If can't ST to PCN: cephalosporin graded challenge or ST w non-irritating concentrations
• Patients with non severe reaction to PCN rarely react to cephalsporins

Cephalosporin Allergy

• Most hypersensitivity reactions to CS are directed at the R group side Chain, not the beta lactam group
• CS allergic pts should avoid CS w similar R group side chains (practice parameter pending)

Cephalosporin Serum-Sickness like Reactions

• Ceflacor (Ceclor) and, less often Cefprozil
• No evidence of Ab mediated basis
• ?Altered mebabolism of parent drug leads to reactive intermediate compoiunds
• No need to avoid other celphosporins in this case

Monobactams and PCN allergy

• Both share a beta lactam ring
• Aztreonam (monobactam) does NOT cross react w other beta lactams except ceftazidime (shares identical R-group side chain)

Carbipenims and PCN allergy

• moderate cross reactivity on skin tests, (50% PCN allergic are ST+ to imipenem) BUT
• clinical cross-reactivity much lower (0-11%)
• NO rections in pts w negative ST to imipenem or meropenem
•  but only

Skin Testing for other Antibiotics

• PCN is only validated ST for antibiotics
• ST w non-irritating concentrations of others not standardized
• Negative ST not predictive re Immed Type HS
• Positive ST to non-irritating concentration suggests presence of drug-specific IgE

Sulfonamide Allergy

(Antimicrobials.. not all sulfas)

• Delayed Maculopapular eczematous eruption most typical (?mechanism)
• Type 1 is RARE; may be detected by ST and Rast but poor sensitivity
• N⁴-sulfonamidoyl hapten is major determinant
• Very common in HIV patiens (44-70%)

Sulfonamide Allergy

(Antimicrobials.. not all sulfas)

• No definable cross reactivity between Sulfonamide antibiotic and non-antibiotic sulfas
• History of Sulfonamide (or any other) antibiotic allergy is a general indicator of higher risk for sulfonamide nonantibiotics (NOT cross reactive)

Vancomycin

• IgE mediated reactions rare
• Red Man Syndrome: Priritus, flushing, erythroderma, hypotension
• Due to nonspecific histamine release-rate related
• Severity correlates w histamine release
• Severity reduced by decr rate to <500mg/hr, reducing concomitant opiates, premedicate w antihistamines

Abacavir

Pharmacogenomics

• nucleoside reverse transcriptase inhibitor associated w  multiorgan hypersensivity rxns (fever, rash, malaise, fatigue, GI, respiratory) in 4%
• Rxns mostly in first 6 weeks
• HLA-B*5701 strongly associated
• Genetic screening reduced incidence of rxns

Serum Sickness

• Immune complex rxns (PCN, Sulfonamides, thiouracils, phenytoin)
• Fever, rash, urticaria, LAN and arthralgias 1-3 weeks after starting;  Duration up to several weeks
• RX:  systemic corticosteroids, H1 antihistamines

Perioperative Drug Reactions

• Quaternary ammonium muscle relaxants most common;  IgE vs direct mast cell activation.  Succinyl choline may act as a bivalent antigen due to large molecular size
• Latex
• Barabiturates ie thiopental
• Abx
• ?Isosulfan blue, ?albumin
• Protamine (immunologic and NON immunologic); increased risk w use of NPH insulin, fish allergy
• Dextran and hydroxyethyl starch: anaphlactoid

Chemotherapeutics

Rxns mechanisms by class

• Taxanes (paclitaxel, docetaxel and excipients ie Cremophor-EL): anaphylactoid- pretreat w OCS+H1
• Platinum cmpnds :IgE-mediated(cisplat, carboplat,oxiplat); typically after several treatment courses;skin testing and desensitization helpful
• Asparaginase:  anaphylactic OR -toid-RX-substitute PEG asparaginase or Erwinia asparaginase for E coli asparaginase

Local Anesthetic Allergy

• Most due to non-allergic or toxic rxns, ? to epi component
•  Group 1 benzoic acid esters (procaine, benzocaine)
• Group 2 amides (lidocaine, bupivicaine, mepivicane)
• Patch testing shows group 1 cross react w each other but not group 2.                ? relevance to immediate type reactions vs contact dermatitis
• Skin tests: false positives occur
• Graded challenge is test of choice: always include placebo-v high placebo assoc reactions in this group of pts

RCM

• Anaphylactoid mechanism: direct MC activation vs complement activation.  ?Report of IgE mediated
• ?DTH/Type IV
• Ionic>non-ionic
• No evidence of seafood or iodine relationship (predispostion or cross reactivity)

RCM Anaphlyactoid Rxns

• Risk factors:  F>M, Ashtma, CV dz, prior RCM rx

Management:

• Non ionic RCM
• Pretreatment regimens somewhat controversial: Pred 50mg at 13, 7 and 1 hr prior, Benadryl 50mg i hr prior, Ephedrine/albuterol, H2 antagonists

AERD

(Prev Sampters)

• Associated w asthma, rhinitis, sinusitis, nasal polyposis (may not have all)
• Other NSAID sx that may be present:  rhinorrhea, conjunctivitis, bronchospasm; rarely: flushing, urticaria, GI sx, laryngospasm, hypotension
• Dependent on COX-1 inhibition, possible w high dose acetominophen
• COX-2 generally safe

AERD

Pathophysiology

• Baseline pathophysiology:  increase in: urinary LTE₄, BAL LTE₄ and TXB₂, cys LT₁ receptor expression on PBM, and response to inhaled LTD₄
• After ASA challenge: increase in urine LTE_4, histamine and tryptase in serum in some and in nasal secretions in most (mast cell activation?)
• With COX-1  inhibition (ASA/NSAIDS): inhibition of PGE₂ that leads to increased leukotrienes (PGE2 downregulates/ inhibits 5 lipoxygenase, therefore COX-1 inhibition removes downregulation ie increases 5-LO)

AERD

Diagnosis

• Oral challenge
• Lysine-ASA inhalation

AERD

Desensitization results in:

• Improvement in upper and lower airway sx
• Decrease in:  uLTE_4,  BHR to LTE_4, serum histamine and typtase, expression of cysLT₁ receptor on PBM
• Data from controlled but not DBPC studies

Allergic reactions to ASA

Cross reactivity

• Underlying mechanism dictates cross reactivity
• YES:  AERD (Cox 1 inhib), Urticaria/ AE rxns in pts with underlying chronic urticaria
• MAYBE:  Urticaria/AE without underlying chronic urticaria or blended reactions with underlying disease  ?challenge
• NO:  true anaphylactic multiorgan system sx: drug specific, ?IgE.  Tolerate other NSAIDS

ACE Inhibitors

Cough

• Incidence up to 20%
• ? Mechanism
• ARBs tolerated

ACE Inhibitors

Angioedema

• Almost always neck and above.  Rarely w urticaria
• Incidence 0 1-0.7%, more common in African-Americans
• Delayed in onset (mean 1.8 years )
• Likely des-Arg bradykinin induced via decreased APP and DPPIV  (ie defect in a non-ACE, non-kininase I pathway of bradykinin degradation)
• May tolerate ARB but cases of AE w ARBs too

Insulin allergy

• Local:   More common, IgE mediated, resolve w continued administration
• Systemic:  usually after gap in therapy, most have immediate local rxns to injections; ST and desensitization may be required if therapy interrupted >24-48 hours
• Many diabetics have + ST without symptomatic allergy

Adverse  Reactions to Biologics

see chart page 926

Adverse  Reactions to Biologics

Cytokine Release Syndrome

• Fever, rash, bronchospasm, capillary leak (can be confused w anaphylaxis), GI sx, aseptic meningitis, encephalopathy
• increased LFTs, Uric Acid, LDH
• High IL-6 and TNFa
• Rituximab (Rituxin-anti CD20) and muromunab (Orthoclone OKT3--anti-CD3)

Adverse  Reactions to Biologics

Interferon

Can cause rxns in all categories:

• a: flu like sx
• b: urticaria and dermatiti
• c: vasculitis, ITP, autoimmune thryoid dz, vitiligo, psoriasis
• d: depression

Adverse  Reactions to Biologics

TNF inhibitors

Not usually IgE mediated

• Infliximab (Remicade): often on first dose, not IgE; but can be delayed ?serum sickness; Abs to infliximab may correlate  w reactions
• Etanercept (Embrel):  Injection site and recall reactions
• Adalimumab (Humira):  more humanized, less frequent rxns; Injection site
• Other rxns: vasculitis, SLE, sarcoid, ILD, psoriasis

Adverse  Reactions to Biologics

Anaphylaxis

• Cetuximab: due to pre-existing Ab agains Alpha-gal.  Linked to  delayed rxns to meat
• Basiliximab anti IL2 (in BMT)
• Muromonab

Omalizumab

• Anaphylaxis of ? mechanism
• In first few doses, within 2 hours
• ?malignancy and CV events

Induction of  Drug Tolerance/'Desensitization'

see chart p 930