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Drug Allergy DEPARTMENT OF IMMUNOLOGY

ASAL GHARIB

Learning objectives ▪ Types of Drug Allergies ◦ Adverse drug reaction ◦ Drug hypersensitivity ◦ Drug allergy

▪ The epidemiology and risk factors for drug allergy

▪ Understand the pathogenesis and immunological mechanisms underlying the different phenotypes of drug allergy

▪ Classification of adverse drug reactions

Adverse Drug Reactions (ADRs) ▪ Type A: predictable dose dependent ◦ 80% of all side effects ◦ pharmacological side effects such as GI bleeding with NSAIDS

▪ Type B: not predictable, not dose dependent ◦ 15-20% of all side effects ◦ Occurs in susceptible individuals ◦ Unintended response to drug taken at normal doses

Type B: Unpredictable Reactions ▪ Drug Intolerance

▪ Drug Idiosyncrasy

▪ Drug Allergy

▪ Pseudoallergic reactions

Adverse Drug Reactions ▪ ADRs have been reported to account for 3-6% of all hospital

admissions and occur in 10-15% of hospitalized patients; ▪ Drug allergy has been estimated to account for up to a third of all

ADRs; ▪ Most epidemiologic studies have dealt with ADRs or adverse drug

events, with few focusing on drug allergy alone; ▪ In hospitalized patients, the incidence of cutaneous allergic reactions

from the rates of hospitalization for ADRs, disclosed an estimated rate of 2.2 per 100 patients and 3 per 1,000 courses of drug therapy;

▪ The true incidence of drug-induced anaphylaxis is also unknown, as most studies have been based on all causes of anaphylaxis or all causes (both allergic and nonallergic) of ADRs.

Classification by Time Course ▪ Immediate ◦ Typically occurs within 1 hour after the last dose

▪ Non-immediate ◦ Occurs at any time, greater than 1 hour after initial drug administration

Demoly P. et al. Allergy 2014; 69: 420–37

Hypersensitivity Reactions ▪ Immune mediated drug hypersensitivity (drug allergy) ◦ Clinical symptoms due to different types of specific immune reactions (T-cell

& B-cell/Ig mediated)

▪ 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”

▪ 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

What is a Drug Allergy ▪ An immunologically mediated response to a

pharmaceutical/formulation/excipient agent in a sensitized person

Limitations of Current Epidemiological Data ▪ Includes all ADR ▪ Does not differentiate immunologically and non-immunologically mediated

drug hypersensitivity ▪ Different study populations ◦ Inpatients or outpatients

▪ Different methodologies ▪ Different methods of assessing drug imputability ▪ Different methods of data analyses

Risk Factors ▪ Drug-related factors ▪ Nature of the drug ▪ Host Risk Factors ▪ Degree of exposure ▪ Route ▪ Cross-sensitization ▪ Reactivity either to drugs with a close structural

chemical relationship or to immunochemically similar metabolites

Drug Related Factors ▪ Nature of the drug ▪ Degree of exposure (dose, duration, frequency) ▪ Route of administration ▪ Cross-sensitization

Nature of the Drug ▪Nature of the drug ◦ Hapten concept (intrinsically reactive); ◦ A typical hapten is penicillin, which can form via beta-lactam ring

a covalent bond to lysine, whereby the bound structure is called peniciloyl. If the binding occurs via the thiazolidin moiety one speaks about minor determinants. It is clear, that both determinants have a different immunogenicity;

◦ Pro-hapten concept (requires conversion to reactive intermediates);

◦ Danger concept (drug related cytotoxicity enhancing immune response);

◦ Pharmacological interaction concept (direct non-covalent binding to immune receptors, T-cell receptors, MHC).

Host Risk Factors ▪ Age

◦ Most of the studies among children and adults not comparable

▪ Sex ◦ No evidence, with the possible exception of cutaneous reactions, that allergic drug reactions

are more common in females than in males.

▪ Genetic factors (HLA type, Acetylator status) ◦ Immunogenetic disposition together with race: ◦ HLA-B*1502: Carbamazepine: SJS/TEN, DRESS; Han Chinese but not Caucasians ◦ HLA-B*5801: Allopurinol: DHS/DRESS like, Han Chinese ◦ HLA-B*5701: Abacavir: DRESS like, Caucasians, but not Hispanics or Africans

▪ Concurrent medical illness (e.g. Ebstein-Barr Virus (EBV), human immunodeficiency virus (HIV), asthma)

▪ Previous drug reaction ▪ Multiple allergy syndrome

Degree of Exposure ▪ Dose ▪ Frequency ▪ Duration ▪ Intermittent repeated administration

Risk Factors Continued ▪ Route ◦ Topical, oral, parenteral

▪ Cross-sensitization ▪ Reactivity either to drugs with a close structural

chemical relationship or to immunochemically similar metabolites

Generalized Immune Stimulation in the Frame of ▪ Acute EBV infections: maculopapular exanthem with aminopenicillins

▪ HIV infections: ◦ Sulfonamides: MPE, SJS/TEN, DRESS ◦ SJS/TEN to various drugs is 500 fold more frequent ◦ Nevirapine and abacavir: frequent side effects

▪ Drug induced autoimmunity: ◦ Drug-induced Lupus ◦ Drug-induced vasculitis

Pathophysiology of Drug Reaction ▪ Antigenicity of drugs

◦ Hapten concept ◦ Prohapten concept ◦ p-i (pharmacological interaction with immune receptors) concept

▪ Classification of drug reactions ◦ Type I ◦ Type II ◦ Type III ◦ Type IV

◦ a, b, c, d reactions

▪ How do drugs stimulate the immune system

▪ Pharmacological interaction with immune receptors (p-i concept) ◦ Direct stimulation of T-cells by drugs binding to the T-cell receptors for antigen ◦ No involvement of the innate immune system, and no generation of an own immune response to the

drug ◦ Stimulation of preactivated T-cells with additional specificity

IgE Reactions ▪ Pruritus

▪ Pruritic Papules

▪ Bronchospasm

▪ Urticaria

▪ Angioedema,

▪ Anaphylaxis

Pictures Courtesy of Uptodate

IgE Reaction ▪ Within 1(-2)* hrs: immediate reactions, mainly IgE mediated;

▪ Urticaria, angioedema, bronchospasm, anaphylaxis, and anaphylaxis related symptoms;

▪ After 1(-2)** hr (often > 6hrs - weeks): delayed reactions, mainly T cell, occasionally IgG mediated: often, but not always skin symptoms.

IgE Sensitization

T Cell Mediated Reactions ▪ Maculopapular exanthem (MPE)

▪ Bullous exanthem

▪ Stevens-Johnson Syndrom (SJS), toxic-epidermal necrolysis (TEN)

▪ Acute generalized exanthematous pustulosis (AGEP)

▪ Drug induced hypersensitivity syndrome (DiHS), or drug reaction with eosinophilia and systemic symptoms (DRESS)

▪ Interstitial nephritis, pancreatitis, colitis, pneumonitis, hepatitis

Maculopapular Exanthem

Bullous Exanthem Bullous Pemphigoid

Images Courtesy of Uptodate

AGEP

Drugs implicated in AGEP

Stevens Johnson Syndrome

IgG and/or Complement ▪ Blood cell dyscrasia

▪ Hemolytic anemia

▪ Thrombocytopenia

▪ Agranulocytosis

▪ Vasculitis

▪ Drug induced autoimmunity (SLE, pemphigus)

Penicillin Allergy ▪ Maria is a 55 year-old female with recurrent

acute sinusitis . ▪ She lives about 15 minutes from UC Irvine.

▪ A good ENT referral source has referred her to

your office as he would like to use a penicillin or a cephalosporin drug

*Slide provided by ACAAI

▪ Penicillin: Maria states that in her 20s, she had some type of reaction to PCN. She does not recall what the reaction was but her PCP told her to never take PCN again

▪ Cipro/Keflex: More than 10 years ago, she had reactions to two different antibiotics. One caused an urticarial reaction and the other caused gastrointestinal upset. She does not know which antibiotic caused which reaction but believes these were Cipro and Keflex

▪ Bactrim: Listed as drug allergy but patient has no idea of her reaction history

▪ She has tolerated azithromycin, doxycycline, and nitrofurantoin but these drugs seem to have quit working

Maria’s Case Continued

Penicillin Allergy ▪ 10% of hospitalized patients have documented history of penicillin

allergy 10% of patients report a history of PCN allergy, but 90-98% of

these individuals are not allergic.

Lee et al, Arch Intern Med. 2000;160(18):2819

▪ 90% of self reported penicillin allergic patients tolerate penicillin

antibiotics after evaluation and testing by board certified allergy and immunology specialist

Park M et al, Ann Allergy Asthma Immunol. 2006;97(5):681

PCN Allergy ▪ Penicillin “allergy” leads to use of an alternative agent(s)

▪ Use of broad spectrum antibiotics like vancomycin, quinolones for instance leads to more resistant organisms and comorbidities

▪ Increased cost of alternative antibiotics

Dangers of “Penicillin Allergy” ▪ Retrospective data from Kaiser Southern California showed that from

a cohort of ~52000 people over 2 years with penicillin “allergy” had: ◦ Longer hospital stays ◦ 23.4% more C.diff ◦ 14% more MRSA ◦ 30% more VRE ◦ $ 20 million increase cost/year for this group of patients

Macy et al. JACI. 2014; 133(3): 790-6

Risk Factors for Penicillin Allergy ▪ Age: 20-50 yrs

▪ Multiple Drug sensitivity

▪ Topical > Parenteral > Oral

▪ Chinese patients with HLA-DRB genotype

Beta-Lactams ▪ Penicillins

▪ Clavulanates

▪ Cephalosporins

▪ Carbapenems

Structure of Beta Lactams

Drug Hypersensitivity ▪ Type I Hypersensitivity: True allergic reactions with anaphylactic

potential

▪ Type II Hypersensitivity: Antibody dependent cell mediated cytotoxicity

▪ Type III Hypersensitivity: Antigen- Antibody immune complex deposition disease ( serum sickness)

▪ Type IV Hypersensitivity: Delayed type reactions

Pathophysiology of Penicillin Allergy ▪ Betalactam ring undergoes spontaneous degradation leading to

production of determinants

The major determinant is “ Penicilloyl” moiety

The minor determinants are penilloate and penicilloate

These bind to serum proteins to form immunogenic haptens

▪ In sensitized individuals specific IgE is made against these determinants, on re exposure to penicillins, IgE- hapten interaction leads to mast cell degranulation causing symptoms

Penicillin Determinants

Penicillin Determinants ▪ Patients allergic to major determinants will have minor reactions on re

exposure to penicillins

▪ Patients allergic to minor determinants will have severe reactions on re exposure to penicillins

PCN Skin Testing and Challenge

Skin Testing ▪ PCN allergy wanes with time. ◦ 50% lose their sensitivity at 5 years ◦ 80% lose their sensitivity at 10 years.

▪ Patients with vague histories of a reaction >10 years ago may be candidates for graded challenge.

▪ If history is convincing or reaction severe, they may be candidate for desensitization/induction of tolerance.

Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73

Penicillin IgE ▪ High specificity (97%-100%) but lower sensitivity (29%-68%)

▪ Therefore, although a positive in vitro test result for penicillin specific IgE is highly predictive of penicillin allergy, a negative in vitro test result does not adequately exclude penicillin allergy

Penicillin Skin Testing ▪ Most reliable method ▪ Negative predictive value approaches 100% ▪ Positive predictive value between 40% and 100% ▪ If negative on prick testing patients should receive

a graded penicillin challenge (Provocative Drug Testing) by an allergist

Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73

Graded Challenge ▪ Administration of progressively increasing doses of a medication until

a full dose is reached

▪ The medication is introduced in a controlled manner to a patient who has a low likelihood of reacting to it.

▪ Not intended to induce drug tolerance

Evaluation of Penicillin Allergy ▪ Patients with negative skin testing, successful tolerance to oral challenge with

penicillin have same risk as general population for reactions to penicillins with future exposure ◦ 2.9-4.5% chance with each future course of a PCN class medication of developing a

new allergy to PCN1

◦ Similar rate of developing a future allergic reaction to a sulfonamide1

▪ Our evaluation does not assess for delayed reactions, patients with no prior history of delayer reactions, the risk delayed reactions with future exposure is same as general population

1.Macy,E. JACI in practice 2013;1:258-63

2.Gerace, K. Abstract 366. AAAAI 2015 Annual meeting

Desensitization for Penicillin Allergy ▪ Indications for Desensitization to penicillins

▪ Absolute indication for penicillins without alternatives and patient has confirmed true IgE mediated penicillin allergy

▪ Pregnant female with syphilis and prior history of penicillin allergy

Contraindications to PCN Testing and Challenge ▪ Steven’s Johnson Syndrome ▪ Hemolytic Anemia ▪ Hepatitis ▪ Nephritis ▪ Oral or skin blisters ▪ Autoimmune Diseases ▪ Neutrophilic dermatitis ▪ Severe Cutaneous Drug Reactions ▪ Drug Induced Vasculitis ▪ Serum Sickness ▪ Organ Specific Drug Reactions

Cephalosporin Administration in PCN History Positive Patient: ▪ Prior to 1980 cephalosporins were often

contaminated with penicillin ◦ Partially responsible for the 1st & 2nd generation cephalosporin

package inserts that state that there is “up to 10% cross-reactivity” to cephalosporins in PCN-allergic patients (NOT TRUE TODAY)

Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73

Solensky, R (2015). Penicillin-allergic patients: Use of cephalosporins, carbapenems, and monobactams. In D.S. Basow (Ed.), UpToDate. Retrieved from http://www.uptodate.com/home/index.html.

Cephalosporin Administration in PCN History Positive Patient: ▪ In PCN allergic patients, clinical sensitivity to cephalosporins occurs in

0.1% to 2%, some with anaphylaxis so PCN skin testing recommended.

Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73

R1 Side Chain Cross Reactivity

R2 Side Chains

Cephalospoirn Allergy ▪ True IgE mediated allergy to cephalosporin is 10 fold less than

penicillin allergy in general population

▪ True IgE mediated allergy to cephalosporins is more often to side chain rather than betalactam ring

▪ True IgE mediated allergy to betalactam ring in cephalosporins is less in third generation cephalosporins

History of PCN Allergy

Cephalosporin Allergy

Our Friend Aztreonam ▪ Aztreonam ( Monobactams’) is less immunogenic and has no

betalactam cross reactivity with penicillins/cephalosporins except share R1 side chain with ceftazidime

▪ Aztreonam can safely be considered in patients with betalactam allergy history for gram negative coverage if there is no history of reaction to ceftazidime, without any testing or challenge

▪ Conversely aztreonam allergic patients may safely be treated with all betalactams without any testing or challenge except ceftazidime

So What to do for Maria… ▪ Penicillin: ◦ 35 years ago, she had reaction to PCN that she cannot recall. ◦ Cipro/Keflex: 10 years ago had urticarial eruption to one and GI upset to the

other. *Bactrim: Drug allergy

Maria’s Dilemma ▪ 80% chance that she has lost her “allergy” to penicillin so the next

step would be Penicillin Skin Testing, Intradermal Testing and Graded Dose Challenge to Penicillin

Summary ▪ Confirm history is a drug allergic reaction

▪ Classify drug allergic reaction

▪ Determine likelihood of drugs in question causing reaction

▪ Determine elements that may influence drug allergy history

▪ Evaluate if subsequent exposure occurred

▪ What is the likely future need of the drug

Case 1 ▪ A 26 year old female reports that when she was a child she had a

reaction to penicillin and was told to never take this medication again.

▪ Her reaction was stomach upset and diarrhea.

▪ She tolerated Augmentin 1 year prior for a sinus infection.

Questions What kind of drug reaction did she possibly have? ◦ A. Anaphylaxis ◦ B. T cell mediated reaction ◦ C. Side Effect ◦ D. IgG complex disease

Questions Thank you!!!

References ▪ ACAAI

▪ Legendre D. eta al. Clin Infect Disease 2013: 1-9

▪ Romano et al. JACI in Practice 2014; 2:3-12

▪ Solensky et al. Ann Allergy Asthma Immunol 2010; 105: 259-273

▪ Picard et al. JACI Practice. 2013; 252-257

▪ Sade et al. Clin Exp. Allergy. 2003; 33: 501-506

▪ Reddy et al. JACI. 2013; 131: AB170

▪ Macy et al. JACI. 2014; 133 (3): 790-6

▪ Demoly et al. Allergy 2014. 69; 420-37.

▪ Drug Allergy Practice Parameter. Annals of Allergy and Immunology. October 2010. Volume 105.

▪ Images Courtesy of UptoDate