Drug Allergy Magdalena Berger MD FRCPC

Allergist and Clinical Immunologist

The Moncton Hospital

NBIMU 2019

Conflict of Interest Disclosure (over the past 24 months)

• Novartis: Speakers panel

Objectives

• Review the classification of adverse reactions to drugs

• Understand the limitations of available diagnostic tests for medication allergy; HISTORY is key

• Review the approach to penicillin allergy

• Briefly discuss vaccine and NSAID allergy cases

• Discuss when to refer patients to an Allergist and what information would be helpful to include in the referral

Case 1 - Penicillin

• 46 yo F developed diffuse maculopapular rash on day 2 of triple therapy for H.pylori eradication 1 years ago. Rash lasted 2 weeks; no blistering, systemically well.

• Also lists allergy to sulpha antibiotics – hives as a child; not sure why she was given this

• Has persistent H.pylori and requested possible PCN allergy clarification for further treatment options.

Case 2 – Flu vaccine

• 35 year old female with large local reaction to flu vaccine 3 years ago. Felt ‘flu-like illness’ for 2 days after vaccination. Nervous to try again. No difficulty with other vaccines which are all up to date.

Case 3 - NSAID

• 47 yo M with urticaria with Advil on 3 occasions 1 year ago. Avoiding ASA and all NSAIDs. Also developed hives after Tylenol 6 months ago which he took for a headache during a viral illness.

• Now has back injury and would like to re-try something if safe to do so.

Predictable - 85-90% reactions - Dose dependent - Related to known

pharmacologic actions of the drug

Unpredictable - Dose independent - Unrelated to known

pharmacologic actions of the drug - Occur only in susceptible

individuals

Adverse Drug Reactions

Idiosyncratic (pharmacogenetics)

ALLERGIC Types I-IV

Classification of adverse drug reactions

• Gel-Coombs classification of immunologic mechanisms

I - IgE mediated activation of mast cells (anaphylaxis – usually <1hr; rarely up to 72

hours)

eg. Anaphylaxis from beta-lactams antibiotics

II - Antibody mediated cell destruction (delayed)

eg. Immune mediated thrombocytopenia from heparin

III - IgG:drug immune complex deposition (delayed)

eg. Serum sickness

IV - T-cell mediated (delayed)

eg. Steven-Johnson Syndrome

Most immunologic medication reactions are Type I or Type IV reactions Immediate hypersensitivity <1hr-72 hrs; delayed >72 hours

Type I – IgE, immediate hypersensitivity

reactions

• Antigen exposure causes IgE-mediated activation of mast cells and basophils

• Release of vasoactive substances such as histamine, prostaglandins, and leukotrienes

Type II IgG/IgM antibody and complement mediated reaction • Uncommon

• Antibody-antigen complex is cleared by the monocyte-macrophage system resulting in cell damage

• Long-term, high dose or frequent drug exposure more common

• Symptoms typically appear at least 5-8 days after exposure

• Clinical presentation varies widely in severity

Drug-induced hemolytic anemia, thrombocytopenia, neutropenia and agranulocytosis

Type III Immune Complex Reaction

• Soluble drug complexes or its metabolite in slight antigen excess bind with drug specific IgG or IgM antibodies.

• Immune complexes are deposited in blood vessel walls and cause injury by activating the complement cascade

• Serum sickness, hypersensitivity vasculitis, drug fever

• Timing: one or more weeks after drug exposure (require large amounts of antibody)

Type IV delayed hypersensitivity reaction

• Drug-specific T lymphocytes become activated.

• In some cases, other cell types are involved directly (macrophages, eosinophils, or neutrophils)

Type IV – clinical presentation

• Prominent skin findings

• Although, occasionally organ involvement occurs without skin findings

• Eg. Drug induced hepatitis, isolated AIN, isolated pneumonitis

• Clinical manifestations include:

• contact dermatitis

• maculopapular eruption/morbilliform eruption

• Drug rash with eosinophilia and systemic symptoms

• SJS/TEN

SJS/TEN

DRESS

AGEP

Angioedema

Aminopenicillins associated with a nonpruritic, nonurticarial rash in up to 10% of patients

Maculopapular eruptions

Maculopapular eruptions

MACULOPAPULAR ERUPTIONS

• Onset is usually within 1 – 2 weeks of medication use

• Shorter onset in patients who have previously reacted

• Can occur 1 – 2 weeks after penicillin discontinued

• Resolved within 3 – 14 days

• Possibly related to the presence of concurrent viral infections

• Not associated with an increased risk of more severe reactions, such as anaphylaxis, with repeat exposure

• Chang C, Mahmood MM, Teuber SS, et al. Overview of penicillin allergy. Clin Rev Allergy Immunol. 2012;43(1-2):84-97

• Schiavino D, Nucera E, De Pasquale T, et al. Delayed allergy to aminopenicillins: clinical and immunological findings. Int J Immunopathol Pharmacol. 2006;19(4):831-840.

Rash Decisions - Definition

• Urbandictionary.com: where the results are not thought out ahead of time, and the results are usually not very good, or beneficial to anyone involved

• Making a decision about a rash

January 15, 2019

Penicillin Allergy

After allergy history is determined to be inconsistent with SCAR, hemolytic anemia, an organ-specific reaction (eg. Acute interstitial nephritis), drug fever, or serum sickness, patients can be stratified into low, moderate, and high risk using the allergy history.

- TIMING: of reaction in relation to medication start and stop

- SIGNS AND SYMPTOMS: particular focus on vital signs, cutaneous manifestations, lymphadenopathy

- PHOTOS: of any rash

- LABS: at the time of reaction (if available): - If suspect immediate hypersensitivity reaction: tryptase

- If suspect delayed immunologic reactions: CBC, urinalysis, creatinine, CRP, liver enzymes

When in doubt if it’s an allergy, this information will be very helpful to the Allergist

• If immediate hypersensitivity suspected (or possible) and have ability to do so: Skin prick testing (SPT) +/- Direct provocation challenge (DPT)

• If delayed hypersensitivity suspected (or possible): • Red flags? – Do not test and do not challenge; use another antibiotic

• No red flags? • If symptoms of intolerance OK to try again

• If symptoms of non-pruritic morbilliform or maculopapular rash OK to try alternate beta lactam (~10% of patients receiving Penicillin will have this)

The approach to penicillin allergy is available in clinical guidelines

NB Anti-Infective Stewardship Committee September 2017

Penicillin allergy is over-reported

80% of Penicillin allergic patients are no longer allergic after 10 years

Cross reactivity with 1st degree cephalosporins is <1%

Case 1 - Penicillin

• SPT and ID to PrePen and PenG administered. Patient was vasovagal but results were negative with appropriate histamine and saline controls.

• Graded dose challenge given • Subjective pruritus after 10 minutes; VSS, no rash on exam. Symptoms resolved on

their own within 20 minutes

• 250mg Amoxicillin given; vasovagal reaction after 15 minutes, no rash on exam. Symptoms resolved on their own within 20 minutes

• Penicillin allergy de-labelled

• Patient received course of antibiotics including penicillin • On day 3 developed maculopapular rash – stopped PCN

• Rash continued x 2 weeks with mild desquamation

Identification of culprit drug

• Skin testing is done for type I reactions, but is not standardized or validated for most drugs

• Exceptions: Beta-lactam antibiotics (cephalosporins and imipenem), neuromuscular blockers, platin drugs, pyrazolones (metamizole), local anesthetics, thiobarbiturates, most enzymes and recombinant or native proteins

• Avoid in drugs that cause direct mast cell degranulation

• Opioids, quinolones, vancomycin

• Testing done with unmetabolized drug

• Exception: penicillin metabolites and metabolite/protein complexes have been characterized

Interpretation

Case 2 – Flu vaccine

• Skin prick and intradermal test performed with FluVal; negative

• Challenge dose of 10% injected – 30 minutes later no adverse reaction

• Full dose given and patient remained for observation for 1 hour with no adverse reaction

Vaccine allergy

• Severe allergic reactions to vaccines are rare

• Reactions are more common in females and those who are atopic

• Almost any vaccine can cause anaphylaxis, usually because of a vaccine component rather than vaccine antigen

• Rate of anaphylaxis after vaccination is 1.3 for every million vaccine doses given

McNeil, Michael M., DeStefano Frank. Vaccine –associated hypersensitivity. JACI. February 2018.

Case 3 - ASA

• Plan to do Celebrex challenge first

• Plan to do Tylenol challenge next

• Would consider ASA challenge if tolerates Celebrex

ASA hypersensitivity

• 5 phenotypes • Non-immunologically mediated (cross-reactive) hypersensitivity:

• NSAID exacerbated respiratory disease (NERD)

• NSAID exacerbated cutaneous disease (NECD) – wheals and/or angioedema in patients with CSU

• NSAID induced urticaria/angioedema (NIUA) – wheals and/or angioedema in otherwise healthy individuals; symptoms are induced by at least two NSAIDS not belonging to the same chemical group

• Immunologically mediated (non cross-reactive) hypersensitivity: • Single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA): immediate rxns

• Single-NSAID-induced delayed hypersensitivity reactions (SNIDHR): within 24-48 hrs; fixed drug eruption, exanthema or severe cutaneous adverse reactions.

Cortellini, G, Caruso C., Romano A. Asprin challenge and desensitization: how, when and why. Current Opinion in Allergy and Clinical Immunology. August 2017.

Summary

• Gell and Coombs classification is still the most useful immunologic classification system for drug allergy

• Penicillin ‘allergy’ is over-reported and there is an approach to clarifying this diagnosis

• History is incredibly important; photos of rashes, limited bloodwork is helpful for clarification

• Approach to various drug allergies is a rapidly evolving area of Allergy research, and referral to an Allergist is indicated with any drug reaction that needs clarification

Thank you!