Drug Allergy Magdalena Berger MD FRCPC Allergist and Clinical Immunologist The Moncton Hospital NBIMU 2019
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!