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Cutaneous Drug Hypersensitivity: Clinical Features, Mechanisms, Diagnosis, and Management
3030827429, 9783030827427

Author / Uploaded
Andreas J. Bircher (editor)
Howard I. Maibach (editor)
Knut Brockow (editor)
Annick Barbaud (editor)

Table of contents :
Foreword: Controversial Topics in Drug Hypersensitivity
References
Preface
Contents
Contributors
Part I: General Aspects of Drug Hypersensitivity
1: Classification and Terminology of Drug Hypersensitivity Reactions
1.1 Clinical Phenotypes
1.2 Severity
1.3 Chronology
1.4 Pathomechanisms
1.5 Summary
References
2: Epidemiology
2.1 Data Sources for Observational Studies on Cutaneous Adverse Drug Reactions
2.2 Prevalence and Incidence of Cutaneous ADR
2.3 Types of Cutaneous ADR
2.4 Culprit Drugs of Cutaneous ADR
2.5 Absolute Risks of Cutaneous ADR to Drugs
2.6 Epidemiology of Severe and Life-Threatening Cutaneous ADR
2.6.1 SJS/TEN
2.6.2 AGEP
2.6.3 DRESS
References
3: Cutaneous Signs and Syndromes of Drug Hypersensitivity
3.1 Introduction
3.2 Clinical Manifestations
3.2.1 Urticaria, Angioedema, and/or Anaphylaxis
3.2.2 Disseminated and Generalized Exanthems
3.2.2.1 Exanthems with Bullae
3.2.2.2 Exanthems with Pustules
3.2.2.3 Vasculitis
3.2.2.4 Exanthems with Severe Systemic Organ Involvement
3.2.2.5 Exanthems with Characteristic Distribution Patterns
3.2.2.6 Maculopapular Exanthem
3.2.3 Major Localized Cutaneous Manifestations
3.2.3.1 Fixed Drug Eruption
3.2.3.2 Photoallergic Reactions to Systemically Applied Drugs
3.2.3.3 Injection Site Reactions
3.3 Specific Clinical Reaction Patterns to Chemotherapeutics and Biopharmaceuticals
3.4 Diagnostics Methods
3.5 Management
References
4: Systemic Organ Manifestations of Drug Allergy
4.1 Hepatic Manifestations of Drug Allergy
4.2 Kidney Injury
4.3 Cardiac Manifestations
4.4 Lung Manifestations
4.5 Role of Human Herpesviruses in Single and Multi-organ Manifestations of Drug Allergy
4.6 Conclusion
References
5: Danger Signs in Drug Hypersensitivity
5.1 Rapidly Occurring Danger Signs
5.2 Late-Occurring Danger Signs
5.3 Systemic Danger Signs
5.4 Assessment of Skin Lesions
References
6: Pathomechanisms of Drug Hypersensitivity Targeting the Liver and Skin
6.1 Drug Hypersensitivity Reaction (Background)
6.2 Coombs and Gell’s Classification of Drug Hypersensitivity Reactions
6.3 Limitations of Coombs and Gell’s Classification of Drug Hypersensitivity
6.4 Drug Hypersensitivity Syndrome (DHS)
6.5 Drug-Induced Liver Injury (DILI)
6.6 Drug Hypersensitivity Reactions Targeting the Skin
6.7 Proposed Classification of Drug Hypersensitivity Incorporating Current Findings
References
Part II: Diagnostic Methods
7: Skin Tests
7.1 Background
7.2 Drug Patch Tests
7.2.1 Test Principle
7.2.2 Test Concentrations
7.2.3 Clinical Application
7.2.4 Limitations
7.3 Drug Prick Tests
7.3.1 Test Principle
7.3.2 Clinical Application
7.3.3 Limitations
7.4 Intradermal Drug Tests (IDTs)
7.4.1 Test Principle
7.4.2 Test Concentrations
7.4.3 Clinical Application
7.5 Strength and Limitations
7.6 Conclusions
References
8: Serological Tests
8.1 Background
8.2 Serological Methods to Characterize the Active Phase of the Reaction
8.2.1 Serum Tryptase Determination
8.2.1.1 Test Principle
8.2.1.2 Clinical Application
8.2.1.3 Strength and Weakness
8.3 Serological Tests to Identify the Culprit Drug
8.3.1 Specific Immunoglobulin E (sIgE) Determination
8.3.1.1 Test Principle
ImmunoCAP
Customized Immunoassays
8.3.1.2 Clinical Application
ImmunoCAP
Conventional RIA
8.3.1.3 Strength and Weakness
8.3.1.4 Advances in Immunoassay Techniques Using Different Carrier Molecules, Solid Phases, Antigenic Determinants, and Multiplex Assays
Carrier Molecule
Solid Phase and Functionalization
Antigenic Determinants
Evaluation of Multiple Drugs in the Same Assay
8.4 Conclusions
References
9: T-Cell Assays for the Investigation of Drug Hypersensitivity
9.1 Background
9.2 Mechanisms of T-Cell Recognition of Drugs
9.3 Test Principle
9.4 Measurement of Proliferation
9.5 Measurement of Functional Changes in T Cells Due to Drug-Induced Activation
9.6 Measurement of T-Cell Phenotypic Changes
9.7 Clinical Application
9.8 Strength and Weakness
9.9 Conclusion
References
10: Basophil Activation Tests
10.1 Background
10.2 Test Principle
10.2.1 General Considerations in BAT
10.3 Clinical Applications
10.3.1 Evaluation of Clavulanic Acid Hypersensitivity
10.3.2 Evaluation of Fluoroquinolone Hypersensitivity
10.3.3 Evaluation of Hypersensitivity to Other Drugs
10.4 Strength and Weakness
10.4.1 Optimal Time Interval from the Acute Phase of the Reaction
10.4.2 Activation Markers
10.4.3 Optimal Management of Drug to Avoid Degradation
10.4.4 Inclusion of the Optimal Drug Metabolite
10.5 Conclusions
References
11: Histopathology of Drug-Induced Exanthemas
11.1 Background
11.2 Basic Principle
11.3 Clinical Application
11.3.1 Histology of Common Drug-Induced Cutaneous Hypersensitivity Reactions
11.3.1.1 Maculopapular Exanthema
11.3.1.2 Symmetrical Drug-Related Intertriginous and Flexural Exanthema (SDRIFE)
11.3.1.3 Urticarial Drug Reactions
11.3.1.4 Hypersensitivity Vasculitis/Leukocytoclastic Vasculitis
11.3.1.5 Photoallergic and Phototoxic Reactions
11.3.1.6 Lichenoid Drug Reactions
11.3.1.7 Fixed Drug Eruption (FDE)
11.3.1.8 Lymphomatoid (Pseudolymphomatous) Drug Reaction
11.3.2 Histology of Severe, Potentially Life-Threatening Forms of Cutaneous Drug Reactions
11.3.2.1 Toxic Epidermal Necrolysis (TEN)/Stevens-Johnson Syndrome (SJS)
11.3.2.2 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
11.3.2.3 Acute Generalized Exanthematous Pustulosis (AGEP)
11.3.3 Special Patterns
11.3.3.1 Epidermal Dysmaturation
11.3.3.2 Interstitial Granulomatous Drug Eruption
11.3.4 Histology of Cutaneous Reactions to Targeted Therapies
11.3.4.1 “Acne-Like Rash”: Suppurative Folliculitis and Perifolliculitis
11.3.4.2 Hand-Foot Skin Reaction (HFSR)
11.3.4.3 RASopathic Skin Eruptions
11.3.4.4 Paradoxical Psoriasiform Rash
11.3.4.5 Lichenoid Drug Reactions from Anti-PD-1 and Anti-PDL-1
11.4 Strength and Weaknesses
11.5 Conclusion
References
Part III: Management
12: Drug Desensitization in Immediate-Type Hypersensitivity
12.1 How Is Drug Hypersensitivity Defined in the Twenty-First Century?
12.1.1 The Importance of Drug Hypersensitivity
12.1.2 Phenotypes and Endotypes of Drug Hypersensitivity
12.1.2.1 Classification Based on the Onset of Symptoms [8]
Immediate Hypersensitivity
Delayed Hypersensitivity
12.1.2.2 Classification Based on the Severity of Symptoms (by the Modified Brown Classification) [17]
12.1.2.3 Classification Based on Molecular Pathways (by Gell and Coombs)
Type I
Type II
Type III
Type IV
Type IVa
Type IVb
Type IVc
Type IVd
12.1.2.4 Other Endotypes
Cytokine-Release Reactions (CRRs)
Infusion-Related Reactions (IRRs)
Mixed Reactions
12.1.3 Biomarkers of Phenotypes and Endotypes of Drug Hypersensitivity
12.1.3.1 Skin Test (ST)
12.1.3.2 Allergen-Specific IgE (sIgE)
12.1.3.3 Mediators
Tryptase
IL-6
Granzyme B/Granulysin
12.1.3.4 Basophil Activation Test (BAT)
12.1.3.5 Patch Testing
12.1.3.6 HLA Markers
12.2 Definition of Desensitization (DS)
12.2.1 Desensitization Protocols: An Example
12.2.2 Inhibition of Skin Testing by Desensitization
12.3 Mechanisms of Desensitization
12.3.1 Desensitization Mechanisms
12.3.2 Desensitization Healthcare Costs
12.3.3 Desensitization Candidates
12.3.3.1 Phenotypes That Can Be Desensitized
12.3.3.2 Endotypes That Can Be Desensitized
12.3.3.3 Contraindications for Desensitization
12.3.3.4 Proposed Algorithm for Desensitization
12.4 Drugs in Which Desensitization Is Feasible
12.4.1 Antibiotics
12.4.1.1 β-Lactams
12.4.2 Chemotherapy (Platins/Taxanes)
12.4.2.1 Platins (Carboplatin, Oxaliplatin, Cisplatin)
12.4.2.2 Taxanes (Paclitaxel and Docetaxel)
12.4.2.3 Monoclonal Antibodies
12.4.3 Progesterone
12.5 Conclusion
References
13: Documentation for Patients with Drug Hypersensitivity: Allergy Pass and Allergy Card
13.1 Introduction
13.2 Documentation Instruments
13.2.1 Purpose and Means of Documentation
13.2.2 Discharge Letter/Certificate
13.2.3 Drug Allergy Passport
13.2.4 Drug Allergy Card
13.3 Requirements for Drug Allergy Documentation
References
Part IV: Drug Hypersensitivity in Specific Populations
14: Cutaneous Drug Hypersensitivity: Clinical Features, Mechanism, Diagnosis, and Management in Children and Adolescent
14.1 Introduction
14.2 Epidemiology of Drug Allergy in Children and Adolescent
14.3 The Role of Viral Infections and Genetic Factors
14.4 β-Lactam Antibiotics
14.4.1 Immediate Drug Reactions
14.4.2 Delayed Drug Reactions
14.5 Diagnostic in Vitro and in Vivo Tests in Suspected Hypersensitivity to β-Lactam Antibiotics
14.5.1 Immediate Drug Reactions
14.5.2 Delayed Drug Reactions
14.6 Non-β-Lactam Antibiotics (NBLAs)
14.7 Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
14.7.1 Classification of NSAID Hypersensitivity in Children
14.7.2 Nonallergic Cross-Intolerant (CI) Reactions
14.7.3 Allergic Non-cross-Intolerant Reactions or Selective Reactions (SR)
14.7.4 Diagnostic Tests and Management in Suspected Hypersensitivity to NSAIDs
14.7.5 Natural History and Desensitization to NSAIDs
14.8 Vaccines
14.8.1 Local Reactions to Vaccines
14.8.2 Systemic Reactions to Vaccines
14.8.3 Management of Patients with a History of an Immediate Reaction to a Vaccine
14.8.4 Management of Patients with History of Allergy to Vaccine Component(s)
14.8.4.1 Egg- and Milk-Allergic Children
14.8.4.2 Gelatin- and Latex-Allergic Patients
14.9 Conclusion
References
15: HIV-Infection and AIDS
15.1 Introduction
15.2 Drug Hypersensitivity in HIV-Infected Patients
15.3 Pathogenesis
15.4 Hypersensitivity to Drugs to Treat and Prevent Opportunistic Infections
15.4.1 Antituberculosis Drugs
15.4.2 Anti-Toxoplasmosis Drugs
15.4.3 Antifungal Drugs
15.5 Antiretroviral Drugs
15.5.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
15.5.2 Non-nucleoside Reverse Transcriptase Inhibitors
15.5.3 Protease Inhibitors
15.5.4 Fusion Inhibitor
15.5.5 CCR5 Inhibitor
15.5.6 Integrase Inhibitors
15.6 Management
15.7 Conclusion
References
16: Oncology: Immune Checkpoint Inhibitors
16.1 Introduction
16.2 Mechanisms
16.3 Clinical Features, Diagnosis, and Grading
16.4 Management
References
17: Drug Hypersensitivity and Clonal Mast Cell Disorders
17.1 Clinical Manifestations
17.2 Mechanisms
17.3 Diagnostic Methods
17.4 Management
References
Part V: Eliciting Drugs
18: Penicillins
18.1 Introduction
18.2 Clinical Manifestations
18.3 Mechanisms
18.3.1 Immediate Reactions
18.3.2 Non-immediate Reactions
18.4 Diagnostic Methods
18.4.1 Clinical History
18.4.2 Skin Tests
18.4.3 In Vitro Diagnostics
18.4.3.1 Immediate Reactions
Immunoassays
Basophil Activation Test (BAT)
18.4.3.2 Non-immediate Reactions
Lymphocyte Transformation Test (LTT)
Enzyme-Linked Immunosorbent Spot (ELISpot)
18.4.4 Drug Provocation Test
18.5 Cross-reactions
References
19: Cephalosporins
19.1 Introduction
19.2 Clinical Features and Mechanisms
19.2.1 Immediate Reactions
19.2.2 Nonimmediate Reactions
19.3 Diagnosis
19.3.1 Clinical History
19.3.2 Allergy Workup
19.3.2.1 Immediate Reactions
19.3.2.2 Nonimmediate Reactions
19.4 Cross-reactivity Among Cephalosporins and Between Cephalosporins and Other β-Lactams
19.4.1 Administration of Penicillins, Aztreonam, and Carbapenems to Patients with Cephalosporin Allergy
19.4.2 Administration of Alternative Cephalosporins to Patients with Cephalosporin Allergy
References
20: Other Antibiotics
20.1 Introduction
20.2 Quinolones
20.2.1 Management
20.3 Macrolides
20.4 Aminoglycoside Antibiotics
References
21: Other Anti-Infectious Drugs
21.1 Chloroquine and Hydroxychloroquine
21.2 Dapsone (Diaminodiphenylsulfone)
21.3 Pentamidine
21.4 Quinine
21.5 Fluconazole
21.6 Itraconazole
21.7 Ketoconazole
21.8 Terbinafine
21.9 Amphotericin B
21.10 Anti-herpes and Anti-CMV Drugs
21.11 Antiretroviral Substances: Abacavir
21.12 Summary
References
22: Cutaneous Hypersensitivity Reactions to Analgesics and Nonsteroidal Anti-Inflammatory Drugs
22.1 Clinical Manifestation
22.1.1 NSAIDs-Exacerbated Cutaneous Disease (NECD)
22.1.2 NSAIDs-Induced Urticaria/Angioedema (NIUA)
22.1.3 Single NSAIDs-Induced Urticaria/Angioedema or Anaphylaxis (SNIUAA)
22.1.4 Single NSAIDs-Induced Delayed Hypersensitivity Reactions (SNIDHR)
22.1.5 Mixed Reactions
22.2 Mechanisms
22.3 Diagnostic Methods
22.3.1 Step 1: Assess the Type of Adverse Reaction to NSAIDs
22.3.2 Step 2: Determine Timing of the Reaction
22.3.3 Step 3: Analyze Clinical Pattern of NSAID-Induced Symptoms and Underlying Chronic Diseases
22.3.4 Step 4: Assess History of Hypersensitivity/Tolerance to Other NSAIDs
22.3.5 Step 5: Confirm/Exclude Cross-Reactivity to Other NSAIDs by Challenge
22.3.6 Step 6: Consider Skin Testing or in Vitro Testing
22.3.7 Step 7: Consider Oral Provocation Challenge with a Culprit Drug
22.4 Cross-Reactions
22.5 Management
22.5.1 Cross-Reactive Types of Hypersensitivity (NECD and NIUA)
22.5.2 Selective Types of SNIUAA and SNIDHR
22.5.3 Desensitization
References
23: Peri-Interventional Hypersensitivity: Anesthetic Drugs and Materials
23.1 Introduction
23.2 Clinical Manifestations
23.3 Mechanisms
23.4 Diagnostic Methods
23.4.1 Skin Tests
23.4.2 In Vitro Diagnostics
23.4.3 Provocation Tests
23.5 Eliciting Drugs
23.5.1 Natural Rubber Latex
23.5.2 Hypnotics
23.5.3 Local Anesthetics
23.5.4 Opioids
23.5.5 Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
23.5.6 Volume Expanders
23.5.7 Hemostatic and Anticoagulant Drugs
23.5.8 Miscellaneous Drugs
23.5.9 Antiseptics and Sterilizers
23.5.10 Blue Dyes
23.5.11 Radiocontrast Media
23.5.12 Additives
23.6 Cross-Reactivity
23.7 Management
References
24: Muscle Relaxants
24.1 Introduction
24.2 Clinical Manifestations
24.2.1 Skin
24.2.2 Respiratory
24.2.3 Cardiovascular Signs
24.2.4 Other Signs
24.3 Mechanisms
24.3.1 Immediate Immune-Mediated Hypersensitivity Reactions
24.3.1.1 IgE Pathway
24.3.1.2 Origin of NMBA-Specific IgE Antibodies and Influence of Environmental Factors
24.3.1.3 IgG Pathway
24.3.1.4 Delayed Immune-Mediated Hypersensitivity Reactions
24.3.2 Non-immune-Mediated Hypersensitivity Reactions
24.4 Diagnostic Methods
24.4.1 Tryptase and Histamine Measurement
24.4.2 Skin Tests
24.4.3 Specific IgE Assays
24.4.4 Cellular Tests
24.4.5 Provocation Tests
24.5 Management of NMBA-Related Hypersensitivity Reactions
24.6 Conclusion
References
25: Anticoagulants
25.1 Introduction
25.2 Indirect Anticoagulants Without Direct Effect on the Plasmatic Coagulation System
25.2.1 Vitamin K Antagonists/Coumarins
25.2.2 Heparins and Derivatives
25.2.2.1 Cell-Mediated, Delayed-Type Hypersensitivity (DTH) to Heparins
25.2.2.2 Immediate-Type Hypersensitivity to Heparins
25.2.2.3 Heparin-Induced Thrombocytopenia (HIT)
25.2.2.4 Heparinoids
25.3 Directly Acting Oral Anticoagulants (DOACs)
25.3.1 Direct Factor Xa Inhibitors
25.3.2 Direct Factor IIa Inhibitors/Thrombin Inhibitors
25.4 Antiplatelet Drugs
25.4.1 Cyclooxygenase Inhibitors
25.4.2 P2Y12 Inhibitors/Thienopyridines
25.4.3 Glycoprotein (GP) IIb-IIIa Receptor Antagonists
25.4.4 Phosphodiesterase III Inhibitors
25.5 Summary
References
26: Biological Drugs
26.1 Clinical Manifestation
26.1.1 Acute Infusion Reactions
26.1.2 Delayed Infusion Reactions
26.2 Mechanisms
26.3 Diagnostic Methods
26.4 Management
References
27: Corticosteroids
27.1 Introduction
27.1.1 A Not-So-Uncommon Condition
27.2 Delayed Allergic Hypersensitivity to Corticosteroids
27.2.1 The Skin: Main Sensitization and Elicitation Route
27.2.2 Clinical Presentation: Neither Specific Nor Spectacular
27.2.3 The Indisputable Value of Patch Testing
27.2.4 The Central Role of Halogenation and C16-Methyl Substitution and Reappraisal of the ABCD Classification
27.3 Immediate Allergic Hypersensitivity to Corticosteroids
27.3.1 Clinical Presentation: Not Specific to Corticosteroids
27.3.2 Diagnosis: Allergy to Excipients Needs to Be Ruled Out
27.3.3 Pathogenesis: Poorly Understood
27.3.4 No Cross-Reactivity Patterns Observed
References
28: Vaccines
28.1 Introduction
28.2 Clinical Manifestations
28.2.1 Injection Site Reactions
28.2.2 Systemic Reactions
28.3 Mechanisms
28.4 Diagnostic Methods
28.5 Management
References
29: Antiepileptic and Psychotropic Drugs
29.1 Introduction
29.2 Clinical Manifestations
29.3 Eliciting Drugs
29.4 Mechanisms
29.5 Predisposing and Risk Factors
29.6 Cross-Reactivity
29.7 Diagnostic Methods
29.8 Management
29.9 Summary
References
30: Antiacid drugs: Proton Pump Inhibitors and H2 Receptor Antagonists
30.1 Clinical Manifestation
30.1.1 Proton Pump Inhibitors
30.2 H2 Receptor Antagonists
30.3 Mechanisms
30.4 Diagnostic Methods
30.4.1 Proton Pump Inhibitors
30.4.1.1 Skin Tests
30.4.1.2 In Vitro Diagnostics
30.4.1.3 Oral Provocation Test
30.4.2 H2 Receptor Antagonists
30.4.2.1 Skin Tests and In Vitro Test
30.4.3 Cross-Reactivity among PPIs
30.5 Cross-Reactivity among H2RA
30.6 Management
References
31: Diagnostic Agents
31.1 Introduction
31.2 Hypersensitivity Reactions to Iodinated Radiocontrast Media and Gadolinium-Based Contrast Agents
31.2.1 Clinical Manifestations
31.2.2 Mechanisms
31.2.3 Diagnostic Methods
31.2.4 Management
31.2.5 Hypersensitivity to Dyes
31.2.6 Clinical Manifestations
31.2.7 Pathogenesis
31.2.8 Diagnostic Methods
31.2.9 Management
References
32: Blood Pressure Agents
32.1 Thiazide Diuretics
32.2 Furosemide
32.3 Calcium Channel Blockers (CCBs)
32.4 Beta- and Alpha-Blockers
32.5 Renin-Angiotensin-Aldosterone System (RAAS) Blockers
32.6 Angiotensin-Converting Enzyme Inhibitors (ACE-I)
32.7 Angiotensin Receptor Blockers (ARBs)
32.8 Direct Renin Antagonists
32.9 Spironolactone
References
33: Iron Preparations
33.1 Introduction
33.2 Epidemiology
33.3 Risk Factors
33.4 Clinical Manifestations
33.5 Pathomechanism
33.6 Management of Iron Infusions
33.7 Management of HSRs
33.8 Diagnosis
33.9 Re-administration
References
34: Vitamins and Supplements
34.1 Clinical Manifestation (Immediate, Delayed, Others)
34.2 Mechanisms
34.3 Diagnostic Methods
34.4 Cross-reactions
34.5 Management
References
35: Antitumor/Cytostatic Drugs
35.1 Skin Reactions Provoked by Cytostatic Drugs
35.2 Hypersensitivity Reactions
35.3 Toxic Erythema
35.4 Other Skin Reactions Associated with Conventional Chemotherapy
35.5 Conclusions
References
36: Additives: Preservatives, Antioxidants, Dyes, and Others
36.1 Aluminum-Induced Granuloma
36.2 Antibiotics in Vaccines
36.3 Benzyl Alcohol
36.4 Carboxymethylcellulose (CMC)
36.5 Dyes
36.6 Egg Protein and Vaccines
36.7 Gelatin
36.8 Metacresol
36.9 Povidone
36.10 Protamine
36.11 Saccharomyces Cerevisiae Used as Media for Recombinant Vaccines
36.12 Sodium Benzoate
36.13 Sulfites
36.14 Surfactants (Nonionic Polyethoxylated)
36.15 Zinc Oxide
36.16 Polyethylene Glycols (PEG)
References
37: Photosensitizing Drugs
37.1 Introduction
37.2 Antimicrobials
37.3 Nonsteroidal Anti-inflammatory Drugs
37.4 Phenothiazines
37.5 Anticancer Drugs
37.6 Other Photosensitizing Drugs
37.7 “Folk” Drugs
37.8 Diagnosis of Drug Photosensitivity
37.9 Conclusions
References
38: Topically Applied Drugs
38.1 Introduction
38.2 Risk Factors
38.3 Topical Pharmacologically Active Agents
38.3.1 Antibiotics
38.3.2 Antiseptics
38.3.3 Antimycotics
38.3.4 Local Anesthetics
38.3.5 Corticosteroids
38.3.6 NSAIDs
38.3.7 Other Active Principles
38.4 Vehicle Components
38.5 Systemic Contact Dermatitis
38.6 Conclusions
References
Index

Citation preview

Cutaneous Drug Hypersensitivity Clinical Features, Mechanisms, Diagnosis, and Management Andreas J. Bircher Howard I. Maibach Knut Brockow Annick Barbaud Editors

123

Cutaneous Drug Hypersensitivity

Andreas J. Bircher • Howard I. Maibach Knut Brockow • Annick Barbaud Editors

Cutaneous Drug Hypersensitivity Clinical Features, Mechanisms, Diagnosis, and Management

Editors Andreas J. Bircher Allergology, Department of Dermatology, University Hospital Basel, Basel & Faculty of Biomedicine Università della Svizzera Italiana Lugano Switzerland Knut Brockow Department of Dermatology und Allergology Biederstein Technical University of Munich Munich Germany

Howard I. Maibach Dermatology Clinic San Francisco, CA USA Annick Barbaud Departement for Dermatology and Allergy Sorbonne Medecine University AP-HP. Sorbonne Universite Tenon Hospital Paris France

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Foreword: Controversial Topics in Drug Hypersensitivity

Drug hypersensitivity (DH) is a complex issue. The clinic is highly heterogeneous, and the mechanisms are routed in both immunological and pharmacological principles. There are different approaches possible to analyze and communicate this wide field. Cutaneous Drug Hypersensitivity edited by Bircher, Maibach, Brockow, and Barbaud emphasizes the practical approach and puts optimal care for the patient in the center [1]. It is clearly intended for the physician encountering patients with suspected DH and provides practical information for specialists, but also for physicians without in-depth knowledge in pharmacology, immunology, dermatology, and allergy. The book is organized in to five areas: starting with general aspects, clinical symptoms, diagnosis, management, and DH in specific populations; it concludes with 19 separate chapters devoted to DH to specific drug classes. Thus, the main aspects of DH for the clinician are covered; if one suspects a drug as elicitor for a particular DH one can quickly obtain more specific information on the particular drug/drug class, which type of DH reactions are known, how to diagnose them, and the relevant cross-reactivity. Such information is helpful for the clinician, who sees patients with a particular DH only rarely and who will look for helpful advice on the management of this DH. DH reactions are man-made diseases which can occur in every specialty of medicine. The acute care for patients with DH is often the responsibility of the physician who has applied the drug, but he/she is rarely an allergist. Nevertheless, some basic knowledge in this field is expected from every physician using drug therapy—and the know-how to handle acute anaphylaxis is a must. On the other hand, the clinical picture of DH is very variable and to manage DH is often a challenge: It is difficult to gain experience in this field, as DH is rare for each drug while it is not rare as a whole. Moreover, many different factors influence the course of the disease, and diagnosis remains crucial. Thus, a presumably allergic situation may be challenging for the specialist as well. Cutaneous Drug Hypersensitivity may offer help for just such situations. The preparation of such a book, which covers a broad area, is always a good opportunity to reflect on the field as a whole: Many aspects are covered in depth, but some controversial issues of drug hypersensitivity (DH) remain. Let us address some of these “hot” issues. Different DH classifications: DH reactions are modern diseases which appeared and grew in parallel with the number of drugs used: As discussed in Chap. 4 (Bircher A: Terminology, classifications, chronology), the v

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classifications of DH are complex. This seems to be problematic, as different classifications are used in parallel and depend on the viewpoint of the physician or researcher: chronology, Gell and Coombs, allergic, pharmacologic interaction concept (p-i), pseudo-allergic/intolerance (“a-p-p”) classifications, etc. [1]. One might ask which classification is correct. But one might forget that the use of different classifications also has some advantages: It makes sense that the clinician facing the acute DH or the physician who has to decide on the diagnostic steps, or the researcher interested in prevention, may approach the patient differently and use different classifications. The initial approach may rely on the timing of the event; if one has to decide on the diagnostic steps, the immune mechanism (Gell and Coombs) must be considered, as it indicates which test should be used; and for the physician/ researcher trying to understand the mechanism, dose dependence, or crossreactivity, the a-p-p classification may be appropriate. Thus, it is advantageous that different classifications are available and used. Most importantly, one should use a certain classification not because it is the only classification one knows, but because it is the best to help in the understanding/diagnosis/ prevention of future DH in the particular case. Contact dermatitis as model for systemic drug hypersensitivity? It is interesting to note that this book on Cutaneous Drug Hypersensitivity, apart from a chapter on topical drugs, does not contain a chapter on contact dermatitis (CD), which is probably the most prevalent cutaneous drug hypersensitivity reaction: Therefore, what is the relationship of CD to systemic DH? In the beginning of immunology, researchers like Karl Landsteiner were fascinated by the extraordinary specificity of the immune reactions. This specificity was elaborated using small chemicals (haptens), which were covalently bound to carrier molecules/proteins. The immune system was able to react with the hapten with high precision, and small alterations of the hapten already abrogated the serological reaction. Later, delayed cellular reactions were described and the delayed appearing immunity to small chemicals was elaborated, which became a model for CD [2]. As the high specificity of the immune reaction (serological and cellular) was later also observed in systemic DH, it was quite logical to assume that the systemic reaction to small drugs was based on the same chemical principles as in CD: The drug given elicited DH because it or a reactive metabolite covalently bound to a carrier molecule and formed a new antigen, which elicited an immune reaction [3]. This hapten concept as basis for DH was supported by the high incidence of systemic allergic reactions to penicillin, which indeed was found to be a classical hapten [4]. The example of beta-lactams, the high specificity observed in clinical cases of CD and DH, and the similar diagnosis by skin tests (patch or intradermal tests) were interpreted as proof for an identical mechanism underlying CD and DH. The hapten model in CD postulated that the chemical/drug is bound by covalent links to a protein in the skin. In systemic DH (initially mostly immediate reactions) the antigens were drug-modified soluble proteins like albumin and transferrin. Later delayed appearing DH were recognized following ingestion of oral or parental drugs. The relevant antigens in systemic reactions have so far not been well defined. The frequent occurrence of skin symptoms

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(“rashes”) during systemic DH suggested that the presumable antigen in these reactions was formed and presented in the skin and the delayed immune reactions were directed to locally available haptens or hapten-modified cells (e.g., keratinocytes); and drug-induced hepatitis was consequently seen as immune reaction to reactive drug metabolites accumulated in the liver [5]. But there are important differences between CD and DH: The clearest refers to the role of co-stimulation to mount an immune response with inflammation. CD is a localized skin reaction and mostly affects the area in contact with the eliciting chemical. Local irritation is an important, dose-dependent component: In CD, the contact sensitizer provides antigenicity and immunogenicity (e.g., stimulation of dendritic cells); both interaction of the hapten with specific immune receptors and the activation of the innate immune system are needed to start an immune reaction [6]. In DH, co-stimulation by the drug or drug metabolite was never investigated systematically and data are missing; co-stimulation of the immune system in systemic DH might go along with symptoms of inflammation, like one observes in systemic viral infections. Co-stimulation by a systemically applied drug would therefore mean sickness/fever/fatigue. Such a reaction does not appear at the beginning of most DH and would not be acceptable. There are some DHs, which show signs of inflammation in their later course (fever, fatigue), when the reaction led to inflammation. But there are no systematic “irritation/danger signals” by a systemically applied drug—not even when the patient develops a DH. In fact, patients with MPE often state that they suffer from pruritus but do generally feel quite well with no general symptoms like fever or fatigue! Over the last 25 years, many studies have shown that drugs eliciting DH are using various pathways of immune activation. Actually, drugs stimulate T cells often by a “pharmacological” off-target activity of the drug with the HLA (or TCR) structures (see below and Table 1); it is not due to “antigen” Table 1 Drug-induced ADRs and HLA allele associations (from [8]) Drugs Abacavir Carbamazepine

Allopurinol Dapsone Phenytoin Lamotrigine Methazolamide Amoxicillin-clavulanate Flucloxacillin Lumiracoxib Ticlopidine Antithyroid drugs

HLA alleles B57:01 B15:02 A31:01 B15:11 B58:01 B13:01 B15:02 A31:01 B15:02 B59:01, CW01:02 DRB115:01-DQB106:02 B57:01 DRB115:01 A33:03 B38:02-DRB108:03

Phenotypes DHS/DRESS SJS/TEN MPE, DHS/DRESS, SJS/TEN SJS/TEN SJS/TEN DHS/DRESS SJS/TEN DHS/DRESS SJS/TEN SJS/TEN DILI DILI DILI DILI Agranulocytosis

DILI drug-induced liver injury, DHS/DRESS drug hypersensitivity syndrome/drug-related/ rash with eosinophilia and systemic symptoms, SJS Stevens-Johnson syndrome, TEN toxic epidermal necrolysis, MPE maculopapular exanthem

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formation (a hapten-protein adduct)! This difference between DH and CD becomes more and more evident: In short, CD are immune reactions to a hapten-protein antigen; DH are often pharmacological reactions stimulating the immune system, where not the drug as antigen but the drug with “off- target” pharmacological activity stimulates immune mechanism. Thus, the method of immune stimulation is different—but both CD and DH involve the specific immune system and thus show a similar high degree of molecule- related specificity. DH and HLA associations: As outlined in Chap. 7 (Thompson et al., pathomechanism of DH), research on DH has made great progress: Allergic type IV reactions according to Gell and Coombs were dissected into type IVa-d; the p-i concept was developed, and in pseudo-allergy the Mas-Related G Protein-Coupled Receptor-X2 (MRGPRX2) was detected [1, 7]. For the practitioner, the strong HLA association in some forms of DH is clinically important, as it provides a reliable tool to prevent severe DH. Table 1 provides the most important currently known HLA associations in DH [8]. In acute manifestation of DH (urticaria/anaphylaxis/angioedema), IgE antibodies and mast cell/basophil degranulation are involved. In contrast, most delayed appearing cutaneous and systemic symptoms involve drug-specific T cells. Some of these T cell reactions show an HLA association. The background for the HLA associations is the p-i concept (= pharmacological interaction with immune receptors): The p-i concept implies that the drug binds directly to proteins of the HLA-TCR complex, both of which have highly polymorphous structures. Importantly, the drug does not bind to the presented immunogenic peptide, as in classical hapten/antigendriven reactions like CD. The drug-HLA (or drug-TCR) complex forms a new entity, which is crucial for T cell activation: The result of this p-i stimulation is exclusively T cell reactions (MPE, DRESS, SJS/TEN). Thereby, the drug may bind to various HLA alleles with distinct affinity: No clear HLA association is found if the drug can bind to various HLA alleles (e.g., phenytoin), but some drugs bind rather selectively to a certain HLA allele only. Examples are abacavir to B*57:01 and allopurinol/oxypurinol binding to HLA-B*58:01 (Table 1). If the patient does not carry the incriminating HLA allele, the drug is tolerated. Severe DH to this drug can be avoided by pretherapeutic screening for HLA phenotypes in a patient, before therapy is started; if she/he carries the HLA allele, therapy with the HLA linked drug is not given and DH is avoided. For example, the incidence of severe DH due to B*57:01 (abacavir) and B*15:02 (carbamazepine) could be dramatically reduced: It represents one of the biggest successes of personalized medicine [9]. Identify the mechanism of DH: Another puzzle of DH is the big heterogeneity of clinical manifestations: The main reason for this heterogeneity is the fact that different mechanisms are involved in the initiation of the immune system activation, but the inflammatory reactions at the end are similar, as the same effector cells of inflammation are involved. For example, the eosinophilic inflammation in DRESS can involve various organs including the skin, but hepatitis, nephritis, myocarditis, and pneumonitis are all due to an eosinophilic inflammation.

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One approach to dissect the clinical manifestations is to use classifications which reflect different mechanisms, like the Gell and Coombs classification for allergic/immune reactions as well as the a-p-p classification, which defines DH based on type and location of drug binding to proteins. On the other hand, the manifestations can look very similar, but the underlying mechanism is quite different. For example, one cannot differentiate on clinical grounds between anaphylaxis due to IgE antibody and an MRGPRX2-associated mechanisms. Both can lead to rapidly appearing anaphylaxis. And it is difficult to differentiate MPE due to DH based on hapten-driven or p-i mechanism, and the exanthem could even be due to a viral infection or GVHD (graft versus host disease). It is, therefore, important that the physician taking care of the patient with DH not only identify the eliciting drug/drug class but also come to a conclusion regarding mechanism, as this is decisive for advice on cross-reactivity, dose dependence, further prevention, and HLA linkage [1]. Thus, not only the drug or drugs causing the reaction need to be known. Also, the underlying mechanism should be included in the analysis of the DH reaction and the advice to the patient. The patient wants to know what was the cause of his drug allergy and what he has to avoid. An allergic or pseudo-allergic reaction to an NSAID may make a big difference for the advice, namely, to avoid all structurally similar products (in case of allergy) or avoid all products which may act similarly (in case of pseudo-allergy/intolerance). Acute reactions and late consequences of DH: A further, still not well- recognized aspect of DH is late reactions appearing in the absence of drug, i.e., after stopping the drug: The majority of DH have early onset symptoms like urticaria, MPE, bullous exanthema, and hepatitis, which start within minutes to weeks of treatment, depending on pre-existing immunity and mechanism. They start under therapy, but as soon as therapy is stopped, they usually improve rapidly. But there are exceptions: (a) Appearance of exanthema after drug therapy is stopped: This is well known for amoxicillin, where the therapy is tolerated for 7–10 days, but after the therapy is stopped, mostly on day 11–13, symptoms appear. This is puzzling since the half-life of the drugs involved is often 20 years ago, often in childhood, and were possibly due to a coincidence of drug intake and viral infection, and this event

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labeled the child as beta-lactam allergic for years or even a lifetime. The diagnosis of a permanent penicillin allergy can rarely be verified in adulthood, as skin/in vitro or provocation tests are negative; most patients tolerate a repeated treatment (“delabeling”). Therefore, most authors recommend direct provocation with a beta-lactam antibiotic to get rid of such a problematic and often wrong label. Only if the reaction is severe (e.g., prolonged morbidity, hospitalization) or acute (anaphylaxis) caution is recommended, and diagnostic procedures (skin tests, in vitro tests) should be performed before provocation is considered. In the remaining cases, the drug allergy label should be suspended, and the beta-lactam can be given without further tests [12]. As provocation tests are often not possible or not recommended, one can minimize the need for a provocation test or substitute it by combining systematically all evidence for or against a DH. The questions to be answered are: Is it a drug hypersensitivity? Against which drug/drugs? What mechanism is involved? By combining all factors an experienced physician can establish a reliable diagnosis in around 70% of acute cases: The evaluation relies on a combination of clinical picture, timing and severity of the DH, detailed history/cofactors of disease manifestations, previous DH and other allergies/intolerances, knowledge of the drug’s pharmacology and of the type/timeline prior to the DH to the drug, and finally skin and in vitro tests. Of course, this approach requires experience and requires the expertise of a specialist, and it is only possible when a large armamentarium is available to prove sensitization (skin tests, LTT, BAT). The more test possibilities are available, the lower the need for a provocation test. In the absence of good animal models, improvement of therapy and better avoidance of DH rely on the study of such patients, who suffer from this iatrogenic and mostly unpredictable disease. The minimum we can offer as physicians is to do our best in management. I hope and believe that this book can help and wish the readers of this book all the best and that they may find what they are looking for. ADR-ACWerner J. Pichler Bern, Switzerland

References 1. Pichler WJ, Hausmann O. Classification of drug hypersensitivity into allergic, p-i, and pseudo-allergic forms. Int Arch Allergy Immunol. 2016;171(3–4):166–179. https://doi. org/10.1159/000453265. PubMed PMID: 27960170. 2. Keil H, Wasserman D, Dawson CR. The relation of chemical structure in catechol compounds and derivatives to poison ivy hypersensitivities in man as shown by patch test. J Exp Med. 1944;80(4):275–87. https://doi.org/10.1084/jem.80.4.275. PMID: 19871415; PMCID: PMC2135472. 3. Park BK, Naisbitt DJ, Gordon SF, Kitteringham NR, Pirmohamed M. Metabolic activation in drug allergies. Toxicology 2001;158(1–2):11–2. 4. Levine BB. Degradation of benzylpenicillin at pH 7.5 to D-benzylpenicilloic acid. Nature. 1960;187:939–40. https://doi.org/10.1038/187939a0. PMID: 13761466.

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5. Tailor A, Faulkner L, Naisbitt DJ, Park BK. The chemical, genetic and immunological basis of idiosyncratic drug-induced liver injury. Hum Exp Toxicol. 2015;34(12):1310– 7. https://doi.org/10.1177/0960327115606529. PMID: 26614821. 6. Martin SF. New concepts in cutaneous allergy. Contact Dermatitis. 2015;72(1):2–10. https://doi.org/10.1111/cod.12311. Epub 2014 Oct 28. PMID: 25348820. 7. Pichler WJ. Immune pathomechanism and classification of drug hypersensitivity. Allergy. 2019;74(8):1457–71. https://doi.org/10.1111/all.13765. Epub 2019 Apr 29. PMID: 30843233 8. Chen CB, Abe R, Pan RY, Wang CW, Hung SI, Tsai YG, Chung WH. An updated review of the molecular mechanisms in drug hypersensitivity. J Immunol Res. 2018;2018:6431694. https://doi.org/10.1155/2018/6431694. Erratum in: J Immunol Res. 2019;2019:2489429. PMID: 29651444; PMCID: PMC5830968. 9. Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, Thorborn D, Benbow A; PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568-79. https://doi.org/10.1056/ NEJMoa0706135. PMID: 18256392. 10. Kano Y, Shiohara T. The variable clinical picture of drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms in relation to the eliciting drug. Immunol Allergy Clin North Am. 2009; 29:481–501 11. Pichler WJ, Srinoulprasert Y, Yun J, Hausmann O. Multiple drug hypersensitivity. Int Arch Allergy Immunol. 2017;172(3):129–138. https://doi.org/10.1159/000458725. Epub 2017 Mar 18. PMID: 28315874; PMCID: PMC5472211. 12. Savic L, Gurr L, Kaura V, Toolan J, Sandoe JAT, Hopkins PM, Savic S. Penicillin allergy de-labelling ahead of elective surgery: feasibility and barriers. Br J Anaesth. 2019;123(1):e110–6. https://doi.org/10.1016/j.bja.2018.09.009. Epub 2018 Oct 19. PMID: 30915983.

Preface

Drug treatment often leads to adverse events, which are an important daily problem in every medical specialty. Most common are medication errors occurring due to the handling of the drug such as interactions, overdose, wrong medication, and other dose-dependent toxic reactions due to known pharmacological or biological effects. Most of these inherently predictable reactions could be avoided by using computerized prescribing systems with corresponding algorithms. On the other hand, hypersensitivity reactions to drugs are unpredictable and belong to the most challenging problems in allergology. First, drug hypersensitivity reactions are among the great imitators of other diseases, implicating a wide differential diagnosis. Their clinical manifestations are manifold, ranging from mild, self-limiting manifestations to severe disorders, from localized skin disease to affection of internal organs to systemic, sometimes life-threatening syndromes, a challenge for any physician. Second, the underlying mechanisms are very variable and not completely understood. Apart from the four classical immune reactions according to Coombs and Gell, an extended subclassification has been proposed, particularly for the type IV cell-mediated reactions. And new mechanisms, such as the p-i concept, have emerged in the last years. In addition, many drugs elicit reactions by directly activating proinflammatory pathways such as directly stimulating effector cells or interfering with mediator production, e.g., the arachidonic or the kinin cascade. This wide array of reactions without specific immune mechanisms is summarized under the umbrella term pseudoallergy. Despite increasing knowledge, the diagnostic possibilities remain a challenge and are still limited for many drugs and types of reactions. Third, the therapeutic armamentarium has increased considerably over the last 100 years; initially simple chemicals called xenobiotics were identified and developed for clinical use. In the last 20 years an era of new therapeutic drug classes and diagnostic agents, such as new imaging substances, biologics such as monoclonal antibodies, or checkpoint inhibitors have seen rapidly increasing use. The downside of this is the emergence of new types of adverse reactions including cytokine activation syndromes and immune-related disorders. Therefore, as long as patients are treated and science develops new therapeutic molecules, adverse reactions and among them hypersensitivity reactions will remain an unwelcome but inevitable companion.

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In this book, with the help and expertise of internationally renowned experts in their field, we have tried to illustrate and clarify the many facets of drug hypersensitivity. Such a comprehensive work is never finished, and it may always be a step or two behind new developments. Still, we sincerely hope that this book contributes to making pharmacotherapy safer and that it may help to avoid problems or solve issues for patients in need of treatment. We sincerely thank all the authors for their work and Springer for patience and longstanding support. Without their concentrated efforts, this book would not have been possible. Basel and Lugano, Switzerland San Francisco, CA, USA Munich, Germany Paris, France

Andreas J. Bircher Howard I. Maibach Knut Brockow Annick Barbaud

Contents

Part I General Aspects of Drug Hypersensitivity 1 Classification and Terminology of Drug Hypersensitivity Reactions�� 3 Andreas J. Bircher 1.1 Clinical Phenotypes�� 4 1.2 Severity �� 4 1.3 Chronology �� 5 1.4 Pathomechanisms�� 7 1.5 Summary �� 8 References�� 9 2 Epidemiology�� 11 Noel Frey and Julia Spoendlin 2.1 Data Sources for Observational Studies on Cutaneous Adverse Drug Reactions �� 11 2.2 Prevalence and Incidence of Cutaneous ADR�� 12 2.3 Types of Cutaneous ADR�� 14 2.4 Culprit Drugs of Cutaneous ADR �� 14 2.5 Absolute Risks of Cutaneous ADR to Drugs�� 15 2.6 Epidemiology of Severe and Life-Threatening Cutaneous ADR�� 16 2.6.1 SJS/TEN�� 16 2.6.2 AGEP�� 17 2.6.3 DRESS�� 17 References�� 17 3 Cutaneous Signs and Syndromes of Drug Hypersensitivity�� 21 Knut Brockow 3.1 Introduction�� 21 3.2 Clinical Manifestations �� 22 3.2.1 Urticaria, Angioedema, and/or Anaphylaxis�� 22 3.2.2 Disseminated and Generalized Exanthems�� 23 3.2.3 Major Localized Cutaneous Manifestations �� 25

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3.3 Specific Clinical Reaction Patterns to Chemotherapeutics and Biopharmaceuticals�� 25 3.4 Diagnostics Methods�� 25 3.5 Management�� 27 References�� 27 4 Systemic Organ Manifestations of Drug Allergy�� 29 Marianne Lerch and Thomas Harr 4.1 Hepatic Manifestations of Drug Allergy�� 29 4.2 Kidney Injury�� 31 4.3 Cardiac Manifestations �� 32 4.4 Lung Manifestations �� 33 4.5 Role of Human Herpesviruses in Single and Multi-organ Manifestations of Drug Allergy �� 34 4.6 Conclusion�� 36 References�� 36 5 Danger Signs in Drug Hypersensitivity�� 43 Andreas J. Bircher and Kathrin Scherer Hofmeier 5.1 Rapidly Occurring Danger Signs�� 43 5.2 Late-Occurring Danger Signs �� 43 5.3 Systemic Danger Signs �� 44 5.4 Assessment of Skin Lesions�� 44 References�� 45 6 Pathomechanisms of Drug Hypersensitivity Targeting the Liver and Skin�� 47 Paul Thomson, Dean Naisbitt, and Monday Ogese 6.1 Drug Hypersensitivity Reaction (Background)�� 47 6.2 Coombs and Gell’s Classification of Drug Hypersensitivity Reactions �� 48 6.3 Limitations of Coombs and Gell’s Classification of Drug Hypersensitivity�� 48 6.4 Drug Hypersensitivity Syndrome (DHS)�� 49 6.5 Drug-Induced Liver Injury (DILI)�� 50 6.6 Drug Hypersensitivity Reactions Targeting the Skin�� 51 6.7 Proposed Classification of Drug Hypersensitivity Incorporating Current Findings�� 54 References�� 54 Part II Diagnostic Methods 7 Skin Tests�� 61 Annick Barbaud 7.1 Background �� 61 7.2 Drug Patch Tests �� 62 7.2.1 Test Principle�� 62 7.2.2 Test Concentrations�� 63 7.2.3 Clinical Application�� 64 7.2.4 Limitations�� 64

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7.3 Drug Prick Tests�� 64 7.3.1 Test Principle�� 64 7.3.2 Clinical Application�� 64 7.3.3 Limitations�� 65 7.4 Intradermal Drug Tests (IDTs)�� 65 7.4.1 Test Principle�� 65 7.4.2 Test Concentrations�� 66 7.4.3 Clinical Application�� 66 7.5 Strength and Limitations�� 67 7.6 Conclusions�� 68 References�� 68 8 Serological Tests �� 69 Maria I. Montañez, Adriana Ariza, Cristobalina Mayorga, and Maria J. Torres 8.1 Background �� 69 8.2 Serological Methods to Characterize the Active Phase of the Reaction�� 70 8.2.1 Serum Tryptase Determination �� 70 8.3 Serological Tests to Identify the Culprit Drug�� 72 8.3.1 Specific Immunoglobulin E (sIgE) Determination �� 72 8.4 Conclusions�� 77 References�� 78 9 T-Cell Assays for the Investigation of Drug Hypersensitivity�� 79 Ying Teo and Michael R. Ardern-Jones 9.1 Background �� 79 9.2 Mechanisms of T-Cell Recognition of Drugs �� 79 9.3 Test Principle�� 80 9.4 Measurement of Proliferation �� 82 9.5 Measurement of Functional Changes in T Cells Due to Drug-Induced Activation�� 82 9.6 Measurement of T-Cell Phenotypic Changes�� 84 9.7 Clinical Application�� 86 9.8 Strength and Weakness �� 87 9.9 Conclusion�� 90 References�� 90 10 Basophil Activation Tests�� 91 Cristobalina Mayorga, Tahia Diana Fernández, Ruben Fernandez-Santamaría, and Alba Rodriguez-Nogales 10.1 Background �� 91 10.2 Test Principle�� 92 10.2.1 General Considerations in BAT�� 92 10.3 Clinical Applications�� 94 10.3.1 Evaluation of Clavulanic Acid Hypersensitivity�� 94 10.3.2 Evaluation of Fluoroquinolone Hypersensitivity�� 94 10.3.3 Evaluation of Hypersensitivity to Other Drugs�� 95

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10.4 Strength and Weakness �� 95 10.4.1 Optimal Time Interval from the Acute Phase of the Reaction�� 95 10.4.2 Activation Markers�� 96 10.4.3 Optimal Management of Drug to Avoid Degradation�� 96 10.4.4 Inclusion of the Optimal Drug Metabolite�� 96 10.5 Conclusions�� 97 References�� 97 11 Histopathology of Drug-Induced Exanthemas�� 99 Katrin Kerl and Helmut Kerl 11.1 Background �� 99 11.2 Basic Principle�� 99 11.3 Clinical Application�� 100 11.3.1 Histology of Common Drug-Induced Cutaneous Hypersensitivity Reactions �� 100 11.3.2 Histology of Severe, Potentially Life-Threatening Forms of Cutaneous Drug Reactions�� 101 11.3.3 Special Patterns�� 102 11.3.4 Histology of Cutaneous Reactions to Targeted Therapies�� 103 11.4 Strength and Weaknesses�� 105 11.5 Conclusion�� 105 References�� 105 Part III Management 12 Drug Desensitization in Immediate-Type Hypersensitivity �� 109 Mariana Castells, Sahar Hamadi, and Maria Sanchez Sanchez 12.1 How Is Drug Hypersensitivity Defined in the Twenty-First Century?�� 109 12.1.1 The Importance of Drug Hypersensitivity�� 109 12.1.2 Phenotypes and Endotypes of Drug Hypersensitivity�� 110 12.1.3 Biomarkers of Phenotypes and Endotypes of Drug Hypersensitivity�� 112 12.2 Definition of Desensitization (DS)�� 113 12.2.1 Desensitization Protocols: An Example�� 113 12.2.2 Inhibition of Skin Testing by Desensitization�� 114 12.3 Mechanisms of Desensitization�� 114 12.3.1 Desensitization Mechanisms�� 114 12.3.2 Desensitization Healthcare Costs�� 117 12.3.3 Desensitization Candidates �� 117 12.4 Drugs in Which Desensitization Is Feasible �� 119 12.4.1 Antibiotics�� 119 12.4.2 Chemotherapy (Platins/Taxanes)�� 119 12.4.3 Progesterone�� 122 12.5 Conclusion�� 123 References�� 123

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13 Documentation for Patients with Drug Hypersensitivity: Allergy Pass and Allergy Card�� 127 Knut Brockow 13.1 Introduction�� 127 13.2 Documentation Instruments�� 127 13.2.1 Purpose and Means of Documentation �� 127 13.2.2 Discharge Letter/Certificate�� 128 13.2.3 Drug Allergy Passport�� 129 13.2.4 Drug Allergy Card�� 129 13.3 Requirements for Drug Allergy Documentation�� 129 References�� 131 Part IV Drug Hypersensitivity in Specific Populations 14 Cutaneous Drug Hypersensitivity: Clinical Features, Mechanism, Diagnosis, and Management in Children and Adolescent�� 135 Marcel Bergmann, Eva Gomes, and Jean-Christoph Caubet 14.1 Introduction�� 135 14.2 Epidemiology of Drug Allergy in Children and Adolescent�� 135 14.3 The Role of Viral Infections and Genetic Factors�� 136 14.4 β-Lactam Antibiotics�� 137 14.4.1 Immediate Drug Reactions �� 138 14.4.2 Delayed Drug Reactions �� 138 14.5 Diagnostic in Vitro and in Vivo Tests in Suspected Hypersensitivity to β-Lactam Antibiotics �� 139 14.5.1 Immediate Drug Reactions �� 139 14.5.2 Delayed Drug Reactions �� 140 14.6 Non-β-Lactam Antibiotics (NBLAs)�� 140 14.7 Nonsteroidal Anti-inflammatory Drugs (NSAIDs)�� 141 14.7.1 Classification of NSAID Hypersensitivity in Children�� 141 14.7.2 Nonallergic Cross-Intolerant (CI) Reactions�� 141 14.7.3 Allergic Non-cross-Intolerant Reactions or Selective Reactions (SR)�� 142 14.7.4 Diagnostic Tests and Management in Suspected Hypersensitivity to NSAIDs �� 142 14.7.5 Natural History and Desensitization to NSAIDs�� 144 14.8 Vaccines�� 144 14.8.1 Local Reactions to Vaccines �� 144 14.8.2 Systemic Reactions to Vaccines�� 144 14.8.3 Management of Patients with a History of an Immediate Reaction to a Vaccine�� 145 14.8.4 Management of Patients with History of Allergy to Vaccine Component(s)�� 145 14.9 Conclusion�� 145 References�� 146

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15 HIV-Infection and AIDS�� 147 Brigitte Milpied-Homsi 15.1 Introduction�� 147 15.2 Drug Hypersensitivity in HIV-Infected Patients �� 147 15.3 Pathogenesis�� 147 15.4 Hypersensitivity to Drugs to Treat and Prevent Opportunistic Infections�� 148 15.4.1 Antituberculosis Drugs �� 148 15.4.2 Anti-Toxoplasmosis Drugs �� 149 15.4.3 Antifungal Drugs�� 149 15.5 Antiretroviral Drugs�� 149 15.5.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)�� 150 15.5.2 Non-nucleoside Reverse Transcriptase Inhibitors �� 151 15.5.3 Protease Inhibitors�� 152 15.5.4 Fusion Inhibitor�� 152 15.5.5 CCR5 Inhibitor �� 152 15.5.6 Integrase Inhibitors �� 152 15.6 Management�� 153 15.7 Conclusion�� 153 References�� 153 16 Oncology: Immune Checkpoint Inhibitors�� 155 Peter Arne Gerber 16.1 Introduction�� 155 16.2 Mechanisms�� 155 16.3 Clinical Features, Diagnosis, and Grading �� 156 16.4 Management�� 158 References�� 159 17 Drug Hypersensitivity and Clonal Mast Cell Disorders�� 161 Patrizia Bonadonna and Knut Brockow 17.1 Clinical Manifestations �� 161 17.2 Mechanisms�� 162 17.3 Diagnostic Methods�� 163 17.4 Management�� 163 References�� 165 Part V Eliciting Drugs 18 Penicillins�� 169 Maria J. Torres, Inmaculada Doña, Tahia Diana Fernández, and Gador Bogas 18.1 Introduction�� 169 18.2 Clinical Manifestations �� 169 18.3 Mechanisms�� 170 18.3.1 Immediate Reactions�� 171 18.3.2 Non-immediate Reactions�� 171

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18.4 Diagnostic Methods�� 172 18.4.1 Clinical History�� 172 18.4.2 Skin Tests�� 172 18.4.3 In Vitro Diagnostics�� 173 18.4.4 Drug Provocation Test�� 175 18.5 Cross-reactions�� 175 References�� 175 19 Cephalosporins�� 177 Antonino Romano, Rocco Luigi Valluzzi, and Francesco Gaeta 19.1 Introduction�� 177 19.2 Clinical Features and Mechanisms �� 177 19.2.1 Immediate Reactions�� 177 19.2.2 Nonimmediate Reactions�� 180 19.3 Diagnosis�� 180 19.3.1 Clinical History�� 180 19.3.2 Allergy Workup�� 180 19.4 Cross-reactivity Among Cephalosporins and Between Cephalosporins and Other β-Lactams�� 184 19.4.1 Administration of Penicillins, Aztreonam, and Carbapenems to Patients with Cephalosporin Allergy�� 184 19.4.2 Administration of Alternative Cephalosporins to Patients with Cephalosporin Allergy�� 185 References�� 185 20 Other Antibiotics�� 187 Josefina Cernadas 20.1 Introduction�� 187 20.2 Quinolones�� 187 20.2.1 Management�� 188 20.3 Macrolides�� 188 20.4 Aminoglycoside Antibiotics�� 189 References�� 190 21 Other Anti-Infectious Drugs �� 193 Werner Aberer 21.1 Chloroquine and Hydroxychloroquine �� 193 21.2 Dapsone (Diaminodiphenylsulfone) �� 193 21.3 Pentamidine�� 193 21.4 Quinine�� 194 21.5 Fluconazole �� 194 21.6 Itraconazole�� 194 21.7 Ketoconazole�� 194 21.8 Terbinafine�� 194 21.9 Amphotericin B�� 194 21.10 Anti-herpes and Anti-CMV Drugs�� 194 21.11 Antiretroviral Substances: Abacavir �� 195 21.12 Summary �� 195 References�� 195

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22 Cutaneous Hypersensitivity Reactions to Analgesics and Nonsteroidal Anti-Inflammatory Drugs �� 197 Marek L. Kowalski and Aleksandra Wardzynska 22.1 Clinical Manifestation�� 197 22.1.1 NSAIDs-Exacerbated Cutaneous Disease (NECD)�� 197 22.1.2 NSAIDs-Induced Urticaria/Angioedema (NIUA)�� 198 22.1.3 Single NSAIDs-Induced Urticaria/Angioedema or Anaphylaxis (SNIUAA)�� 198 22.1.4 Single NSAIDs-Induced Delayed Hypersensitivity Reactions (SNIDHR)�� 199 22.1.5 Mixed Reactions �� 199 22.2 Mechanisms�� 199 22.3 Diagnostic Methods�� 200 22.3.1 Step 1: Assess the Type of Adverse Reaction to NSAIDs�� 201 22.3.2 Step 2: Determine Timing of the Reaction �� 201 22.3.3 Step 3: Analyze Clinical Pattern of NSAID-Induced Symptoms and Underlying Chronic Diseases�� 201 22.3.4 Step 4: Assess History of Hypersensitivity/Tolerance to Other NSAIDs�� 201 22.3.5 Step 5: Confirm/Exclude Cross-Reactivity to Other NSAIDs by Challenge�� 203 22.3.6 Step 6: Consider Skin Testing or in Vitro Testing �� 203 22.3.7 Step 7: Consider Oral Provocation Challenge with a Culprit Drug�� 203 22.4 Cross-Reactions�� 204 22.5 Management�� 204 22.5.1 Cross-Reactive Types of Hypersensitivity (NECD and NIUA) �� 204 22.5.2 Selective Types of SNIUAA and SNIDHR�� 204 22.5.3 Desensitization�� 204 References�� 204 23 Peri-Interventional Hypersensitivity: Anesthetic Drugs and Materials�� 207 Andreas J. Bircher and Knut Brockow 23.1 Introduction�� 207 23.2 Clinical Manifestations �� 207 23.3 Mechanisms�� 208 23.4 Diagnostic Methods�� 209 23.4.1 Skin Tests�� 209 23.4.2 In Vitro Diagnostics�� 209 23.4.3 Provocation Tests�� 209

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23.5 Eliciting Drugs�� 209 23.5.1 Natural Rubber Latex�� 210 23.5.2 Hypnotics�� 210 23.5.3 Local Anesthetics�� 210 23.5.4 Opioids�� 211 23.5.5 Nonsteroidal Anti-inflammatory Drugs (NSAIDs)�� 211 23.5.6 Volume Expanders�� 211 23.5.7 Hemostatic and Anticoagulant Drugs �� 211 23.5.8 Miscellaneous Drugs�� 211 23.5.9 Antiseptics and Sterilizers�� 212 23.5.10 Blue Dyes�� 212 23.5.11 Radiocontrast Media �� 212 23.5.12 Additives �� 212 23.6 Cross-Reactivity�� 213 23.7 Management�� 213 References�� 213 24 Muscle Relaxants �� 215 Paul Michel Mertes and Charles Tacquard 24.1 Introduction�� 215 24.2 Clinical Manifestations �� 216 24.2.1 Skin �� 216 24.2.2 Respiratory�� 216 24.2.3 Cardiovascular Signs�� 216 24.2.4 Other Signs�� 216 24.3 Mechanisms�� 216 24.3.1 Immediate Immune-Mediated Hypersensitivity Reactions�� 217 24.3.2 Non-immune-Mediated Hypersensitivity Reactions�� 218 24.4 Diagnostic Methods�� 218 24.4.1 Tryptase and Histamine Measurement�� 219 24.4.2 Skin Tests�� 219 24.4.3 Specific IgE Assays�� 220 24.4.4 Cellular Tests�� 220 24.4.5 Provocation Tests�� 220 24.5 Management of NMBA-Related Hypersensitivity Reactions�� 220 24.6 Conclusion�� 221 References�� 222 25 Anticoagulants�� 223 Kathrin Scherer Hofmeier 25.1 Introduction�� 223 25.2 Indirect Anticoagulants Without Direct Effect on the Plasmatic Coagulation System�� 224 25.2.1 Vitamin K Antagonists/Coumarins �� 224 25.2.2 Heparins and Derivatives�� 224

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25.3 Directly Acting Oral Anticoagulants (DOACs)�� 225 25.3.1 Direct Factor Xa Inhibitors �� 225 25.3.2 Direct Factor IIa Inhibitors/Thrombin Inhibitors�� 226 25.4 Antiplatelet Drugs�� 226 25.4.1 Cyclooxygenase Inhibitors�� 226 25.4.2 P2Y12 Inhibitors/Thienopyridines�� 226 25.4.3 Glycoprotein (GP) IIb-IIIa Receptor Antagonists �� 227 25.4.4 Phosphodiesterase III Inhibitors �� 227 25.5 Summary �� 228 References�� 228 26 Biological Drugs �� 233 Alessandra Vultaggio 26.1 Clinical Manifestation�� 233 26.1.1 Acute Infusion Reactions�� 233 26.1.2 Delayed Infusion Reactions�� 234 26.2 Mechanisms�� 234 26.3 Diagnostic Methods�� 236 26.4 Management�� 237 References�� 237 27 Corticosteroids �� 239 Marie Baeck and An Goossens 27.1 Introduction�� 239 27.1.1 A Not-So-Uncommon Condition�� 239 27.2 Delayed Allergic Hypersensitivity to Corticosteroids�� 239 27.2.1 The Skin: Main Sensitization and Elicitation Route �� 239 27.2.2 Clinical Presentation: Neither Specific Nor Spectacular�� 240 27.2.3 The Indisputable Value of Patch Testing�� 242 27.2.4 The Central Role of Halogenation and C16-Methyl Substitution and Reappraisal of the ABCD Classification�� 242 27.3 Immediate Allergic Hypersensitivity to Corticosteroids�� 246 27.3.1 Clinical Presentation: Not Specific to Corticosteroids�� 246 27.3.2 Diagnosis: Allergy to Excipients Needs to Be Ruled Out�� 246 27.3.3 Pathogenesis: Poorly Understood �� 247 27.3.4 No Cross-Reactivity Patterns Observed�� 247 References�� 247 28 Vaccines�� 251 Giovanna Zanoni and Mariasole Migliorini 28.1 Introduction�� 251 28.2 Clinical Manifestations �� 251 28.2.1 Injection Site Reactions�� 251 28.2.2 Systemic Reactions �� 251

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28.3 Mechanisms�� 252 28.4 Diagnostic Methods�� 254 28.5 Management�� 255 References�� 256 29 Antiepileptic and Psychotropic Drugs�� 257 Andreas J. Bircher and Knut Brockow 29.1 Introduction�� 257 29.2 Clinical Manifestations �� 258 29.3 Eliciting Drugs�� 258 29.4 Mechanisms�� 261 29.5 Predisposing and Risk Factors�� 261 29.6 Cross-Reactivity�� 262 29.7 Diagnostic Methods�� 262 29.8 Management�� 264 29.9 Summary �� 265 References�� 265 30 Antiacid drugs: Proton Pump Inhibitors and H2 Receptor Antagonists �� 267 Patrizia Bonadonna and Carla Lombardo 30.1 Clinical Manifestation�� 268 30.1.1 Proton Pump Inhibitors �� 268 30.2 H2 Receptor Antagonists�� 268 30.3 Mechanisms�� 269 30.4 Diagnostic Methods�� 269 30.4.1 Proton Pump Inhibitors �� 269 30.4.2 H2 Receptor Antagonists�� 270 30.4.3 Cross-Reactivity among PPIs �� 271 30.5 Cross-Reactivity among H2RA�� 271 30.6 Management�� 271 References�� 271 31 Diagnostic Agents �� 273 Knut Brockow 31.1 Introduction�� 273 31.2 Hypersensitivity Reactions to Iodinated Radiocontrast Media and Gadolinium-Based Contrast Agents�� 273 31.2.1 Clinical Manifestations �� 273 31.2.2 Mechanisms�� 275 31.2.3 Diagnostic Methods�� 275 31.2.4 Management�� 276 31.2.5 Hypersensitivity to Dyes�� 276 31.2.6 Clinical Manifestations �� 276 31.2.7 Pathogenesis�� 277 31.2.8 Diagnostic Methods�� 277 31.2.9 Management�� 277 References�� 277

xxvi

32 Blood Pressure Agents �� 279 Shira Rosenberg-Bezalel, Keren Mahlab-Guri, and Zev Sthoeger 32.1 Thiazide Diuretics�� 279 32.2 Furosemide�� 280 32.3 Calcium Channel Blockers (CCBs)�� 280 32.4 Beta- and Alpha-Blockers �� 280 32.5 Renin-Angiotensin-Aldosterone System (RAAS) Blockers�� 281 32.6 Angiotensin-Converting Enzyme Inhibitors (ACE-I) �� 281 32.7 Angiotensin Receptor Blockers (ARBs)�� 282 32.8 Direct Renin Antagonists�� 282 32.9 Spironolactone�� 282 References�� 283 33 Iron Preparations�� 287 Esther Helen Steveling-Klein 33.1 Introduction�� 287 33.2 Epidemiology�� 289 33.3 Risk Factors�� 289 33.4 Clinical Manifestations �� 289 33.5 Pathomechanism �� 289 33.6 Management of Iron Infusions�� 289 33.7 Management of HSRs �� 290 33.8 Diagnosis�� 290 33.9 Re-administration�� 290 References�� 290 34 Vitamins and Supplements�� 291 Stefan Wöhrl 34.1 Clinical Manifestation (Immediate, Delayed, Others)�� 291 34.2 Mechanisms�� 292 34.3 Diagnostic Methods�� 293 34.4 Cross-reactions�� 293 34.5 Management�� 293 References�� 294 35 Antitumor/Cytostatic Drugs �� 297 Mauro Pagani 35.1 Skin Reactions Provoked by Cytostatic Drugs �� 297 35.2 Hypersensitivity Reactions �� 297 35.3 Toxic Erythema �� 301 35.4 Other Skin Reactions Associated with Conventional Chemotherapy �� 303 35.5 Conclusions�� 303 References�� 303

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36 Additives: Preservatives, Antioxidants, Dyes, and Others �� 305 Annick Barbaud 36.1 Aluminum-Induced Granuloma�� 305 36.2 Antibiotics in Vaccines�� 306 36.3 Benzyl Alcohol�� 306 36.4 Carboxymethylcellulose (CMC)�� 306 36.5 Dyes�� 307 36.6 Egg Protein and Vaccines�� 308 36.7 Gelatin�� 308 36.8 Metacresol�� 308 36.9 Povidone �� 308 36.10 Protamine�� 309 36.11 Saccharomyces Cerevisiae Used as Media for Recombinant Vaccines�� 309 36.12 Sodium Benzoate�� 309 36.13 Sulfites�� 309 36.14 Surfactants (Nonionic Polyethoxylated) �� 310 36.15 Zinc Oxide�� 310 36.16 Polyethylene Glycols (PEG) �� 310 References�� 311 37 Photosensitizing Drugs�� 313 Margarida Gonçalo 37.1 Introduction�� 313 37.2 Antimicrobials�� 314 37.3 Nonsteroidal Anti-inflammatory Drugs�� 316 37.4 Phenothiazines�� 317 37.5 Anticancer Drugs�� 317 37.6 Other Photosensitizing Drugs �� 318 37.7 “Folk” Drugs�� 318 37.8 Diagnosis of Drug Photosensitivity�� 318 37.9 Conclusions�� 318 References�� 319 38 Topically Applied Drugs�� 321 Liesbeth Gilissen and An Goossens 38.1 Introduction�� 321 38.2 Risk Factors�� 321 38.3 Topical Pharmacologically Active Agents�� 322 38.3.1 Antibiotics�� 322 38.3.2 Antiseptics�� 322 38.3.3 Antimycotics �� 323 38.3.4 Local Anesthetics�� 324 38.3.5 Corticosteroids�� 324 38.3.6 NSAIDs�� 324 38.3.7 Other Active Principles �� 325

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38.4 Vehicle Components �� 326 38.5 Systemic Contact Dermatitis�� 326 38.6 Conclusions�� 326 References�� 327 Index�� 329

Contributors

Werner Aberer Department of Dermatology, Medical University of Graz, Graz, Austria Michael R. Ardern-Jones Department of Dermatology, University Hospitals Southampton NHS Trust, Southampton General Hospital, Southampton, UK Clinical Experimental Sciences, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton, UK Adriana Ariza Allergy Research Group, Instituto de Investigación Biomédica de Málaga—IBIMA, Malaga, Spain Marie Baeck Department of Dermatology, Cliniques universitaires SaintLuc, Université Catholique de Louvain, Bruxelles, Belgium Annick Barbaud Departement for Dermatology and Allergy, Sorbonne Medecine University, AP-HP. Sorbonne Universite, Tenon Hospital, Paris, France Marcel Bergmann Pediatric Allergy Unit, Department of Child and Adolescent, University Hospitals of Geneva, Geneva, Switzerland Centro Pediatrico del Mendrisiotto, Mendrisio, Switzerland Andreas J. Bircher Allergology, Department of Dermatology, University Hospital Basel, Basel, Switzerland Faculty of Biomedicine, Università della Svizzera Italiana, Lugano, Switzerland Medical Faculty, University of Basel, Basel, Switzerland Gador Bogas Allergy Unit, IBIMA—Hospital Regional Universitario de Malaga—UMA, Málaga, Spain Patrizia Bonadonna Allergy Unit, Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy Multidisciplinary Outpatients Clinic for Mastocytosis (GISM), Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy Knut Brockow Department of Dermatology und Allergology Biederstein, Technical University of Munich, Munich, Germany Mariana Castells Brigham and Women’s Hospital, Boston, MA, USA

xxix

xxx

Jean-Christoph Caubet Pediatric Allergy Unit, Department of Child and Adolescent, University Hospitals of Geneva, Geneva, Switzerland Josefina Cernadas Drug Allergy Unit, University Hospital S João, Porto, Portugal Inmaculada Doña Allergy Unit, IBIMA—Hospital Regional Universitario de Malaga—UMA, Málaga, Spain Tahia Diana Fernández Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain Research Laboratory, IBIMA–Hospital Regional Universitario de Malaga– UMA, Málaga, Spain Ruben Fernandez-Santamaría Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain Noel Frey Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland Hospital Pharmacy, University Hospital Basel, Basel, Switzerland Francesco Gaeta Allergy Unit, Columbus Hospital, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy Peter Arne Gerber Department of Dermatology , Medical Faculty HeinrichHeine-University of Duesseldorf, Duesseldorf, Germany Liesbeth Gilissen Department of Dermatology, University Hospitals KU Leuven, Leuven, Belgium Eva Gomes Serviço de Imunoalergologia, CHUP, Porto, Portugal Margarida Gonçalo Clinic of Dermatology, University Hospital and Faculty of Medicine, University of Coimbra, Coimbra, Portugal An Goossens Department of Dermatology, University Hospital, Katholieke Universiteit Leuven, Leuven, Belgium Sahar Hamadi Brigham and Women’s Hospital, Boston, MA, USA Thomas Harr Service d’Immunologie et d’Allergologie, Hôpitaux Universitaires de Genève, Geneva, Switzerland Helmut Kerl Department of Dermatology, Medical University Graz, Graz, Austria Katrin Kerl Department of Dermatology, Ludwig-Maximilian University Hospital of Munich, Munich, Germany Marek L. Kowalski Department of Immunology and Allergy, Medical University of Lodz, Lodz, Poland Marianne Lerch Allergy/Dermatology Unit, Department of Internal Medicine, Kantonsspital Winterthur, Winterthur, Switzerland Carla Lombardo Dermatology Unit, Ospedale Santa Chiara, A.P.S.S., Trento, Italy

Contributors

Contributors

xxxi

Keren Mahlab-Guri Allergy and Clinical Immunology Unit, Kaplan Medical Center, Rehovot, Israel Affiliated to Hebrew University and Hadassah Medical School, Jerusalem, Israel Cristobalina Mayorga Allergy Research Group, Instituto de Investigación Biomédica de Málaga—IBIMA, Malaga, Spain BIONAND—Andalusian Centre for Nanomedicine and Biotechnology, Malaga, Spain Allergy Unit, Hospital Regional Universitario de Málaga, Malaga, Spain Paul Michel Mertes Service d’anesthésie-réanimation chirurgicale, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg Cedex, France Mariasole Migliorini Green Channel Centre of the Veneto Region, Immunology Unit, University Hospital, Azienda Ospedaliera Universitaria Integrata, Verona, Verona, Italy Brigitte Milpied-Homsi Hôpital St André, Service de Dermatologie, Bordeaux, France Maria I. Montañez Allergy Research Group, Instituto de Investigación Biomédica de Málaga—IBIMA, Malaga, Spain BIONAND—Andalusian Centre for Nanomedicine and Biotechnology, Malaga, Spain Dean Naisbitt MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK Monday Ogese University of Liverpool, Liverpool, UK Mauro Pagani Medicine Department, ASST Mantova, Mantova, Italy Alba Rodriguez-Nogales Allergy Research Group, Instituto Investigación Biomédica de Málaga-IBIMA, Málaga, Spain

de

Antonino Romano Oasi Research Institute-IRCCS, Troina, Italy Fondazione Mediterranea GB Morgagni, Catania, Italy Shira Rosenberg-Bezalel Allergy and Clinical Immunology Unit, Kaplan Medical Center, Rehovot, Israel Affiliated to Hebrew University and Hadassah Medical School, Jerusalem, Israel Maria Sanchez Sanchez Harvard Medical School, Boston, MA, USA Kathrin Scherer Hofmeier Medical Faculty, University of Basel, Basel, Switzerland Department of Dermatology, Allergology Unit, Cantonal Hospital Aarau, Aarau, Switzerland Dermatology and Allergology Cantonal Hospital Aarau and Medical Faculty, University of Basel, Basel, Switzerland

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Julia Spoendlin Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland Hospital Pharmacy, University Hospital Basel, Basel, Switzerland Esther Helen Steveling-Klein Division of Allergy and Department of Dermatology, University Hospital Basel, Basel, Switzerland Zev Sthoeger Allergy and Clinical Immunology Unit, Kaplan Medical Center, Rehovot, Israel Affiliated to Hebrew University and Hadassah Medical School, Jerusalem, Israel Charles Tacquard Service d’anesthésie-réanimation chirurgicale, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg Cedex, France Ying Teo Department of Dermatology, University Hospitals Southampton NHS Trust, Southampton General Hospital, Southampton, UK Clinical Experimental Sciences, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton, UK Paul Thomson MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK Maria J. Torres Allergy Research Group, Instituto de Investigación Biomédica de Málaga—IBIMA, Malaga, Spain BIONAND—Andalusian Centre for Nanomedicine and Biotechnology, Malaga, Spain Allergy Unit, Hospital Regional Universitario de Málaga, Malaga, Spain Departamento de Medicina, Universidad de Málaga, Malaga, Spain Rocco Luigi Valluzzi Multifactorial and Systemic Diseases Research Area, Predictive and Preventive Medicine Research Unit, Division of Allergy, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy Alessandra Vultaggio Careggi University Hospital, Immunoallergology Unit, Firenze, Italy Aleksandra Wardzynska Department of Immunology and Allergy, Medical University of Lodz, Lodz, Poland Stefan Wöhrl Floridsdorf Allergy Center (FAZ), Vienna, Austria Giovanna Zanoni Green Channel Centre of the Veneto Region, Immunology Unit, University Hospital, Azienda Ospedaliera Universitaria Integrata, Verona, Verona, Italy

Contributors

Part I General Aspects of Drug Hypersensitivity

1

Classification and Terminology of Drug Hypersensitivity Reactions Andreas J. Bircher

A classification is a definition comprising a system of definitions Friedrich von Schlegel (1772–1829)

Key Points • Any classification or term has its drawbacks. • For better comparison generally accepted terms and classifications should be used. • For anaphylaxis severity grades have been defined; no such generally accepted allocation exists for exanthematous reactions. • Application of chronological courses may help to attribute reactions to particular mechanisms. Adverse drug reactions are a common problem in clinical practice. They may cause considerable morbidity and, in some cases, result in mortality. Drug hypersensitivity reactions belong to the more complex problems in allergology, due to the wide variety of clinical manifestations and the very diverse underlying mechanisms. Therefore, it is important to classify suspected adverse drug reactions accordingly, in the daily situation for a thorough diagnosis, and in research for comparison of diagnostic procedures and homogenization of multicenter studies. The application of classifications to the different categories of drug hypersensitivity reactions and the use of a generA. J. Bircher (*) Allergology, Department of Dermatology, University Hospital Basel, Basel, Switzerland Faculty of Biomedicine, Università della Svizzera Italiana, Lugano, Switzerland e-mail: [email protected] © Springer Nature Switzerland AG 2022 A. J. Bircher et al. (eds.), Cutaneous Drug Hypersensitivity, https://doi.org/10.1007/978-3-030-82743-4_1

ally accepted terminology are crucial for several reasons. If categories are generally accepted and feasible, they can help to enhance the clinical management of patients by allowing an exact definition of the problem, to enhance the comparison among different centers by using a uniform terminology and categories, and, finally, to validate the test procedures in research. However, due to the complexity of drug hypersensitivity reactions, there is still a considerable heterogeneity among existing classifications and their use. Due to the fact that the pathogenesis of many drug hypersensitivity reactions is still not clearly elucidated (cf. Chap. 6). A consensus statement from the WHO has proposed a general definition: “Drug hypersensitivity is defined as objectively reproducible symptoms or signs initiated by exposure to a defined stimulus at a dose tolerated by normal persons” or “A response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function” [1, 2]. However, any definitions, classifications, and terms have some shortcomings, and they are often used in different ways and may change over time. Adverse drug reactions may be categorized by using various criteria: 1. Clinical phenotype (skin, mucosa, internal organs, blood cells) 3

A. J. Bircher

4

2. Severity and prognosis (grading, scores) 3. Chronology (timing: initiation/elicitation/ evolution) 4. Mechanisms (immunologic, pseudoallergic, p-i concept)

1.1

Clinical Phenotypes

Adverse drug reactions may mimic many other diseases and have been therefore also termed the great imitators of diseases in analogy to syphilis. Evidently, adverse drug reactions may first be categorized by the observed clinical manifestations. General symptoms such as pruritus, fever, and fatigue may be present. Clinical manifestations (cf. Chap. 3) include rather rapidly occurring signs and symptoms such as sudden pruritus, flush, urticaria, angioedema, bronchospasm, abdominal cramps, and circulatory symptoms. Manifestations in at least two organ systems are defined as anaphylaxis; in very severe cases, it may result in anaphylactic shock. With a longer delay occurring symptoms of usually several hours to several days include macular, maculopapular, and papular exanthems; more rarely pustular, vesicular, or bullous exanthems may be observed. A special case is the distinct fixed drug eruption with a usually singular, asymmetrically localized dark-red infiltrate with often a central blister, typically reappearing at the same site upon re-exposure with the same drug. The severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), as well as acute generalized exanthematous pustulosis (AGEP) and the drug hypersensitivity syndrome (DHS) or drug rash with eosinophilia and systemic symptoms (DRESS) have distinct features that have been implemented, e.g., for DRESS in diagnostic criteria (Table 1.1) [3, 4]. The involvement of internal organs such as the liver, kidneys, etc. (cf. Chap. 4) is initially often missed, because of unspecific symptoms and signs and confusion with underlying diseases such as preexisting hepatopathy. Also, the affec-

tion of circulating cells, e.g., thrombocytopenia or neutropenia, result in deferral of indirect symptoms and signs and may be sometimes overlooked.

1.2

Severity

Severity grades are particularly important with regard to prognosis and treatment. Anaphylaxis is typically categorized in four stages. Anaphylaxis is defined as acute, life-threatening reaction, involving at least two organ systems

Table 1.1 Validation score for DRESS [3, 4] RegiSCAR criteria 1. Fever ≥38.5 °C 2. Lymphadenopathy minimal 1 cm, ≥2 anatomical localizations 3. Eosinophilia Absolute ≥0.7–1.49 × 109/L ≥1.5 × 109/L Eosinophilia (if leukocytes 50% Exanthem compatible with DRESS Skin biopsy compatible with DRESS 6. Organ involvement (liver, kidney, lung, heart, pancreas, other organs) One organ ≥2 organs 7. Resolution ≥15 days 8. Other causes ANA Blood culture Serology for HAV/HBV/ HCV/ Chlamydia/M. pneumoniae Other serologies/PCR

Scoresa −1 0 1 N/U Y – – N/U Y

–

N Y (=1) Y (=2) Y (=1) Y (=2)

–

N

Y

– N

N U

Y Y

N

Y

–

–

N

–

– – N

– – Y

Y (=1) Y (=2) – No positives and ≥3 negative

Minimal score -4, maximal score 9. Final score: 5=definite case N no, Y yes, U unknown

a

1 Classification and Terminology of Drug Hypersensitivity Reactions

[5], resulting from the sudden release of mediators from mast cells and basophils [6, 7]. The symptoms of anaphylaxis mainly involve the skin, the gastrointestinal and respiratory tract, and the cardiovascular system and may result in cardiovascular shock, cerebral hypoxia, and death. A commonly used classification of anaphylaxis assigns the involvement of organ systems to four grades (Table 1.2) [6]. No such generally accepted classification is available for exanthems. Mostly the terms mild, moderate, and severe are used; however, there are no clear-cut criteria for distinction. A former task force group of European Academy of Allergy and Clinical Immunology (EAACI) has proposed to include five criteria: type of skin lesions, extension,

5

systemic involvement, duration, and need of treatment. Possible criteria for classification of exanthems into mild, moderate, and severe are outlined in Table 1.3. For TEN only a prognostic score SCORTEN (Table 1.4) has been established [8].

1.3

Chronology

Drug hypersensitivity reactions may also be classified by their timing or chronology, i.e., particularly first onset of symptoms and signs, as well as dynamics of evolution and duration. For clinical use it is important to separate the asymptomatic exposure period to a drug, the sensitization phase within this period, and the elicitation phase lead-

Table 1.2 Classification of grades of anaphylaxis [6] Grade Skin and oral mucosa I Pruritus, urticaria, flush, angioedema II Pruritus, urticaria, flush, angioedema

Gastrointestinal tract – Nausea Cramps

III

Pruritus, urticaria, flush, angioedema

Vomiting, defecation

IV

Pruritus, urticaria, flush, angioedema

Vomiting, defecation

Respiratory tract Cardiovascular system – – Tachycardia (increase by ≥20/ min) Hypotension (decrease by ≥20 mmHg systolic pressure) Laryngeal edema Shock/loss of consciousness Bronchospasm Cyanosis Respiratory Cardiovascular arrest arrest Rhinitis Hoarseness Dyspnea

Classification according to the most severe symptom; no single symptom is mandatory Table 1.3 Proposed criteria for severity grading of exanthematous reactions Mild reaction Short durationa (2 weeks

No severity criteria, but alert signs present • Skinb: Extension 50%, mucosal involvement • Systemic involvement: Fever >38.5 °C, lymphadenopathy (two sites or more) • Organ involvement: Liver, kidney, lung, hematological system Therapy mandatoryc

No therapy Therapy needed needed No hospitalization Hospitalization/inpatient care 1–7 days

Hospitalization >7 days

Duration after stopping the eliciting drug Solitary skin involvement c According to the particular status of the patient (e.g., pregnancy, age, underlying diseases). Therapy may include topical and/or systemic medications a

b

A. J. Bircher

6 Table 1.4 SCORTEN: predicted mortality of TEN [8] Independent prognostic factor Age Malignancya Detached body surface area Tachycardia Serum urea Serum glucose Serum bicarbonate SCORTEN total

≥40 years Yes ≥10% ≥120/min >10 mmol/L >14 mmol/L >20 mmol/L

Weight 1 1 1 1 1 1 1 7

Predicted mortality SCORTEN 0–1: >3.2% SCORTEN 2: >12.1% SCORTEN 3: 35.3% SCORTEN 4: >58.3% SCORTEN ≥5: >90% a Evolving cancer or hematological malignancy

ing to the clinical manifestations. It is a common misconception that sensitization (induction) and elicitation phases are lumped together. This results in such statements [9] that chronology encompasses 7 to 8 to 21 days in type III reactions, and 1–21 days in mild T cell-mediated reactions such as eczema or several weeks for SCAR such as TEN/SJS or DRESS. In the latter re-exposure is contraindicated; in some accidentally re-exposed patients, the syndrome reappeared after a few days. In an immunologically naïve, i.e., not sensitized patient, the first manifestations may appear the earliest after a sensitization phase of at least 5–7 days, typically around the 8–10th day after starting the treatment. That means the total exposure phase to a drug encompasses at least the sensitization phase but may be longer, e.g., in SCAR or DRESS. In the sensitization process, about 1 week is required for induction and expansion of drug-reactive cells, production of drug-specific antibodies or T cells, and development of symptoms subsequent to drug exposure. In previously exposed during the current therapy cycle sensitized patients, the elicitation period is dependent on the pathomechanism involved. However, if a p-i mechanism is present, these time periods of sensitization for T cell-mediated reactions do not apply. In IgE-antibody-mediated hypersensitivities, the elicitation period may depend in part on the route of administration; it typically encompasses few minutes to several

hours. For example, in pediatric patients sensitized to pegaspargase, allergic reactions started significantly earlier after intravenous infusion than after intramuscular injection [10]. For unknown reasons also the rate of allergic reactions was higher in the intravenous versus the intramuscular group. The evolution of symptoms such as urticaria, angioedema, bronchospasm, and anaphylaxis is typically short, lasting some hours, although urticaria may sometimes recur for several days. In T cell-mediated reactions, the typical latency period between renewed drug exposure and development of first skin signs such as a discrete erythema may appear between 6 and 12 h extending up to 2–4 days; the single lesions evolve over a time period of several days and may become confluent and fade within 7–14 days after discontinuation of the drug. In some instances, despite discontinuation of therapy, e.g., at day 7, typically around day 8–10 after starting a treatment, a drug-induced exanthem may still appear. This indicates sensitization during the treatment course of 5–7 days and elicitation within a period of 2–3 days. A particular observation concerns contrast media. A single dose of a radio contrast medium may sensitize and still elicit after 5–8 days an exanthem; upon re-exposure the patient will react within 1–2 days [11]. If several drugs have been taken, a precise assessment of chronology may help to single out the putative eliciting drug [12]. In 1963, the terms “immediate” and “delayed” were used by Coombs and Gell to delineate the mechanisms of IgE-antibody-mediated type I from T cell-mediated reactions, although at that time neither IgE nor T cells were identified yet. Later, some authors have proposed for allergic reactions to penicillin antibiotics the terms “immediate” for onset from 2 to 20 min, “accelerated” for reactions between 2 and 48 h, and “late” for reactions occurring after 72 h [13]. Around 2000, Romano et al. [14] have proposed to facilitate this allocation by separating “immediate reactions” (up to 1 h) from “nonimmediate reactions” (all other reactions occurring after 1 h). Since then this classification has been widely used in many articles as well as

1 Classification and Terminology of Drug Hypersensitivity Reactions

for the validation of test procedures [15, 16]. However, this represents a simplification, because immediate reactions mediated by IgE-antibody or pseudoallergic mechanisms typically occur within a few minutes but may begin as late as up to several hours, and delayed reactions may start as early as within 6–12 h. Therefore, the utility of a purely binary separation into “immediate” and “non-immediate” reactions has been debated for the last 15–20 years [17]. Any classification has its shortcomings; however, using the terms “immediate” and “delayed” for timing as well as for mechanisms creates an overlap in their meaning, which may also result in misunderstandings and confusion. Therefore, in the future it may be feasible to use more neutral, purely chronological terms such as “early onset” (reactions starting between 0 and 6 h), “intermediate onset” (reactions starting between 6 and 12 h), and “late onset” (reactions starting from 12 h on) (Fig. 1.1), as it has been discussed by a former task force group of EAACI. Although these are also arbitrary terms, they do not imply any particular pathomechanism and can be used and understood early onset 0-6h

intermediate onset (6-12h)

immediate (2-20m)

0

4

by any health staff or layperson. Because no distinct deduction of pathomechanism can be drawn from the clinical manifestation alone, an exact description of the clinical phenotype and chronological sequences might help to establish a more precise hypothesis on a mechanism, which will assist in the attribution to culprit drugs and the selection of the correct diagnostic tools in clinical practice [18]. It may also allow for a better attribution to currently known mechanisms (cf. Chap. 6).

1.4

Pathomechanisms

One of the more general, still commonly used classifications for adverse drug reaction in general is shown in Table 1.5 [19, 20]. The two most common types encompass types A and B. Type A corresponds to a pharmacological, foreseeable, and predictable effect of a drug; these reactions depend on dosing, drug pharmacokinetics, and drug interactions and are typically in alignment with the effect of the respective molecule. A typilate onset (>12h)

non-immediate (>1h)

immediate (3d)

FDE 12

AGEP 16 hours

Fig. 1.1 Onset of drug hypersensitivity reactions. The separation at a cut-off of 1 h into immediate or nonimmediate reactions does not sufficiently reflect the extension of the pathophysiologically determined immediate-type reactions up to 6 h (“deferred”) and the delayed-type clinical manifestations that occasionally

SCAR

MPE 20

24

2 days

4

6

begin as early as 8–12 h (“accelerated”). (Adapted from [12]). A purely time-related classification may better suit the need of harmonization. FDE fixed drug eruption, AGEP acute generalized exanthematous pustulosis, MPE maculopapular exanthema, SCAR severe cutaneous adverse reactions

A. J. Bircher

8 Table 1.5 General classification of adverse drug reactions [19] Mnemotechnical Type term A Augmented

B

Bizarre

C

Chronic

D

Delayed

E

End of treatment

F

Failure

Mechanisms Pharmacological toxic drug reaction

Main features Common Dose-dependent predictable effect of a drug

Example – Hemorrhage due to anticoagulant overdose – Hair loss due to cytostatic drugs – Anaphylaxis from diclofenac – Maculopapular exanthem from aminopenicillins – ACE inhibitor angioedema

Hypersensitivity reaction; Uncommon Unpredictable reaction in idiosyncrasy allergy or predisposed patients, not pseudoallergy dependent on the pharmacologic effect of the drug Mostly cumulative toxic Rare – Nephropathy from effect Long-term exposure to a drug analgesics – Secondary malignoma due Late-onset adverse effect Rare to previous cytostatic Usually dose-related, therapy becomes apparent sometime – Teratogenic effect of after the use of the drug retinoids or thalidomide – Corticosteroid withdrawal, Therapy withdrawal/ Uncommon e.g., flare-up of eczema or weaning Rebound psoriasis Relapse – Opiate withdrawal syndrome Treatment failure Common – Antibiotic resistance No effect – Inadequate dose, interaction

cal example is bleeding after an overdose of an anticoagulant, or hypoglycemia after an overdose of insulin. Type A reactions comprise about 80% of all drug reactions. Type B reactions include effects which cannot be derived from the pharmacological activity of the respective drug. They are mostly unpredictable, unless sensitization has been previously documented or particular HLA antigens are present, and mostly less dose- dependent than the type A reactions. An individual predisposition is necessary because only a minority of exposed subjects will experience such a reaction. In some patients, an enzyme deficiency is present, e.g., glucose-6-phosphate dehydrogenase deficiency, leading to hemolysis after certain drugs (primaquine, azathioprine) or an imbalance in the arachidonic acid cascade, resulting in rhinosinusitis or bronchospasm or angioedema and urticaria upon intake of NSAIDs. Therefore, most of these type B reactions have features of hypersensitivity reactions, which can be further subclassified into immunologically

mediated reactions called “drug allergies” and the non-immunologically mediated reactions, often called “pseudoallergic” or “intolerance” reactions. Some authors use the term “idiosyncrasy” for reactions involving enzyme deficiencies. Immunologically mediated reactions can be further subclassified into the Coombs and Gell classification (cf. Chap. 6), whereas the pseudoallergic reactions encompass a large group of different, often not well-understood mechanisms.

1.5

Summary

Drug hypersensitivities represent complex and challenging problems in clinical practice as well as in their workup. Generally accepted classifications may facilitate further insights into mechanisms and help to identify culprits more precisely. Finally, comparison of data among research centers should be better comparable, if the same classifications and terms are applied.

1 Classification and Terminology of Drug Hypersensitivity Reactions

References 1. Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature for allergy for global use: report of the nomenclature review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004;113(5):832–6. 2. Johansson SGO, Hourihane JOB, Bousquet J, Bruijnzeel-Koomen C, Dreborg S, Haahtela T, et al. A revised nomenclature for allergy: an EAACI position statement from the EAACI nomenclature task force. Allergy. 2001;56(9):813–24. 3. Martínez Cabriales S, Rodríguez Bolaños F, Shear N. Drug reaction with eosinophilia and systemic symptoms (DReSS): how far have we come? Am J Clin Dermatol. 2019;20(2):217–36. 4. Kardaun SH, Sidoroff A, Valeyrie-Allanore L, Halevy S, Davidovici BB, Mockenhaupt M, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol. 2007;156(3):609–11. 5. Sampson H, Muñoz Furlong A, Campbell R, Adkinson NF, Bock SA, Branum A, et al. Second symposium on the definition and management of anaphylaxis: summary report--second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117(2):391–7. 6. Ring, J., Beyer K, Biedermann T, Bircher A, Fischer M, Fuchs Th et al. Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 Update. Allergo J Int 2021, 30: 20–49. 7. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernández Rivas M, et al. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy. 2014;69(8):1026–45. 8. Guégan S, Bastuji-Garin S, Poszepczynska-Guigné E, Roujeau J-C, Revuz J. Performance of the SCORTEN during the first five days of hospitalization to predict the prognosis of epidermal necrolysis. J Invest Dermatol. 2006;126(2):272–6. 9. Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, et al. International consensus on drug allergy. Allergy. 2014;69(4):420–37.

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10. Petersen WC, Clark D, Senn SL, Cash WT, Gillespie SE, McCracken CE, et al. Comparison of allergic reactions to intravenous and intramuscular pegaspargase in children with acute lymphoblastic leukemia. Pediatr Hematol Oncol. 2014;31(4):311–7. 11. Bircher AJ, Brockow K, Grosber M, Scherer HK. Late elicitation of maculopapular exanthemas to iodinated contrast media after first exposure. Ann Allergy Asthma Immunol. 2013;111(6):576–7. 12. Bircher A. Classification des réactions médica menteuses allergiques. In: Progrès en dermato- allergologie - Marseille 2017. Montrouge: John Libbey Eurotext; 2017. p. 137–42. 13. Levine BB. Immunologic mechanisms of peni cillin allergy - a haptenic model system for the study of allergic diseases of man. N Engl J Med. 1966;275(20):1115–25. 14. Romano A, Quarantino D, Di Fonso M, Papa G, Venuti A, Gasbarrini G. A diagnostic protocol for evaluating nonimmediate reactions to aminopenicillins. J Allergy Clin Immunol. 1999;103(6):1186–90. 15. Torres MJ, Blanca M, Fernandez J, Romano A, Weck A, Aberer W, et al. Diagnosis of immediate allergic reactions to beta-lactam antibiotics. Allergy. 2003;58(10):961–72. 16. Romano A, Blanca M, Torres MJ, Bircher A, Aberer W, Brockow K, et al. Diagnosis of nonimmediate reactions to beta-lactam antibiotics. Allergy. 2004;59(11):1153–60. 17. Bircher AJ, Scherer K. Drug hypersensitivity reactions during hematopoietic stem cell transplantation. In: Häusermann P, Steiger J, Passweg J, editors. Transplantation dermatology. Basel: Karger; 2012. p. 150–64. 18. Bircher AJ, Scherer K. Drug hypersensitivity reactions: inconsistency in the use of the classification of immediate and nonimmediate reactions. J Allergy Clin Immunol. 2012;129(1):263–4. 19. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356(9237):1255–9. 20. Rawlins MD. Clinical pharmacology. Adverse reactions to drugs. Br Med J (Clin Res Ed). 1981;282(6268):974–6.

2

Epidemiology Noel Frey and Julia Spoendlin

2.1

Data Sources for Observational Studies on Cutaneous Adverse Drug Reactions

Cutaneous adverse drug reactions (ADRs) have mainly been evaluated in hospital-based study populations or in data originating from spontaneous reporting systems (pharmacovigilance) for many years. However, reliable information on the frequency of occurrence (e.g., incidence rates) of such cutaneous ADR in the general population is yet sparse, because missing information or other biases usually complicate the quantification of their absolute frequency of occurrence in such data sources (Table 2.1). Hospital-based study populations lack information on the population at risk (i.e., the total number of patients taking the drug of interest irrespective of whether they developed the ADR or not) and can only evaluate the frequency of occurrence among hospitalized patients. However, hospitalized patients are on average sicker and thus not representative of the general population since they are exposed to

N. Frey · J. Spoendlin (*) Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland e-mail: [email protected] Hospital Pharmacy, University Hospital Basel, Basel, Switzerland © Springer Nature Switzerland AG 2022 A. J. Bircher et al. (eds.), Cutaneous Drug Hypersensitivity, https://doi.org/10.1007/978-3-030-82743-4_2

more drugs. On the other hand, the major limitations of spontaneous reporting systems are underor selective reporting of ADR, such that particularly milder and long-latency ADR are less likely to be reported (reporting bias). Additionally, information on the population at risk is not readily available and has to be extrapolated from sales statistics or other data sources which are associated with imprecision and strong assumptions [1]. Thus, most previously conducted observational studies on cutaneous ADR focused on describing their demographic distribution and at identifying culprit drugs, for which these data sources are suitable sources of information [2–8]. However, reported results are still heterogeneous due to different geographic coverage of the data or differences in methods of data collection and study design. Over the past decades, large electronic healthcare databases (i.e., data collected longitudinally within health-care systems such as administrative claims or data from primary care practice) have become an important tool for epidemiologic research due to their large size, abundant information, and pre-collected data that is relatively low in cost. The epidemiology of Stevens- Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), for example, has been studied in large claims databases (USA and Korea) and in a UK-based primary care database [9–11]. The large size of these data sources allows to study rare ADR including the quantification of absolute 11

N. Frey and J. Spoendlin

12 Table 2.1 Explanation of epidemiologic terms frequently used in medical science Measure Definition Measures of frequency Prevalence The proportion of a particular population in whom a specific disease is present at a specific point of time Number of new cases Incidence proportion of a disease during a specified time interval (or cumulative incidence/ risk)

Incidence rate

Number of new cases of a disease during a specified time interval, where the denominator is the sum of person-time at risk Risk estimates Ratio of the Relative risk probability of an event occurring in an exposed group divided by the probability of the event occurring in a nonexposed (comparison) group. Usually presented as relative risks (comparing incidence rates or incidence proportions) or odds ratios Absolute The probability that a risk patient will develop a disease of interest— mostly reported as incidence proportion

Example 5% of patients were affected by hypertension on January 5, 2018 10% of 100 initially hypertension- free patients developed hypertension during a time period of 6 months 10 new cases of hypertension occur per 1000 persons per year

Patients exposed to phenytoin are 20 times more likely to develop SJS/TEN than patients not exposed to phenytoin

On average, 2 out of 10,000 patients taking phenytoin develop SJS/ TEN within 2 weeks after first drug intake

The epidemiologic terms described above do not exclusively apply for medical science. They also do not only account for diseases but may be quantified for any event of interest

risks because the population at risk is clearly defined for all drugs that are validly captured in the database. However, lack of clinical informa-

tion for case validation and missing information on certain drug exposures (e.g., over-the-counter medication, drugs given in hospital) can be limitations. Furthermore, not all ADR may be recorded as such in the database. Table 2.2 describes the advantages and limitations of different data sources used for epidemiologic research.

2.2

Prevalence and Incidence of Cutaneous ADR

A meta-analysis of 39 prospective hospital-based studies published in 1998 reported that on average 15% of patients experience an ADR during hospitalization and that ADR account for approximately 4% of all hospital admissions [12]. Cutaneous ADR have been reported to account for 15% of all ADR, suggesting that approximately 2% of all hospitalized patients experience a cutaneous ADR. This number is corroborated by two large hospital- based observational studies. The Boston Collaborative Drug Surveillance Program (BCDSP) reported that 2.2% of 22,227 hospitalized patients developed a cutaneous ADR between 1975 and 1982 [2]. Furthermore, the Comprehensive Hospital Drug Monitoring (CHDM) study, which is based in 3 Swiss hospitals, reported a prevalence of cutaneous ADR of 2.7% among 48,005 hospitalized patients between 1974 and 1993 [3]. However, more recently conducted prospective hospital-based observational studies reported a lower prevalence of cutaneous ADR among hospitalized patients. A 10-month prospective cohort study reported a prevalence of cutaneous ADR of 0.7% among hospitalized patients in Mexico in 2006, although with a small sample size and more restrictive inclusion criteria than previous hospital-based studies (n = 35 cases; biopsies were performed in unclear cases). The ratio of women to men was 1.3:1 [13], which is consistent with results from previous hospital-based studies [2, 4]. In 2003, a hospital-based prospective observational study based in France reported that, over the course of 6 months,

2 Epidemiology

13

Table 2.2 Advantages and limitations of data sources used to study the epidemiology of ADR Data source Spontaneous reporting systems (pharmacovigilance)

Advantages – Evaluate ADR in large populations – Physicians or patients report ADR from a real-world setting

Hospital-based study populations

– Clinical information for extensive case validation usually available – Exposure can be assessed by patient interview

– Large patient collectives Health-care databases (administrative claims or – Readily available pre-collected data with longitudinal follow-up primary care) – Available information on the population at risk (the number of patients who took the drug is recorded—allows quantifying absolute risks)

Limitations – Incomplete reporting: Especially mild and long-latency ADRs are less likely reported – Information on the population at risk is lacking (i.e., how many people took the drug of interest and did not develop the disease) – Selected study population: Hospitalized patients are often sicker and exposed to more drugs than the overall population – Large study populations are often not available (or associated with extensive effort and cost) – Long-term follow-up of patients usually not available – Population at risk unknown – Comparable comparison group may be difficult to find – Clinical information to validate diagnoses may be limited – Missing data on exposure or confounders (e.g., in-hospital medication, over-thecounter medication)

ADR adverse drug reaction

0.36% of hospitalized patients e xperienced an allergic cutaneous ADR. The prevalence of cutaneous ADR was most likely lower in this study because only allergic reactions were included. In 19% of the 48 reported cases (all cases were confirmed by a dermatologist and pharmacologist), the cutaneous allergic ADR was the primary reason for hospital admission. The proportion of affected female and male patients were similar [5]. The studies from France and Mexico identified human immunodeficiency virus (HIV) and lupus erythematosus as risk factors for cutaneous ADR. Another retrospective study from Malaysia further reported older age as a risk factor for cutaneous ADR [6]. The female preponderance of cutaneous ADR has mainly been observed for milder reactions, whereas severe cutaneous ADR, such as SJS/ TEN or exfoliative dermatitis, affected women and men similarly [4]. A cross-sectional population survey on the epidemiology of urticaria, which is one of the most frequently diagnosed

cutaneous ADRs, reported that 70% of the affected patients were women [14]. This higher risk for cutaneous ADR in women has at least partly been attributed to their longer life expectancy and the intake of more medications [15]. Those prior studies were hospital-based, but assessing the epidemiology of cutaneous ADR in an outpatient setting remains challenging. In an analysis of eight studies, ADR were reported to affect 3–40% of outpatients, whereas cutaneous ADR were observed in approximately 3–5% of outpatients [16]. To date, only one study reported a population-based incidence rate of cutaneous ADR using data from a spontaneous reporting system covering four Italian regions. The overall incidence rate was 5.5 cases per 100,000 inhabitants per year, with a female-male ratio of 1.6:1 and an increasing incidence rate with increasing age [15]. However, such results have to be interpreted carefully given the known problem of underreporting of ADRs in pharmacovigilance systems.

N. Frey and J. Spoendlin

14

2.3

Types of Cutaneous ADR

Almost all recently conducted hospital-based studies and studies based on data from spontaneous reporting systems reported that the majority of patients who experienced a cutaneous ADR were diagnosed with exanthematous/maculopapular eruptions (22–94%) or urticaria with or without angioedema (5–50%) [2–8, 13, 15, 17, 18]. The epidemiology of cutaneous urticaria has been studied in a German cross-sectional population survey, which observed a lifetime prevalence of 1.8% in the general population [14]. Three studies have further reported that fixed drug eruptions accounted for 14–25% of all cutaneous ADR [7, 19, 20]. Other observed cutaneous reactions were erythema multiforme, vasculitis, drug rash with eosinophilia and systemic symptoms (DRESS), SJS/TEN, and acute generalized exanthematous pustulosis (AGEP). However, these reactions affected 2), with ELISpot 9.8 Strength and Weakness and other assays, this has not reached consensus although we recommend using the mean of backThe LPA has been the most widely used test, with ground samples plus two standard deviations wide-ranging published sensitivity (14.9–75%) above control values. Consideration of usage of and specificity (63–100%) [9], but these statistics the appropriate formulation or metabolite of the are likely to be drug and phenotype dependent drug that would normally be active in vitro is also [4]. For example, while, overall, it has been esti- important. False negatives can occur if the metabmated to have a sensitivity of 60–70% for beta- olite instead of the drug tested is responsible for lactams, for SJS/TEN sensitivity is reported to be the reaction. As with other tests, pure substances lower (35%) [7]. Compared to the LTT, ELISpot are preferable to avoid excipients in drug’s contesting showed higher sensitivity (71%) in SJS/ founding results. TEN although this was not the case for other However, T-cell assays have the major advanreaction phenotypes [7]. The reported sensitivity tage of identifying the culprit drug without causof T-cell tests for delayed drug hypersensitivity ing harm to the patient and can additionally be testing overall remains variable, although is used to explore cross-reactivity. Given the risks thought to have high specificity. However, due to associated with drug provocation testing in severe drug challenge being unethical, particularly in reactions, these tests play a crucial role in delinsevere cutaneous adverse reactions, the confirma- eating the allergy status of patients. Further tion of specificity is limited. Additionally, timing tweaks to the protocols for testing such as incluof the test is important, and a higher sensitivity sion of subject-derived antigen-presenting cells, 24 h after exposure)

Proposed mechanism IgE-mediated

T-cell mediated

SR selective reactions, NSAIDs nonsteroidal anti-inflammatory drugs, SNIUAA single NSAID-induced urticarial/angioedema or anaphylaxis, SNIDR single NSAID-induced delayed reactions, MPE maculopapular eruption, FDE fixed drug eruptions, AGEP acute generalized exanthematous pustulosis, DRESS drug reaction with eosinophilia and systemic symptoms, SJS Stevens-Johnson syndrome, TEN toxic epidermal necrolysis

M. Bergmann et al.

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14.7.5 Natural History and Desensitization to NSAIDs

Large local reactions are characterized by large painful swelling occurring 24–72 h after vaccination and may represent an Arthus reaction The natural history of NSAID hypersensitivity in in children with preexisting high levels of children remains unknown. Periodical re- IgG. Measurement of vaccine-specific IgG is recevaluation, mainly with diagnostic DPT, can be ommended in these children to evaluate necessity of further booster vaccinations. proposed in these patients. The formation of persistent aluminum granuFew data are available about safety and effectiveness of desensitization in children with con- lomas at injection sites has been described in firmed NSAID hypersensitivity. It can be children after immunization as a possible, but proposed in selected children after assessment of rare, side effect of vaccines containing aluminum risk and benefits. Indications to perform desensi- hydroxide. These reactions seem to occur more tization, particularly with aspirin, are theoreti- frequently at recall doses, suggesting a potential cally the same as in adults, but most conditions cumulative dose response. Based on positive PT requiring long-term NSAID intake, e.g., NERD in a majority of these children, a delayed-type IV or ischemic cardiac diseases, are rare in children. hypersensitivity is suspected [15]. An age/weight/disease adjusted of established adult protocol is for now proposed in these 14.8.2 Systemic Reactions selected indications.

to Vaccines

14.8 Vaccines Adverse reactions to vaccines are frequently reported in children, particularly during the first years of life and due to administration of multiple doses during this specific period. In an Australian review including 970 children, ADR have been described in as much as 48% of children, mainly local (63%). MPE and anaphylaxis have been observed in 8% and 0.5% of children, respectively [12]. Clinical history is crucial and has to take into account the nature of reaction (local versus systemic), the timing between vaccine administration, and reaction (immediate versus delayed) in order to evaluate the need of an allergy work-up [13, 14].

14.8.1 Local Reactions to Vaccines Mild local reactions to vaccines are frequent and due to an unspecific inflammatory response to the injection itself. No allergy work-up is necessary, and further vaccinations can be administrated according to the national schedule without any precautionary measures.

Although very rare, systemic reactions after vaccination are a frequent cause of consultation. Clinical history should be accurate in order to try to discriminate between immediate (20 ng/mL were associated with severe anaphylaxis only in venomallergic subjects, but not in NSAID-hypersensitive patients [11]. There may be a slightly higher reaction rate to vaccines in children with mastocytosis as compared to the general population [12]. At the moment there is no evidence for an increased incidence of drug hypersensitivity in patients with monoclonal mast cell activation syndrome.

17.2 Mechanisms Mastocytosis is a proliferative disorder of hematopoietic MC progenitors, leading to an expansion and accumulation of excessive numbers of MCs in one or more organs, mainly the skin and bone marrow and less frequently the gastrointestinal tract, liver, and spleen [13]. The prevalence of overt mastocytosis has been estimated to be about 0.9–1.3 per 10,000 inhabitants [14]. The molecular basis of the disease is an activating

17 Drug Hypersensitivity and Clonal Mast Cell Disorders Table 17.2 World Health Organization classification of criteria for systemic mastocytosis [15] Major criterion Minor criteria

Criteria for systemic mastocytosisa – Multifocal dense aggregates of ≥15 mast cells in the bone marrow and/or other extracutaneous tissues – >25% morphologically atypical mast cells in bone marrow smears or spindle shaped in bone marrow biopsy sections or other extracutaneous organs – Aberrant expression of CD25 and/or CD2 by mast cells in the bone marrow or other extracutaneous organs – D816V c-kit mutation in the bone marrow, blood, or other extracutaneous organs – Serum tryptase levels persistently >20 μg/l

One major and one minor or three minor criteria are required for diagnosing a systemic mastocytosis

a

163

cautionary measures should be applied on an individual basis (e.g., higher dilutions for skin testing and slower dose increments in provocation tests in anaphylaxis). A drug provocation test should be considered; the risk of iatrogenically inducing a severe reaction in a patient with SM has to be balanced against the benefit of possible unnecessary avoidance. Slow dose increments, emergency preparedness, and a team experienced with anaphylaxis treatment are required. If a drug hypersensitivity is confirmed or not indicated as the patient does not need the culprit drug, that drug should be avoided in the future, and a drug allergy passport or drug alert card should be issued.

17.4 Management mutation in codon 816 (D816V), coding for the MC growth factor receptor KIT. To diagnose systemic mastocytosis (SM) according to the World Health Organization (WHO), several criteria have to be fulfilled (Table 17.2) [15]. SM is subdivided into different clinical forms according to aggressiveness and prognosis. The most common form is indolent SM (ISM) and most often associated with anaphylaxis, whereas other more advanced forms are rare. Some patients display symptoms of MC mediator release but do not strictly fulfill the WHO criteria for SM, despite having KIT-mutated clonal MCs and usually expressing CD25 on bone marrow MCs: the cases were defined with various terms including (mono)clonal MC activation syndrome (MMAS) and clonal MC activation disorders [c-MCAD] [16].

17.3 Diagnostic Methods All patients with drug hypersensitivity reactions should be referred to an allergy specialist for counseling and allergy testing. Testing of patients with mastocytosis is done as in allergic patients without mast cell diseases. However, due to a larger number of effector mast cells, testing should be done by allergists experienced in treating drug hypersensitivity and anaphylaxis, and

If there has been no previous hypersensitivity reaction, there is no reason to withhold medications to patients with mastocytosis. However, some precautionary measures for the drugs will be discussed in the paragraphs below [6]. The anesthetic management of patients with mastocytosis requires a thorough understanding of mastocytosis, a detailed patient history including anesthesiology records from previous surgeries, avoidance of previously not tolerated drugs, and meticulous preparation to treat possible adverse events during anesthetics and RCM administration [6, 7]. Any regular maintenance medication taken to maintain MC cell stability and limiting the effects of MC mediators should be continued during the operation. Among the factors that can trigger a release of mediators, a great role is assigned at physical triggers: sudden temperature changes in patients and the operating room, infusion of cold solutions, wide tissue trauma, frictions, and other mechanical factors should all be avoided. If available, drugs with lower mast cell releasing property in vitro may be selected by the anesthetist (Table 17.3) [6]. Premedication with benzodiazepines may be considered in selected patients, as MC degranulation can be triggered by anxiety. Although no evidence clearly supports administration of premedication prior to anesthesia to prevent or

P. Bonadonna and K. Brockow

164

Table 17.3 Drug recommendations in general anesthesia in patients with mastocytosis Perioperative drugs Intravenous analgesics Opioids

Analgesic General anesthetics Hypnotics

Benzodiazepine Halogenated gases and nitrous oxide

Neuromuscular blocking agents (NMBAs) Depolarizing NMBA Nondepolarizing steroidal NMBAs Nondepolarizing benzylisoquinoline NMBAs Anticholinergic Plasma substitutes

Low risk

Avoid (if possible)

Fentanyl Sufentanil Remifentanil Alfentanil Paracetamol (acetaminophen)

Morphine Codeine

Propofol Etomidate Ketamine Midazolam Desflurane Isoflurane Sevoflurane Nitrous oxide

Thiopental

Pancuronium Vecuronium Cisatracurium Atropine Crystalloids Albumin

reduce severity of reactions, premedication with benzodiazepines, H1/H2 antihistamines, corticosteroid, and montelukast should be considered depending on the risk of the individual patient [6, 9]. Patients at higher risk are those who had previously presented with anaphylaxis or are undergoing major surgery and general anesthesia. No special requirements are needed for regional or local anesthesia in patients with mastocytosis, with the exception that local anesthetics of the “amide” group are preferred over those in the “esters” group (e.g., procaine, chloroprocaine, tetracaine, benzocaine) because of a better safety profile [6]. The necessity to administer premedication with antihistamines and corticosteroids in patients with mastocytosis is not documented, but this measure may be considered in selected cases to reduce severity in possible reactors. The medical team should be advised on how to manage possible severe reactions [6].

Succinylcholine Rocuronium Atracurium Mivacurium Gelatine

In adults with SM without known tolerability of ASA or NSAIDs, these have been administered with caution and under medical supervision in several centers. Although the literature is not totally clear, it may, however, be prudent to allow patients with mastocytosis who have never experienced a hypersensitivity reaction to NSAIDs to start taking them with increasing dosages. Graded challenges of an NSAID on any patient with SM who has no history of their use may be used to establish safety. Patients who have already experienced an anaphylaxis may be at a higher risk for NSAID hypersensitivity reactions; it seems appropriate to administer the first dose in a clinical setting (challenge test). In patients with mastocytosis and NSAID hypersensitivity, tolerant alternatives should be identified by drug provocation tests. There is not enough evidence to advocate avoidance and pretesting for drugs in children with mastocytosis.

17 Drug Hypersensitivity and Clonal Mast Cell Disorders

References 1. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernandez Rivas M, et al. Anaphylaxis: guidelines from the european academy of allergy and clinical immunology. Allergy. 2014;69:1026–45. 2. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. Second symposium on the definition and management of anaphylaxis: summary report--second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117:391–7. 3. Brockow K, Jofer C, Behrendt H, Ring J. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy. 2008;63:226–32. 4. Schuch A, Brockow K. Mastocytosis and anaphylaxis. Immunol Allergy Clin N Am. 2017;37:153–64. 5. Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi S, Dal Fior D, et al. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol. 2009;123:680–6. 6. Bonadonna P, Pagani M, Aberer W, Bilo MB, Brockow K, Oude Elberink H, et al. Drug hypersensitivity in clonal mast cell disorders: ENDA/EAACI position paper. Allergy. 2015;70:755–63. 7. Carter MC, Metcalfe DD, Matito A, Escribano L, Butterfield JH, Schwartz LB, et al. Adverse reactions to drugs and biologics in patients with clonal mast cell disorders: a Work Group Report of the Mast Cells Disorder Committee, American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2019;143(3):880–93. 8. Bonadonna P, Zanotti R, Pagani M, Caruso B, Perbellini O, Colarossi S, et al. How much specific is

165 the association between hymenoptera venom allergy and mastocytosis? Allergy. 2009;64:1379–82. 9. Matito A, Morgado JM, Sanchez-Lopez P, Alvarez- Twose I, Sanchez-Munoz L, Orfao A, et al. Management of anesthesia in adult and pediatric mastocytosis: a study of the Spanish network on mastocytosis (rema) based on 726 anesthetic procedures. Int Arch Allergy Immunol. 2015;167:47–56. 10. Hermans MAW, van der Vet SQA, van Hagen PM, van Wijk RG, van Daele PLA. Low frequency of acetyl salicylic acid hypersensitivity in mastocytosis: the results of a double-blind, placebo-controlled challenge study. Allergy. 2018;73:2055–62. 11. Seitz CS, Brockow K, Hain J, Trautmann A. Non- steroidal anti-inflammatory drug hypersensitivity: association with elevated basal serum tryptase? Allergy Asthma Clin Immunol. 2014;10:19. 12. Parente R, Pucino V, Magliacane D, Petraroli A, Loffredo S, Marone G, et al. Evaluation of vaccination safety in children with mastocytosis. Pediatr Allergy Immunol. 2017;28:93–5. 13. Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Investig. 2007;37:435–53. 14. Brockow K. Epidemiology, prognosis, and risk factors in mastocytosis. Immunol Allergy Clin N Am. 2014;34:283–95. 15. Valent P, Akin C, Hartmann K, Nilsson G, Reiter A, Hermine O, et al. Advances in the classification and treatment of mastocytosis: current status and outlook toward the future. Cancer Res. 2017;77:1261–70. 16. Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol. 2012;157:215–25.

Part V Eliciting Drugs

18

Penicillins Maria J. Torres, Inmaculada Doña, Tahia Diana Fernández, and Gador Bogas

Key Points

18.1 Introduction

• The skin is the organ most often affected by hypersensitivity reactions to penicillins, especially in children, with urticaria/angioedema and maculopapular exanthema being the most frequent entities. It can be difficult to differentiate from infectious exanthema. • Patterns of sensitization vary over time depending on patterns of penicillin consumption, making the inclusion of appropriate determinants in skin tests necessary to increase sensitivity. • Accurate diagnosis is crucial for making clinical recommendations, as cross-reactive patients must avoid the whole penicillin group while patients with selective reactions need only to avoid those beta-lactams that present a side chain structure similar to the culprit.

Penicillins (PEN) are the drugs most frequently involved in hypersensitivity reactions mediated by specific immunological mechanisms. The number of beta-lactam (BL) compounds available has been increasing over time, leading to the appearance of hypersensitivity reactions with a wide range of clinical manifestations. Accurate diagnosis is crucial to prescribe the appropriate medication and avoid the use of alternative antibiotics that can be more toxic and more expensive and induce bacterial resistance, leading to prolonged hospitalizations [1].

M. J. Torres (*) Allergy Unit, IBIMA—Hospital Regional Universitario de Malaga—UMA, Málaga, Spain Centro Andaluz de Nanomedicina y Biotecnología— BIONAND, Málaga, Spain e-mail: [email protected] I. Doña · G. Bogas Allergy Unit, IBIMA—Hospital Regional Universitario de Malaga—UMA, Málaga, Spain e-mail: [email protected]; [email protected] T. D. Fernández Research Laboratory, IBIMA–Hospital Regional Universitario de Malaga–UMA, Málaga, Spain e-mail: [email protected] © Springer Nature Switzerland AG 2022 A. J. Bircher et al. (eds.), Cutaneous Drug Hypersensitivity, https://doi.org/10.1007/978-3-030-82743-4_18

18.2 Clinical Manifestations The skin is the organ most often affected by hypersensitivity reactions to BL, with the most frequent clinical entities being urticaria/angioedema and maculopapular exanthema (MPE). Depending on the immunopathogenic mechanisms involved, skin rashes may appear immediately, from a few minutes to an hour (immediate reactions), or delayed, from hours to days after drug administration (non-immediate reactions). Although they can occur after the first dose of the drug, they can also occur after several days or even weeks of treatment [2]. Skin conditions such as hives or angioedema may appear in isolation, alongside upper airway 169

M. J. Torres et al.

170

PENICILLOYL

PENICILLINS H HH R N S O

O

protein

N

Name

R

O R

NH S

O -Na+

CO2

R

NH HN

NH2

CO2-Na+

Name O

HO

Benzylpenicillin

Penicillin V

NH2

NH2

Amoxicillin

Ampicillin

Fig. 18.1 Model of penicillin protein haptenation. The amino group (NH2) interacts with the BL ring of the PEN to form the penicilloyl determinant. R represents the side chain for different penicillins

involvement, or be associated with anaphylaxis. Reactions affecting only the skin are usually mild, resolving completely within several days after stopping the drug. Life-threatening reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are less frequent [2]. Exanthema is the most frequent cutaneous manifestation, especially in children, being in many cases difficult to differentiate from infectious exanthema. The rash is usually erythematous, maculopapular, or morbilliform. Itching and fever are common, and desquamative lesions are rare. It usually appears between 4 and 14 days after starting medication and disappears within 1–2 weeks after stopping. Urticaria is associated with angioedema in up to 50% of cases although it may occur in isolation or associated with an anaphylactic reaction. It usually appears within minutes to hours after the drug is given, but also may occur days or weeks later. Other cutaneous reactions are rarely induced by PEN, although isolated cases of fixed drug eruption, acute generalized exanthematous pustulosis, multiforme erythema, and SJS/TEN have been described following the use of AX and AX-clavulanic acid (CLV) [3].

18.3 Mechanisms PEN reactions are mediated by immunological mechanisms. These drugs, like all BLs, are molecules of low molecular weight (2% of treatments, gentamicin and amikacin in 0.1–2%, and kanamycin in 0.1–0.5%. Anaphylaxis is very uncommon. Few anaphylactic reactions to streptomycin and gentamicin have been reported. In most of these reactions, an IgE-mediated mechanism was suspected on the basis of skin-test positivity [30, 31]. There is no evidence of positive serum IgE to aminoglycosides [24]. In anaphylactic reactions to streptomycin, systemic reactions have been observed after prick tests. Therefore, the starting concentrations suggested for prick tests range from 0.1 to 1 mg/mL, gradually reaching the concentration of 20 mg/

J. Cernadas

190 Table 20.1 Recommended test concentrations for aminoglycosides Drug Gentamycin Neomycin Amikacin Tobramycin

SPT 40 mg/mL

IDT 4 mg/mL

IVS: 40 mg/mL

4 mg/mL

PT 20% 20% 20% 20%

Comments Petrolatum Petrolatum Petrolatum Petrolatum

SPT skin prick test, IDT intradermal test, PT patch test, dilution for ITD in NaCl

mL if needed. If negative, intradermal testing can be done with nonirritating concentrations. Nonirritative intradermal testing has been established for gentamicin and tobramycin to be 4 mg/mL (Table 20.1) [31, 32]. Patch test with gentamicin, neomycin, amikacin, tobramycin (all at 20%), and streptomycin (1%), in petrolatum, seems sufficient to elicit positive tests (Table 20.1). Aminoglycosides should be avoided in patients with a diagnosis of hypersensitivity. Crossreactions among aminoglycosides are common, approaching 50%, in patients with contact dermatitis. Cross-reactivity is less common to streptomycin (1–5%) [33]. Streptomycin shows no cross-reactivity with other aminoglycosides that share deoxystreptamine [34]. Some experts recommend avoidance of all aminoglycosides in neomycin-sensitive patients. Desensitization is possible by the intravenous route in patients with urticaria or angioedema due to streptomycin [35, 36], and for tobramycin both intravenously and via inhalational route [35].

References 1. Cernadas JR, Brockow K, Romano A, Aberer W, Torres MJ, Bircher A, Campi P, Sanz ML, Castells M, Demoly P, Pichler WJ. European Network of Drug Allergy and the EAACI interest group on drug hypersensitivity. General considerations on rapid desensitization for drug hypersensitivity—a consensus statement. Allergy. 2010;65:1357–66. 2. Manfredi M, Severino M, Testi S, Macchia D, Ermini G, Pichler WJ, Campi P. Detection of specific IgE to quinolones. J Allergy Clin Immunol. 2004;113:155–60. 3. Aranda A, Mayorga C, Ariza A, Doña I, Rosado A, Blanca-Lopez N, Andreu I, Torres MJ. In vitro evaluation of IgE-mediated hypersensitivity reactions to quinolones. Allergy. 2011;66:247–54.

4. Blanca-López N, Andreu I, Torres Jaén MJ. Hypersensitivity reactions to quinolones. Curr Opin Allergy Clin Immunol. 2011;11:285–91. 5. Sachs B, Riegel S, Seebeck J, Beier R, Schichler D, Barger A, et al. Fluoroquinolone- associated anaphylaxis in spontaneous adverse drug reaction reports in Germany. Differences in reporting rates between individual fluoroquinolones and occurrence after first- ever use. Drug Saf. 2006;29:1087–100. 6. Scherer K, Bircher A. Hypersensitivity reactions to fluoroquinolones. Curr Allergy Asthma Rep. 2005;5:15–21. 7. Rouzaire P, Nosbaum A, Mullet C, Diot N, Dubost R, Bienvenu F, Guilloux L, Piriou L, Bienvenu J, Bérard F. Immediate allergic hypersensitivity to quinolones associates with neuromuscular blocking agent sensitization. J Allergy Clin Immunol. 2013;1:273–9. 8. Schmid DA, Depta JP, Pichler WJ. T cell-mediated hypersensitivity to quinolones: mechanisms and cross-reactivity. Clin Exp Allergy. 2006;36:59–69. 9. Venturini Díaz M, Lobera Labairu T, del Pozo Gil MD, Blasco Sarramián A, González MI. In vivo diagnostic tests in adverse reactions to quinolones. J Investig Allergol Clin Immunol. 2007;17:393–8. 10. Empedrad R, Darter AL, Earl HS, Gruchalla RS. Nonirritating intradermal skin test concentration for commonly prescribed antibiotics. J Allergy Clin Immunol. 2003;112:629–30. 11. Seitz CS, Bröcker EB, Trautmann A. Diagnostic testing in suspected fluoroquinolone hypersensitivity. Clin Exp Allergy. 2009;39:1738–45. 12. Rouzaire P, Nosbaum A, Denis L, Bienvenu F, Bérard F, Cozon G, Bienvenu J. Negativity of the basophil activation test in quinolone hypersensitivity: a breakthrough for provocation test decision-making. Int Arch Allergy Immunol. 2012;157:299–302. 13. Lantner RR. Ciprofloxacin desensitization in a patient with cystic fibrosis. J Allergy Clin Immunol. 1995;96(6 Pt 1):1001–2. 14. Lobera T, Audícana MT, Alarcón E, Longo N, Navarro B, Muñoz D. Allergy to quinolones: low crossreactivity to levofloxacin. J Investig Allergol Clin Immunol. 2010;20:607–11. 15. González I, Lobera T, Blasco A, del Pozo MD. Immediate hypersensitivity to quinolones: moxifloxacin cross-reactivity. J Investig Allergol Clin Immunol. 2005;15:146–9. 16. Araujo L, Demoly P. Macrolides allergy. Curr Pharm Des. 2008;14:2840–62.

20 Other Antibiotics 17. Holmes NE, Hodgkinson M, Dendle C, Korman TM. Report of oral clarithromycin desensitization. Br J Clin Pharmacol. 2008;66:323. 18. Mori F, Barni S, Pucci N, Rossi E, Azzari C, de Martino M, Novembre E. Sensitivity and specificity of skin tests in the diagnosis of clarithromycin allergy. Ann Allergy Asthma Immunol. 2010;104:417–9. 19. Seitz CS, Bröcker EB, Trautmann A. Suspicion of macrolide allergy after treatment of infectious diseases including Helicobacter pylori: results of allergological. Allergol Immunopathol (Madr). 2011;39(4):193–9. 20. Mori F, Barni S, Pucci N, et al. Sensitivity and specificity of skin tests in the diagnosis of clarithromycin allergy. Ann Allergy Asthma Immunol. 2010;104:417. 21. Benahmed S, Scaramuzza C, Messaad D, Sahla H, Demoly P. The accuracy of the diagnosis of suspected macrolide antibiotic hypersensitivity: results of a single blinded trial. Allergy. 2004;59:1130–3. 22. Milković-Kraus S, Macan J, Kanceljak-Macan B. Occupational allergic contact dermatitis from azithromycin in pharmaceutical workers- a case series. Contact Dermatitis. 2007;56(2):99–102. 23. Seitz CS, Bröcker EB, Trautmann A. Suspicion of macrolide allergy after treatment of infectious diseases including Helicobacter pylori: results of allergological testing. Allergol Immunopathol. 2011;39:193–9. 24. Saenz de San Pedro B, Gómez A, Quiralte J, Florido JF, Martín E, Hinojosa B. FDE to macrolides. Allergy. 2002;57:55–6. 25. Pascual C, Crespo JF, Quiralte J, Lopez C, Wheeler G, Martin-Esteban M. In vitro detection of specific IgE antibodies to erythromycin. J Allergy Clin Immunol. 1995;95:668–71.

191 26. Swamy N, Laurie SA, Ruiz-Huidobro E, Khan DA. Successful clarithromycin desensitization in a multiple macrolide-allergic patient. Ann Allergy Asthma Immunol. 2010;105:489–90. 27. Gilbert DN, Leggett JE: Aminoglycosides. In Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th edition. Mandell D, Mandell GL, Bennett JE, Dolin R. Philadelphia: Churchill Livingstone Elsevier; 2010:359–384. 28. de Padua CA, Uter W, Schnuch A. Contact allergy to topical drugs: prevalence in a clinical setting and estimation of frequency at the population level. Pharmacoepidemiol Drug Saf. 2007;16:377–84. 29. Sánchez-Pérez J, López MP, De Vega Haro JM, García-Díez A. Allergic contact dermatitis from gentamicin in eyedrops, with cross-reactivity to kanamycin but not neomycin. Contact Dermatitis. 2001;44:54. 30. Connolly M, McAdoo J, Bourke JF. Gentamicin- induced anaphylaxis. Ir J Med Sci. 2007;176:317. 31. Schulze S, Wollina U. Gentamicin-induced anaphylaxis. Allergy. 2003;58:88. 32. Romano A, Viola M, Di Fonso M, Rosaria Perrone M, Gaeta F, Andriolo M. Anaphylaxis to streptomycin. Allergy. 2002;57:1087–8. 33. Menéndez Ramos F, Llamas Martín R, Zarco Olivo C, Dorado Bris JM, Merino Luque MV. Allergic contact dermatitis from tobramycin. Contact Dermatitis. 1990;22:305–6. 34. Schorr WF, Ridgway HB. Tobramycin-neomycin cross-sensitivity. Contact Dermatitis. 1977;3:133–7. 35. Earl H, Sullivan TJ. Acute desensitization of a patient with CF to both beta-lactam and aminoglycoside antibiotics. J Allergy Clin Immunol. 1987;79:477–83. 36. Russell B. Desensitization to streptomycin and PAS. Br Med J. 1953;2:1322.1.

Other Anti-Infectious Drugs

21

Werner Aberer

21.1 Chloroquine and Hydroxychloroquine

21.2 Dapsone (Diaminodiphenylsulfone)

This synthetic antimalarial and amebicidal drug Traditionally used in the treatment of leprosy and has been reported to cause pruritus, urticaria and dermatitis herpetiformis, it is also part of the angioedema, maculopapular rashes and other treatment for Pneumocystis carinii pneumonitis exanthems, photosensitivity, erythema multi- in HIV patients. forme, SJS and even TEN, AGEP and DRESS Cutaneous manifestations include maculopapusyndrome, erythema annulare centrifugum, pso- lar eruptions but also exfoliative dermatitis and SJS riasis exacerbation, lichenoid eruption, purpura, as well as hypersensitivity syndromes with fever, vasculitis, oral pigmentation and ulceration, and skin eruptions, and internal involvement. The bullous pemphigoid. mechanism remains unclear in most instances and The underlying mechanism remains unclear in diagnostic methods remain negative. In the case of most instances and testing negative. The conse- DHS, immediate discontinuation is mandatory as quences are divergent: whereas chloroquine drug well as treatment with glucocorticosteroids. should not be prescribed for patients with psoriasis or other exfoliative skin conditions, the drug might be administered to patients who have expe- 21.3 Pentamidine rienced prior hydroxychloroquine sulfate- associated exanthems with a low risk of Widely used to treat Pneumocystis carinii pneure-expression of the exanthema or appearance of monitis in AIDS patients, morbilliform eruptions other clinical forms. occur frequently (15%), as well as pruritus, contact urticaria, rash and exanthemas, and injection site reactions, whereas SJS and TEN are rare. Regarding diagnostic methods for seemingly W. Aberer (*) allergic reactions, skin tests are not validated, Department of Dermatology, Medical University of in vitro tests not available, and challenge tests Graz, Graz, Austria e-mail: [email protected] dangerous.

© Springer Nature Switzerland AG 2022 A. J. Bircher et al. (eds.), Cutaneous Drug Hypersensitivity, https://doi.org/10.1007/978-3-030-82743-4_21

193

W. Aberer

194

21.4 Quinine This alkaloid mainly used as an antimalarial drug but also as an antipyretic and analgesic might cause pruritus, urticaria, angioedema, exanthems, photosensitivity, fixed drug eruption, DRESS syndrome, erythema multiforme, SJS and TEN, oral mucous ulceration, lichenoid eruption, purpura, vasculitis, acral necroses, and pigmentation. Diagnostic procedures are poorly defined, however, in are cases an IgE-mediated mechanism has been suspected.

21.5 Fluconazole This antifungal agent for the treatment of infections of the nail, skin, oral, and vaginal mucosa as well as systemic candidiasis and cryptococcal meningitis in HIV patients quite rarely causes cutaneous manifestations, ranging from exanthems to AGEP, fixed drug eruption, erythema multiforme, SJS, and TEN; rarely anaphylactic reactions occur. The mechanisms for these reactions are unknown, and skin tests proved helpful in single cases only.

21.6 Itraconazole This first-generation triazole antifungal agent used for the treatment of histoplasmosis, coccidioidomycosis, sporotrichosis, candidosis, and aspergillosis causes, with a rather low incidence, urticaria, angioedema, macular and purpuric eruptions, AGEP, fixed drug reactions, and photosensitivity. The mechanisms are unknown, and skin testing is not evaluated.

21.7 Ketoconazole This synthetic antifungal imidazole derivative used in the treatment of skin and systemic mycoses rarely causes irritant and contact dermatitis upon topical use and pruritus, exanthems, urti-

caria and angioedema, fixed drug eruption, as well as anaphylactic shock upon systemic use. In the latter an IgE-mediated hypersensitivity seems possible, and skin test and provocation are helpful in some instances.

21.8 Terbinafine This allylamine antifungal agent for the treatment of onychomycoses and other dermatomycoses may cause cutaneous reactions with a wide spectrum, from mild exanthems to TEN, in about 10% of patients. The mechanisms are unknown and the testing procedures not standardized.

21.9 Amphotericin B Being effective in the treatment of fungal infections including candida, aspergillus, and cryptococcus, it remains the gold standard in the treatment of severe fungal infections in immunosuppressed hosts. AGEP and maculopapular rashes are rare but sometimes severe. Validated diagnostic methods are not available.

21.10 Anti-herpes and Anti-CMV Drugs Acyclovir and valaciclovir rarely cause irritant or allergic contact dermatitis upon repeated topical use; systemic administration then might cause generalized eczema, vesicular eruption, phlebitis, and urticaria. Systemic application, orally or i.v., according to the official leaflets of the producer companies, frequently causes pruritus and rashes (including photosensitivity), occasionally urticaria, and rarely angioedema. In daily life this is almost never observed, and according to the literature, acyclovir “generally is well tolerated” [1]. Patch testing is indicated for skin effects after topical application to prove delayed-type hypersensitivity reactions.

21 Other Anti-Infectious Drugs

The antiviral drug foscarnet quite frequently causes different types of reactions. Others such as famciclovir, ganciclovir, and cidofovir are reported to cause rashes, urticaria, pruritus, and application site reactions from time to time, but causality and diagnostic recommendations are scarcely proven.

21.11 Antiretroviral Substances: Abacavir Abacavir frequently causes rashes (maculopapular or urticarial, without systemic symptoms), but only very rarely erythema multiforme, SJS, and TEN. Regarding validated diagnostic tests, abacavir is an exception in this group of drugs: patch testing with 10% abacavir revealed a specificity of 100% and sensitivity of 79% for patients with confirmed HLA-B*5701 genotype [2].

21.12 Summary

195

malarial and anti-pneumocystis carinii drugs, quinine, and antifungal and antibiotic drugs; but the causal connection was seldomly proven, mostly due to limited testing procedures. The position paper on skin test concentrations for systemically administered drugs summarizes that only for beta-lactam antibiotics “the value of skin tests has been adequately demonstrated” [3]. Commercially available in vitro test does not exist, and re-exposure is not justified due to the potential danger. This leads to the consequence that decisions have to be made usually based on the individual situation, the exact history and clinical picture of the patient, the expertise of the physician, and the special environment. Proper documentation is essential for the expert to make a sound therapeutic decision [4]. Currently most data are collected in expert books such as the Drug Allergy by D. Vervloet [5].

References

1. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed; 2018. ISBN 1-25-958473-0. Regarding anti-infectious drugs, abundant litera- 2. Philips EJ, Sullivan JR, Knowles SR, Shear NH. Utility of patch testing in patients with hyperture does exist almost exclusively for the beta- sensitivity syndromes associated with abacavir. AIDS. lactam antibiotics, regarding data on the 2002;16:2223–5. manifestations, mechanisms, diagnostic meth- 3. Brockow K, Garvey LH, Aberer W, et al. Skin test ods, and their management. For all the other concentrations for systemically administered drugs – an ENDA/EAACI drug allergy interest group position groups, starting with the non-beta-lactam antibipaper. Allergy. 2013;68:702–12. otics and covering drugs against fungal, viral, 4. Brockow K, Aberer W, Atanaskovic-Markovic S, et and retroviral disease and antiparasitic drugs, the al. Drug allergy passport and other documentation descriptive literature on proven cutaneous side for patients with drug hypersensitivity – an ENDA/ EAACI drug allergy interest group position paper. effects and detailed recommendations for testing Allergy. 2016;71:1533–9. and management is scarce. The most severe cuta 5. Vervloet D, Pradal M, Birnbaum J, Koeppel MC. Drug neous skin side effects SJS and TEN have been Allergy. www.editions-de-conde.fr.

reported for many of these drugs, including anti-

Cutaneous Hypersensitivity Reactions to Analgesics and Nonsteroidal Anti- Inflammatory Drugs

22

Marek L. Kowalski and Aleksandra Wardzynska

Key Points •

•

• •

acute skin reactions to NSAIDs are manifested as urticaria and/or angioedema, while delayed skin Nonsteroidal anti-inflammatory drugs may reactions are expressed in diverse forms such as induce a variety of both immediate and exanthematous eruptions, fixed drug eruptions, delayed cutaneous symptoms. purpura, or erythema nodosum. Severe reactions Non-immunological, cross-reactive mecha- to NSAIDs both immediate (anaphylaxis) and nism is the most common, although IgE- delayed type (SCARs), including Stevens- mediated and T-cell-mediated mechanisms Johnson syndrome and toxic epidermal necrolymay be involved as well. sis, have been also described [1]. The diagnosis is mostly based on clinical hisFrom a practical standpoint, four major clinitory and drug provocation tests. cal phenotypes of hypersensitivity reactions to Avoidance of cross-reactive NSAIDs is impor- aspirin and other NSAIDs with unique or pretant, and for most patients, alternative drugs dominant skin manifestation can be distinguished can be recommended based on identified type [2] (Fig. 22.1). of reaction.

22.1 Clinical Manifestation Hypersensitivity reaction following NSAIDs can be manifested by a wide spectrum of symptoms both from skin and from other organs. The timing of reactions varies from immediate, occurring within minutes, to delayed type reactions developing over more than 24 h. The most frequent Marek L. Kowalski was deceased at the time of publication. M. L. Kowalski · A. Wardzynska (*) Department of Immunology and Allergy, Medical University of Lodz, Lodz, Poland e-mail: [email protected] © Springer Nature Switzerland AG 2022 A. J. Bircher et al. (eds.), Cutaneous Drug Hypersensitivity, https://doi.org/10.1007/978-3-030-82743-4_22

22.1.1 NSAIDs-Exacerbated Cutaneous Disease (NECD) Up to 30% of patients with chronic spontaneous urticaria may experience exacerbation of their skin symptoms (urticaria and angioedema) within minutes to 3–4 h after exposure to NSAIDs. In rare cases hypersensitivity reaction to a NSAID may precede the development of chronic urticaria. Patients with this type of hypersensitivity will react with similar symptoms to COX-1-inhibiting NSAIDs, but usually tolerate highly selective COX-2 inhibitors. These patients are more likely to react to NSAIDs during exacerbation of chronic urticaria and tend to tolerate NSAIDs during remission of underlying skin disease [2]. 197

M. L. Kowalski and A. Wardzynska

198

Cutaneous NSAIDs Hypersensitivity reactions Non-immunologically mediated (cross-reactive)

NIUA NSAID-induced urticaria/ angioedema

NECD NSAIDexacerbated cutaneous disease

Acute

Immunologically mediated (selective) SNIUAA Single NSAIDinduced urticaria/ angioedema or anaphylaxis

SNIDHR Single NSAIDinduced delayed reactions

Delayed

Fig. 22.1 Types of cutaneous hypersensitivity to NSAIDs

22.1.2 NSAIDs-Induced Urticaria/ Angioedema (NIUA) NSAIDs may also induce urticaria and/or angioedema in healthy subjects, with no history of chronic skin symptoms. Urticaria and/or angioedema usually appears within 1 to 6 h following drug ingestion. In some patients, most commonly after ibuprofen or diclofenac, angioedema without urticaria may develop. In children this type of NSAID hypersensitivity may manifest as isolated periorbital edema. Positive immediate type skin tests to inhalant allergens are common among patients with NIUA and often are associated with current symptoms of atopic diseases (rhinitis, asthma) [3]. Specifically sensitization to mite allergens (Dermatophagoides farinae and Dermatophagoides pteronyssinus) has been associated with NIUA. It is not clear if NIUA may precede the appearance of chronic spontaneous urticaria. In up to 20% of patients with NIUA, skin symptoms may be accompanied by respiratory symptoms.

22.1.3 Single NSAIDs-Induced Urticaria/Angioedema or Anaphylaxis (SNIUAA) In this type of NSAID hypersensitivity, symptoms are evoked by a single NSAID or by two or more NSAIDs with similar chemical structure (i.e., belonging to the same chemical group), while other chemically non-related NSAIDs are well tolerated. Symptoms usually develop rapidly: within half an hour up to 1 h after oral drug intake and within minutes following drug injection. Although urticaria and angioedema are the most common manifestation, in about 1/3 of patients, angioedema (including laryngoedema) may develop. Systemic anaphylaxis is common, reported, e.g., in 1/3 of reactions after pyrazolones and leading in single cases to death. The most common triggers of SNIUAA are pyrazolones (in those countries where they are still in use) followed by diclofenac and paracetamol [4].

22 Cutaneous Hypersensitivity Reactions to Analgesics and Nonsteroidal Anti-Inflammatory Drugs

22.1.4 Single NSAIDs-Induced Delayed Hypersensitivity Reactions (SNIDHR) Reactions to NSAIDs developing within 24–48 h after drug administration represent delayed type hypersensitivity and manifest predominantly by variety of skin symptoms such as exanthematous eruptions, fixed drug eruptions or erythema multiforme, purpura, or erythema nodosum. The most severe delayed type reactions to NSAIDs including Stevens-Johnson syndrome, toxic epidermal necrolysis, and exfoliative dermatitis have also been described [2].

22.1.5 Mixed Reactions

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(e.g., antibiotics), but non-immunological mechanisms of hypersensitivity seem to be unique for NSAIDs. A distinctive feature of majority of hypersensitive reactions to aspirin and other NSAIDs is that patients sensitive to a single NSAID (e.g., aspirin) cross-react with similar symptoms to other often chemically not related anti-inflammatory compounds. This phenomenon was elucidated in 1975 by Andrew Szczeklik with his colleagues, who demonstrated that the capacity of NSAIDs to induce respiratory and/or skin symptoms is closely related to its pharmacological mechanism, namely, ability to prostaglandin inhibition. Following discovery that prostaglandins can be generated by two enzymes COX-1 and COX-2 and that NSAIDs vary considerably in their capacity to COX-1 or COX-2 inhibition (Table 22.1). It was documented that only those NSAIDs which are strong COX-1 inhibitors can induce respiratory or skin symptoms while selective COX-2 inhibitors are generally well tolerated. According to “cyclooxygenase theory,” development of skin reactions after a NSAID in patients with NECD is related to inhibition of COX-1, an enzyme responsible for metabolism of arachidonic acid to prostaglandins and thromboxane. It has been documented that only NSAIDs with potent COX-inhibitory activity may induce the reaction, while weak COX-1 inhibitors or selective COX-2 inhibitors are generally well tolerated.

Physicians diagnosing a patient with NSAID hypersensitivity should be aware that the classification is not clear-cut, and reactions induced by NSAIDs may be blended, i.e., represent mixed type of hypersensitivity. Furthermore, skin reactions can be accompanied by symptoms from other organs, most commonly from the respiratory system. In approximately 10% of patients with NECD, respiratory symptoms resulting from bronchoconstriction will develop. In one study [5], respiratory symptoms were reported in 18.2% of patients with cross-reactive type of urticaria/angioedema and in 4.6% patients with SNIUAA. On the other hand, NSAID-induced respiratory symptoms in patients with NSAID- exacerbated respiratory diseases (N-ERD) can be Table 22.1 NSAID classes according to their pharmacoaccompanied by skin symptoms in about 10% of logical action against cyclooxygenase cases. More recently association of rhinocon- Class Drugs junctivitis symptoms with NSAIDs-induced skin Strong COX-1 Acetylsalicylic acid, ibuprofen, inhibitors ketoprofen, dexketoprofen, reactions has been described [6].

22.2 Mechanisms Hypersensitivity reactions to NSAIDs may involve either immunological (allergic) or non- immunological (non-allergic) reactions. Immunological mechanisms involving either IgE-driven reactions or delayed type IV responses are shared with other drug allergies

Weak COX-1 inhibitors Preferential COX-2 inhibitors Selective COX-2 inhibitors

fenoprofen, flurbiprofen, naproxen, indomethacin, ketorolac, diclofenac, nabumetone, sulindac, tolmetin, piroxicam, mefenamic acid Paracetamol, salsalate Nimesulide, meloxicam

Celecoxib, etoricoxib, parecoxib

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Postulated mechanism suggests that inhibition of COX-1 activity by a NSAID in a hypersensitive subject deprives inflammatory cells of protective prostaglandin E2, resulting in activation of inflammatory cells (basophils, mast cell, and eosinophils) and release of several mediators responsible for development of symptoms. At baseline patients more cysteinyl leukotrienes, and urinary leukotriene E4 is further increased during hypersensitivity reaction. Similar to NECD patients, those with NIUA cross-react to NSAIDs with COX-1 inhibitory activity and usually tolerate COX-2 inhibitors; thus, similar mechanism of hypersensitivity was proposed, although experimental evidence for this mechanism is lacking. In addition patients with NIUA have often positive skin tests to aeroallergens; thus, the role for an underlying IgE mechanism remains unclear. The role of genetic background in NECD and NIUA has not been elucidated, but 17% NIUA children had positive family history for NSAID hypersensitivity. As opposed to the cross-reactive types of hypersensitivity (NECD and NIUA), selective types of reactions (SNIUA or SNIDHR), which occur after single NSAID, are immunologically mediated. Patients with SNIUAA tolerate well chemically non-related NSAIDs, even if they are strong COX-1 inhibitors. However, they will react to NSAIDs belonging to the same chemical group (Table 22.2). Clinical pattern and timing of reactions suggest immediate IgE-driven mechanism of hypersensitivity. In a proportion of SNIUAA patients, specific IgE to a culprit drug can be detected, either by skin testing or by immunoassays in serum [4]. However, pathomechanism of these reactions seems to be more complex, since hapten modification of human serum albumin by NSAIDs in SNIUAA patients was also reported. Symptoms developing in the skin or in other organs more than 24 h after exposure to a NSAID are immunologically mediated, since cross- reactivity has been observed only between closely antigenically related molecules. Putative mechanism involves T-cell-mediated delayed type of hypersensitivity.

Table 22.2 NSAID classes according to their chemical structure Class Salicylic acid derivates Propionic acid derivatives Indole and indene acetic acid Anthranilates (fenamates) Oxicams Phenylpyrazolones Para-aminophenol derivatives

Drugs Aspirin (acetylsalicylic acid), salicylic acid, salsalate Ibuprofen, dexibuprofen, naproxen, ketoprofen, dexketoprofen Indomethacin, tolmetin, sulindac, ketorolac, diclofenac, nabumetone Mefenamic acid, meclofenamic acid Piroxicam, tenoxicam Antipyrine, aminopyrine, dipyrone (novaminsulfone) Acetaminophen

22.3 Diagnostic Methods Diagnosis of specific type of NSAID hypersensitivity is prerequisite for proper management of a patient with history of reaction to analgesics. Carefully collected clinical history should be aimed at possible fitting of the reported reaction into one of specific types of NSAID hypersensitivity, as proposed by current classification. History should include analysis of the clinical spectrum of the reaction (skin and/or other organs involvement), timing between the last dose and symptom onset (acute, delayed), and detailed information on the culprit drug(s). It is critical that detailed history of previously taken and tolerated NSAIDs is recorded (history of aspirin tolerance may be critical), which may help to hypothesize on the mechanism of the reaction (selective or cross-reactive). Careful analysis of existing comorbidities like chronic urticaria, asthma, or rhinosinusitis with nasal polyps is important for initial diagnosis. Further diagnostic steps can be taken only, if based on history, a specific type of hypersensitivity has been hypothesized. If history is suggesting immunological (selective) type of reaction, further diagnostic steps, e.g., skin testing or in vitro testing (serum sIgE or LPT), can be considered. If cross-reactive type of NSAID hypersensitivity is suspected, no

22 Cutaneous Hypersensitivity Reactions to Analgesics and Nonsteroidal Anti-Inflammatory Drugs

immunological testing is justified and options for in vitro testing are limited. Identification of a culprit drug may require oral provocation test to be performed, and oral challenge with acetylsalicylic acid may be necessary to confirm or exclude a cross-reactive type of hypersensitivity. A practical “seven step” diagnostic algorithm has been proposed, allowing to identify/confirm the culprit NSAIDs and to determine the type of NSAID hypersensitivity [2, 7] (Fig. 22.2). A detailed analysis of patient’s history (steps 1 to 4) may allow to establish in majority of patients the specific type of NSAID hypersensitivity. Further steps (5–7) involving skin testing, in vitro testing, and oral provocation challenges may be necessary if the history is unequivocal and does not allow for firm diagnosis.

22.3.1 Step 1: Assess the Type of Adverse Reaction to NSAIDs Type A adverse reactions, which are associated with chronic treatment with a NSAID, usually in higher than usual doses are manifested with gastrointestinal, hematological, or nephrotoxic symptoms and rarely involve skin. Thus, presence of skin symptoms after a single, moderate dose of a NSAID allows to diagnose type B hypersensitivity, which will require to move to the next diagnostic step.

22.3.2 Step 2: Determine Timing of the Reaction Skin symptoms developing within minutes or during the first hour after the oral NSAID intake are most likely to represent immunological IgE-mediated reaction (SNIUAA). Majority of patients with cross-reactive type of hypersensitivity (NECD, NIUA) develop reactions within 1 to 2 h, but reactions starting several hours later are not uncommon. Only in few, highly susceptible NECD or NIUA patients exposed to the dose of NSAIDs significantly exceeding individual sensitivity threshold or after parenteral dosing, the reaction may develop earlier (within first hour).

201

Skin symptoms developing more than 24 h after a drug intake may be suspected as T-cell-mediated delayed type hypersensitivity (SNIDHR).

22.3.3 Step 3: Analyze Clinical Pattern of NSAID-Induced Symptoms and Underlying Chronic Diseases Presence of acute cutaneous symptoms (rash, urticaria, and/ or angioedema) within first hours after intake of NSAID does not allow to distinguish cross-reactive (NECD or NIUA) from selective type of hypersensitivity (SNIUAA). However, rapid development of urticaria and/or angioedema associated with systemic anaphylaxis (e.g., hypotension) strongly suggests a selective type, IgE-mediated type of hypersensitivity. Skin symptoms in patients with history of chronic spontaneous urticaria suggest diagnosis of NECD, while lack of chronic skin symptoms speaks in favor of diagnosis of either NECD or SNIUAA. If skin rash or urticaria after NSAIDs is accompanied by respiratory symptoms (dyspnea, wheezing, cough, rhinorrhea, or nasal congestion), N-ERD can be suspected, and history of chronic asthma with chronic rhinosinusitis and nasal polyps should be evaluated. In patients with delayed type of reaction (SNIDHR), usually no underlying disorders are present.

22.3.4 Step 4: Assess History of Hypersensitivity/Tolerance to Other NSAIDs If a patient reports symptoms evoked in the past by several NSAID (either COX-1 or COX-2 inhibitors), belonging to different chemical groups (e.g., ibuprofen and diclofenac), non- immunologically mediated, cross-reactive type of hypersensitivity may be suspected. History of three or more immediate reactions to two different NSAIDs confirms the diagnosis of cross-reactive NSAID hypersentitivity with >90% even without provocation test. Two or more reactions to the same NSAID with good tolerance to another

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Based on the history

Step 1

• Assess the type of adverse reaction to NSAIDs

Step 2

• Determine timing of the reaction

Step 3

• Analyze clinical pattern of NSAID-induced symptoms and underlying chronic diseases

Step 4

• Assess history of hypersensitivity /tolerance to other NSAIDs

Based on diagnostic procedures

Step 5

• Confirm/exclude cross-reactivity to other NSAIDs by oral challenge

Step 6

• Consider skin testing or in vitro testing

Step 7

• Consider oral provocation challenge with a culprit drug

Fig. 22.2 Seven steps to diagnose NSAID hypersensitivity. (Modified from: Kowalski ML, Makowska JS. Seven steps to the diagnosis of NSAID hypersensitivity: how to

apply a new classification in real practice? Allergy Asthma Immunol Res. 2015;7:312–20)

NSAID with strong COX-1 inhibitory activity suggest selective type of hypersensitivity [2]. It should be emphasized that patients with SNIUAA

may experience reactions to another NSAID, but belonging to the same chemical group and sharing common epitopes.

22 Cutaneous Hypersensitivity Reactions to Analgesics and Nonsteroidal Anti-Inflammatory Drugs

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Table 22.3 Non-irritating test concentrations NSAIDs [8] Drugs Celecoxib Metamizole Paracetamol Ibuprofen Naproxen Ketoprofen

Skin prick test Undiluted 40–400 mg/mL 10–100 mg/mL – – –

Intradermal test – 0.004–4 mg/mL 100 mg/mL – – –

22.3.5 Step 5: Confirm/Exclude Cross-Reactivity to Other NSAIDs by Challenge If the history is not clear-cut, in order to distinguish between cross-reactive and selective type of hypersensitivity, oral challenge test may be necessary. In patients with history of reactions to NSAID other than aspirin, skin symptoms developing after oral challenge with aspirin confirm cross-reactive type of hypersensitivity. On the other hand, a negative challenge test with aspirin or another strong COX-1 inhibitor suggests selective, immunologically mediated type of acute NSAID hypersensitivity.

22.3.6 Step 6: Consider Skin Testing or in Vitro Testing If cross-reactive type is suspected (NECD, NIUA), skin testing is not indicated. Skin testing with a culprit drug should be considered only if a clinical history suggests IgE-mediated, selective type of hypersensitivity. Protocols separate for each NSAID have been published, although only testing for pyrazolones has been validated in larger populations (Table 22.3). A risk of systemic anaphylactic reaction related to skin testing with the culprit NSAID should be carefully considered against possible benefits [9]. If history is suggestive of delayed type cutaneous reaction (contact dermatitis, fixed drug eruption, maculopapular rash), skin patch tests can be performed. Intradermal tests with

Patch test (concentration/vehicle) 5–10%/petrolatum 10%/petrolatum 10%/petrolatum 5%/petrolatum 5%/petrolatum 5%/petrolatum

delayed reading have high specificity, but low sensitivity [8]. In vitro cell activation tests (BAT, CAST- ELISA, ASPItest) have been used to confirm diagnosis of acute type of NSAID hypersensitivity, but have not been validated and are not recommended for routine practice. In patients with delayed type of NSAID hypersensitivity (SNIDHR), lymphocyte activation tests have been used, but have limited diagnostic value.

22.3.7 Step 7: Consider Oral Provocation Challenge with a Culprit Drug Oral challenge with the culprit drug may be performed to confirm hypersensitivity to NSAIDs. It has been recommended for NECD, NIUA, or SNIUAA but not for SNIDHR [10]. Several challenge protocols have been published, and, for example, for aspirin the EAACI/GA2LEN guideline recommends single-blind placebocontrolled 2-day aspirin challenges, after the patient has been without any skin eruptions for 1–2 weeks [10]. Before the decision on performing oral challenge is taken, the benefit of positive or negative result should be considered and the potential risk and effort associated with a challenge taken into account. Oral provocation tests with NSAIDs have good performance (sensitivity and specificity is exceeding 90%); however, the challenge is time-consuming and may be associated with a risk of difficult to control systemic reaction [10].

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22.4 Cross-Reactions Assessment of cross-reactivity is an important component of diagnosis in patient with hypersensitivity to NSAIDs, affecting both diagnostics approaches and influencing treatment modalities. In patients with selective type of hypersensitivity, cross-reactivity will only occur with other NSAIDs with similar chemical structure (e.g., patient sensitized to metamizole will react to other pyrazolones), while in cross-reactive types of hypersensitivity, reactions to all NSAIDs inhibiting COX-1 can occur.

22.5 Management Management of NSAID hypersensitivity depends on the type of hypersensitivity: avoidance measures and recommendations for alternative drugs and drug desensitization can be properly implemented only if a specific type of hypersensitivity is established. The most important is classification of a reaction as either cross-reactive (non- immunologically mediated) or selective (immunologically mediated).

22.5.1 Cross-Reactive Types of Hypersensitivity (NECD and NIUA) Patients should avoid not only a culprit NSAID but also all NSAIDs with strong COX-1 i nhibitory activity (Table 22.1). Paracetamol can be recommended, as alternative drug, if analgesic or antipyretic treatment is necessary. However patients with NECD may react to paracetamol. If more intensive anti-inflammatory treatment is necessary, the highly selective COX-2 inhibitors (celecoxib and etoricoxib), which are generally well tolerated in this patients’ population, can be prescribed. Since there have been single reports of NECD patients reacting to selective COX-2 inhibitors, it is recommended that before prescription oral challenge is performed in a controlled setting to confirm their tolerability.

22.5.2 Selective Types of SNIUAA and SNIDHR In a patient with hypersensitivity to a single NSAID (e.g., metamizole or diclofenac), the drug can be easily replaced by another NSAID with either strong COX-1 or COX-2 selective activity, but unrelated chemical structure (Table 22.2). However, NSAIDs belonging to the same chemical class should be avoided, since structural similarity among drugs within each class may result in immunological cross- reactivity (e.g., between pyrazolones). The patient should be provided with a list of brand and International nonproprietary names (INN) of NSAIDs belonging to the same chemical group.

22.5.3 Desensitization Clinical indications for drug desensitization in patients with cutaneous manifestations of NSAID hypersensitivity have not been established. Only patients with NIUA can be successfully desensitized to aspirin, which may allow for chronic treatment in patient with, e.g., cardiovascular diseases. In patients with NECD, desensitization to aspirin is difficult to achieve and does not provide any clinical benefit. In patients with SNIUAA and SNIDHR, desensitization is not recommended.

References 1. Kowalski ML, Agache I, Bavbek S, et al. Diagnosis and management of NSAID-exacerbated respiratory disease (N-ERD)—a EAACI position paper. Allergy. 2019;74:28–39. 2. Kowalski ML, Woessner K, Sanak M. Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug-related urticaria and angioedema. J Allergy Clin Immunol. 2015;136:245–51. https://doi.org/10.1016/j. jaci.2015.06.021. 3. Doña I, Blanca-López N, Torres MJ, García-Campos J, García-Núñez I, Gómez F, et al. Drug hypersensitivity reactions: response patterns, drug involved, and temporal variations in a large series of patients. J Investig Allergol Clin Immunol. 2012;22:363–71.

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4. Canto MG, Andreu I, Fernandez J, Blanca M. Selective 8. Brockow K, Garvey LH, Aberer W, Atanaskovic- Markovic M, Barbaud A, Bilo MB, et al. Skin test immediate hypersensitivity reactions to NSAIDs. concentrations for systemically administered drugs— Curr Opin Allergy Clin Immunol. 2009;9:293–7. an ENDA/EAACI drug allergy interest group position 5. Lee Y, Shin YS, Park HS. New phenotypes in paper. Allergy. 2013;68(6):702–12. https://doi. hypersensitivity reactions to nonsteroidal anti- org/10.1111/all.12142. inflammatory drugs. Curr Opin Allergy Clin Immunol. 9. Zalewska-Janowska A, Spiewak R, Kowalski 2019;19(4):302–7. ML. Cutaneous manifestation of drug allergy and 6. Doña I, Pérez-Sánchez N, Eguiluz-Gracia I, et al. hypersensitivity. Immunol Allergy Clin North Am. Progress in understanding hypersensitivity reactions 2017;37(1):165–81. to nonsteroidal anti-inflammatory drugs. Allergy. 10. Nizankowska-Mogilnicka E, Bochenek G, Mastalerz 2020;75(3):561–75. L, Swierczyńska M, Picado C, Scadding G, et al. 7. Kowalski ML, Makowska JS. Seven steps to the EAACI/GA2LEN guideline: aspirin provocation diagnosis of NSAIDs hypersensitivity: how to apply tests for diagnosis of aspirin hypersensitivity. Allergy. a new classification in real practice? Allergy Asthma 2007;62:1111–8. Immunol Res. 2015;7:312–20.

Peri-Interventional Hypersensitivity: Anesthetic Drugs and Materials

23

Andreas J. Bircher and Knut Brockow

Key Points

A. J. Bircher (*) Allergology, Department of Dermatology, University Hospital Basel, Basel, Switzerland

including administration of often several pre-, intra-, and postoperative drugs, exposure to potentially allergenic materials and agents, as well as complications due to surgical and anesthetic interventions. There is a wide variation of the incidence of perioperative reactions among different countries. Overall, these hypersensitivity reactions are uncommon; the incidence is estimated to be roughly from 1:300 to 1:15,000 but may be underestimated. General risk factors and modifying aggravating factors [1–3] causing more severe reactions and factors increasing the likelihood of sensitization and therefore an intraoperative hypersensitivity are listed in Table 23.1. Perioperative mortality encompasses a wide range from 0% up to 4% [2]. Despite its rarity, the identification of potential elicitors and exclusion of the many differential diagnoses are crucial for future surgical interventions and require an interdisciplinary approach, particularly cooperation between the anesthetist and an experienced allergist [4]. In this chapter, the main culprit drugs and agents, excluding neuromuscular blockers (NMBA) and antibiotics, are briefly presented, and diagnostic possibilities are discussed.

Faculty of Biomedicine, Università della Svizzera Italiana, Lugano, Switzerland e-mail: [email protected]

23.2 Clinical Manifestations

• Manifestation of perioperative anaphylaxis may be difficult to recognize because of particular patient setting. • Many different systemic and topical drugs and materials may be involved. • Diagnostic work-up requires interdisciplinary cooperation. • Skin tests are the first and main diagnostic tool for identifying culprit agents. • Several drugs used in anesthesia have direct histamine-liberating capacities or may directly induce hypotonia upon rapid infusion.

23.1 Introduction Hypersensitivity reactions in the perioperative period are challenging. Surgical routine or emergency procedures include a variety of problems,

K. Brockow

Department of Dermatology und Allergology Biederstein, Technical University of Munich, Munich, Germany e-mail: [email protected] © Springer Nature Switzerland AG 2022 A. J. Bircher et al. (eds.), Cutaneous Drug Hypersensitivity, https://doi.org/10.1007/978-3-030-82743-4_23

Immediate hypersensitivity, particularly anaphylaxis, is the most common clinical manifestation. Depending on the type of drug and route 207

208 Table 23.1 Factors associated with an increased risk/ severity of perioperative anaphylaxis Older age Female gender Beta-blocking drugs Angiotensin-converting enzyme (ACE) inhibitors Angiotensin-II-receptor antagonists (sartans) Previous anaphylaxis during anesthesia Previous unexplained reactions during general anesthesia Bronchial asthma Arterial hypertension Elevated basal tryptase Mastocytosis Atopic background Spina bifida Multiple surgical interventions Known sensitization to drugs Multiple drug allergy syndrome

of administration, onset of anaphylaxis may vary. In cases of fatal anaphylaxis, median times to cardiac arrest varied with route of administration being 5 min after intravenous, 15 min after subcutaneous injection, and 30 min after oral intake [4]. Late-onset and prolonged or biphasic reactions, e.g., with subcutaneous blue dyes, which are slowly absorbed, have been observed [2]. Severity of hypersensitivity reactions may range from mild urticaria to life-threatening anaphylaxis. There are several grading classifications used; the most common is the Ring and Messmer classification. Recognition of anaphylaxis may be hampered due to the particular situation of a covered-up, sedated or unconscious, ventilated patient and a hypotensive state due to positioning, pharmacologic drug effects, and/or blood loss. Subjective prodromal symptoms such as pruritus, headache, metallic taste, or inadequate behavior are therefore missing. Symptoms such as malaise, pruritus, dizziness, and dyspnea cannot be ascertained in an unconscious patient. Other signs may include flushing, urticaria, angioedema, nausea, vomiting, diarrhea, rhino- conjunctivitis, and bronchospasm; these, too, may be difficult to be recognized in an interventional setup [2, 5]. Therefore, first signs may include drop in saturation, hypotension, and difficulties in ventilating the patient identified by the anesthesiologist. The temporal relationship to a particular drug or

A. J. Bircher and K. Brockow

manipulation may confine the differential diagnosis of the manifold elicitors [4–6]. More details are found in the chapter on NMBA. Occasionally there are hypersensitivity reactions with a delayed onset in the postoperative period [7]. These mostly T-cell-mediated delayedtype hypersensitivity reactions are significantly less frequent in the perioperative setting, typically presenting after completion of surgery or the intervention, when the patient has been transferred to postoperative care. A possible contributing cause to this low frequency might be the alteration of cellular immunity after extensive surgery and blood transfusion. Maculopapular exanthemas, fixed drug eruption, allergic contact dermatitis, and rarely more severe exanthems (SDRIFE, DHS/ DRESS, and SCAR) have been reported. Drugs that should be taken into consideration as elicitors of an exanthem include antibiotics, particularly penicillins and cephalosporins; opioids including morphine, fentanyl, and buprenorphine in transdermal systems; the NMBA suxamethonium; local anesthetics (lidocaine, benzocaine); the anesthetic gases sevoflurane/isoflurane; nonsteroidal antiinflammatory drugs (NSAIDs), metamizole, and coxibs (COX-2 inhibitors); iodinated radiocontrast media; as well as the vasoconstricting agents phenylephrine and pseudoephedrine/ephedrine [7].

23.3 Mechanisms In immediate reactions a number of different mechanisms may result in similar clinical manifestations. These include problems arising from anesthetic or surgical management, pharmacological effects of drugs, allergic IgE-mediated reactions, rarely IgG-mediated immune complex reactions [2], and finally nonallergic, nonspecific activation of mast cells and basophils by complement activation or via the recently discovered MRGPRX2 receptor [4, 8]. Therefore, clinical manifestations do not permit to unequivocally conclude to an underlying mechanism. Only positive immediate readings of skin tests, specific IgE (sIgE) determinations, and some cellular tests can demonstrate a sIgE-mediated allergic mechanism. Delayed-type allergic reactions are diagnosed by patch and intradermal tests with late readings [7].

23 Peri-Interventional Hypersensitivity: Anesthetic Drugs and Materials

23.4 Diagnostic Methods All patients with a systemic manifestation including urticaria/angioedema, delayed exanthem, or contact dermatitis should be investigated. The optimal time frame is not known. It is recommended that testing takes place the earliest 3–4 weeks and optimally up to 4–6 months after the incident, to avoid false-negative results. After taking a thorough history and detailed analysis of the anesthetic chart, best in cooperation with an anesthesiologist, diagnostic tests should be carefully planned [4, 6].

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Table 23.2 Commercially available sIgE for drugs Natural rubber latex (and recombinant H. brasiliensis components) Penicilloyl G Penicilloyl V Ampicilloyl Amoxicilloyl Cefaclor Suxamethonium (succinylcholine) Morphine Pholcodine Bovine gelatin Alpha-galactosidase Chlorhexidine Ethylene oxide

23.4.1 Skin Tests

23.4.3 Provocation Tests

The initial diagnostic approach is skin tests, starting with skin prick tests and, if negative, followed by intradermal tests in adequate concentrations and solutions. For skin testing, recommended procedures and dilutions for the various drugs and agents can be found in the recent literature [2, 4–6, 9].

Provocation tests, if possible, represent the gold standard [10]. In non-immunologically mediated reactions, they may be the only feasible diagnostic approach. Provocation tests are performed, if skin tests and available in vitro tests are equivocal or negative, with the aim to exclude hypersensitivity to the suspected drug or to test a safe alternative. In immediate reactions the particular effects of many drugs used in the perioperative setting, particularly muscle relaxation and respiratory depression, may limit the possibility to perform provocation tests. However, some specialized centers in Europe have begun to do provocation tests with all drugs used for general anesthesia including muscle relaxants in a specialized setting involving anesthetists. For other drugs, e.g., local anesthetics, NSAID, or antibiotics, provocation tests are better standardized and may be performed in allergy departments according to recommended guidelines [10].

23.4.2 In Vitro Diagnostics Other laboratory tests are limited in availability and validity. In acute perioperative reactions, mast cell tryptase measurements may help to verify mast cell activation in support of a mast cell-mediated hypersensitivity reaction. A clinically relevant increase is proposed, if serum tryptase levels at the time of reaction are >2 μg/L + 1.2 times baseline tryptase. Permanently elevated baseline values (>20 μg/L) indicate presence of clonal mast cell disorders (mastocytosis) [3, 4]. Measurements of sIgE are available to a limited number of substances and used to complement skin test results (Table 23.2). However, sensitivity and specificity of sIgE considerably vary and are dependent on total IgE levels. Basophil activation tests have been examined and validated in larger patient collectives with beta-lactams and neuromuscular blocking agents only [8]. Other in vitro tests such as histamine release and sulfidoleukotriene tests have even less demonstrated validity.

23.5 Eliciting Drugs The most common drug classes inducing perioperative anaphylaxis are NMBA in some countries, whereas in others, antibiotics are the leading cause. These two medication groups are discussed extensively elsewhere in this book. Below, other important elicitors for anesthetic drugs and materials are briefly discussed.

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23.5.1 Natural Rubber Latex

Table 23.3 Types of local anesthetics Amino esters Cocainea Piperocaine (metycaine) Procaine Chloroprocaine Benzocainea Tetracaine (amethocaine)a Proparacaine Amino amides Lidocaine (lignocaine) Mepivacaine Prilocaine Bupivacaine, levobupivacaine Etidocaine Ropivacaine Proxymetacaine (propitocaine)a Dibucaine (cinchocaine)a Articaine (carticaine)

Until 10 years ago, latex was one of the most common perioperative allergens. Particularly in children with spina bifida, myelomeningocele, and urogenital malformations, as well as in patients with multiple surgeries, sensitization was common. Atopic patients and health staff and workers exposed to natural rubber have an increased risk. Because powdered gloves were removed and allergenic peptides were reduced in medical utensils, the frequency of sensitization and allergic reactions has dramatically declined [4, 6]. Commercial standardized skin test solutions are less available; however, commercial specific IgE to latex and its recombinant allergens (Hev b) are available (Table 23.2).

Topical use only

a

23.5.2 Hypnotics Propofol is the substance of choice for most situations; rare IgE-mediated reactions have been reported. The antigenic determinant 2-isopropyl group of the molecule (2,3-diisopropylphenol) has been identified [6]. The concern that traces of egg lecithin and soybean could be a risk in egg and soy allergic patients has been disproven, and avoidance is not recommended [11]. Reactions to benzodiazepines such as midazolam and intravenous diazepam are also very rare; in the latter the propylene glycol solvent could be the allergen [5]. Thiopental is the only barbiturate still occasionally in use; rarely IgE-mediated reactions have been reported. Immediate allergic reactions to etomidate, ketamine, and anesthetic gases appear to be extremely rare.

23.5.3 Local Anesthetics Acute adverse reactions with sometimes anaphylaxis- like clinical picture occur within minutes after the application of local anesthetics (LA), most commonly during dental procedures or interventions to relieve local pain. Nonallergic reactions are responsible for the majority of LA-induced incidents [12].

There are two main groups, ester and amide derivatives (Table 23.3); currently mostly amide LA are used [2, 13] for injection, whereas the ester types are applied topically and rarely injected. Regarding the huge number of local anesthetic procedures applied every day worldwide, the incidence of allergic reactions is minute. Differential diagnoses include anxiety with hyperventilation, panic attacks, and vasovagal syncope. Accidental intravascular injections may result in pharmacologic action and toxicity; particularly even the low doses of epinephrine may result in palpitations and sweating in sensitive patients with comorbidities, e.g., hyperthyroidism, arterial hypertension, or cardiac conditions [12]. Both ester and amide LAs may very rarely induce IgE-mediated sensitization and anaphylaxis [12], as well as delayed T-cell-mediated allergic contact dermatitis or local plaque-like swellings. Cross-reactivity may be present within one group, but not between the two groups. Rarely, preservatives such as parabens, sulfites [2], or other additives (hyaluronidase) should be taken into consideration as elicitors. Diagnostic procedures include skin prick and intradermal tests and finally subcutaneous provocation tests. Skin tests should be done with preservative- and epinephrine-free products, provocation tests with commercial preparations,

23 Peri-Interventional Hypersensitivity: Anesthetic Drugs and Materials

particularly if proving tolerance. Recommended non-irritating test concentrations and procedures can be found in the literature [2, 4, 9, 12]. In vitro tests, e.g., determination of sIgE or cellular tests (basophil activation, lymphocyte transformation), are not commercially available and are only performed in specialized laboratories mainly for research purposes [2, 4, 6, 12].

23.5.4 Opioids Opioids are indispensable for general anesthesia. Most of the rare reactions are due to nonspecific mast cell activation. IgE-mediated reactions to the phenanthrenes morphine and codeine and potential cross-reactivity among these two have been reported. Pethidine as well as phenylpiperidines (alfentanil, fentanyl, remifentanil, sufentanil, and meperidine) and diphenylhep tanes (methadone and propoxyphene) mainly cause direct histamine liberation [4].

23.5.5 Nonsteroidal Anti- inflammatory Drugs (NSAIDs) Hypersensitivities from NSAIDs are uncommon in the postoperative period. In general, nonimmunological reactions due to COX-1 inhibition are more frequent for pyrazolones, including metamizole (novamine sulfone), as well as diclofenac, an IgE-mediated mechanism may be present [6]. Some NSAIDs may also elicit delayed-type exanthems and phototoxicity. More details on hypersensitivities from COX-1 and COX-2 inhibitors can be found in the chapter on NSAID elsewhere in this book.

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to the carbohydrate alpha-gal may also react to gelatins. The incidence of reactions is much lower for albumin and exceptional for hydroxyethyl starch. Skin tests and sIgE are available for gelatins and alpha-Gal and skin tests only for hydroxyethyl starch [2, 5, 6].

23.5.7 Hemostatic and Anticoagulant Drugs The hemostatic drugs aprotinin, protamine, and thrombin [5], as well as heparins, are very rare elicitors of immediate hypersensitivity reactions. Aprotinin, a serine protease inhibitor, is used intravenously to prevent bleeding, and as a component of biologic sealants [2], the intravenous drug was withdrawn from the market. Intravenous protamine has been reported to cause anaphylactic reactions, and IgG and IgE antibodies to protamine have been identified [5, 14]. Heparins may very rarely elicit immediate reactions upon intravenous use and delayed allergic plaque reactions and exanthems, when given subcutaneously. Details on manifestations and diagnostic procedures of heparin hypersensitivity can be found in the chapter on anticoagulants elsewhere in this book.

23.5.8 Miscellaneous Drugs

There have been exceptional reports of intraoperative hypersensitivity to some other drugs such as tranexamic acid, atropine, neostigmine, and uterotonic drugs such as oxytocin [6]. The latter may induce hypotonia upon rapid infusion mimicking anaphylaxis [4]. Hyaluronidase is an animal-derived enzyme that degrades hyaluronic acid and can be used as 23.5.6 Volume Expanders a drug or as an adjuvant, e.g., in local anesthetics. Both immediate reactions and delayed reactions This group includes dextrans, gelatins, albumin, have been reported during ocular surgery and and hydroxyethyl starch. Gelatins and dextrans epidural injection [6]. The following groups of drugs and agents are responsible for the rare reactions; IgE- mediated reactions due to gelatins and IgG- (23.5.9.–23.5.12.) include some hidden allergens mediated reactions with complement activation that are sometimes applied during interventions, by dextrans have been reported. Patients positive but not routinely documented in anesthetic proto-

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cols. Therefore, they should be searched for and possibly included in test series of patients with unexplained anaphylaxis, even if they have not been protocolled.

23.5.9 Antiseptics and Sterilizers Chlorhexidine is a widely used antiseptic and disinfectant that can trigger irritant dermatitis, allergic contact dermatitis, as well as life-threatening anaphylaxis [8, 15]. Sensitization may have been induced through body care products such as toothpaste, mouthwash, and household cleaning products. The frequency of perioperative reactions varies, being quite frequent in the UK and Scandinavia and uncommon in France. Immediate reactions are mediated by IgE and typically appear within 30 min after contact. Upon skin contact, reactions are often mild; however, when applied to mucous membranes (conjunctiva, oral cavity, urogenital) or peritoneum or by intravenous catheter, reactions can start fast and be severe. Allergy to chlorhexidine is diagnosed by skin tests and sIgE [2, 6], and also the basophil activation test has been proposed [8]. Apart from irritant and allergic contact dermatitis to iodine, the polyvinylpyrrolidone (povidone) moiety of the molecule may induce anaphylaxis; its appearance is, however, exceptional [11]. Povidone may be present as hidden allergen in other drugs, e.g., paracetamol or vaginal ovula, which in case of sensitization should also be avoided. Skin prick tests but not intradermal testing are recommended [4]. The sterilizing agent ethylene oxide is a gas widely used for sterilizing multiple medical plastic devices. Due to its chemical reactivity, it is an irritant as well as a hapten. Ethylene oxide can react with various protein moieties and therefore become a complete allergen. Cases of anaphylaxis during hemodialysis and perioperative anaphylaxis in myelomeningocele patients have been reported. Interventions without ethylene oxide are a challenge, because in some situations it cannot be substituted. Due to gaseous state and irritant properties of ethylene oxide and substitutes, the diagnosis can be made by determination of sIgE only [16].

23.5.10 Blue Dyes The blue dyes patent blue V and isosulfan blue, which are both triarylmethane dyes, and the chemically different methylene blue are commonly used for lymph node biopsy and sentinel lymph node dissection. All three have been rarely reported to cause anaphylactic reactions [17]. Onset of clinical symptoms may be delayed. Occurrence of blue wheals has been reported. It has been assumed that sensitization may occur through cosmetic and household products or colored food stuff, because both triarylmethane dyes are approved for such use [17]. Incidence is estimated being 1% to 2%, with severe reactions comprising only 0.2% to 1.1% of cases [5]. Diagnosis can be made with skin prick and intradermal tests; sIgE tests are not commercially available. Intradermal tests may be complicated by long-standing blue tattooing.

23.5.11 Radiocontrast Media In patients with immediate- or delayed-onset hypersensitivity reactions, radiocontrast media (RCM) should also be taken into consideration. In emergency situations, such as insertion of cardiac stents, their use is not always documented. The frequently labeled iodine allergy in patients with hypersensitivity to RCM is not justified [18]. Patients with allergy to seafood or fish are not at risk [11]. On the contrary, the very rare iodine mumps, often mistaken as angioedema, and iododerma are related to iodine [19]. Details on manifestations and diagnosis of radiocontrast media hypersensitivity can be found in the chapter on imaging media elsewhere in this book.

23.5.12 Additives Additives encompass substances such as carboxymethylcellulose (E466); macrogols or polyethylene glycols, polysorbates, mannitol; sulfites (E220 ff); and parabens (E 214 ff). In rare cases they have elicited immediate reactions [6]. Skin prick test may be helpful in identifying

23 Peri-Interventional Hypersensitivity: Anesthetic Drugs and Materials

sensitization [4]. Further information is available in the chapter on additives elsewhere in this book.

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culprit drug in order to provide safe anesthesia in the future. Where details of drug exposures are not available, it is recommended to test with latex, chlorhexidine, ethylene oxide, and a bat23.6 Cross-Reactivity tery of drugs, e.g., propofol, fentanyl, remifentanil, and an NMBA, to ensure safe future In the perioperative setting, among the drug anesthesia [4]. Drugs that have later been readclasses commonly representing a potential cross- ministered uneventfully do not need to be tested. reactivity are NMBA, beta-lactam antibiotics, Exposure to latex and skin disinfectants may be NSAIDs, local anesthetics, and RCM. In patients anticipated even without recording, and tests with suspected hypersensitivity reaction and pos- should be added, whereas testing of other subitive test results to such a drug, an alternative stances, such as ethylene oxide, lidocaine, excipdrug is looked for and proven, which then will be ients, or contrast media, may be considered tolerated in the next procedure. Skin tests are the according to the history. Causality of each indimain diagnostic method excluding sensitization, vidual drug should be assessed from test results but if available and possible, also laboratory tests and the chronology of the reaction. If a culprit is and provocation tests are applied. identified, safe suitable alternatives are looked for (see “Cross-Reactivity”). After completion of the investigations, the patient should be 23.7 Management informed about the results and implications for further anesthesia, and an allergy passport should Perioperative and peri-interventional hypersensi- be issued. It has been shown that after exclusion tivity reactions are among the more difficult of drugs with sensitization in skin tests (+/− labexplorations for the allergist. Although the oratory tests, if available) and with negative patients are in a well-monitored situation and provocation tests (to NSAIDs, antibiotics, and detailed anesthetic protocols are available, the local anesthetics), the following anesthesias are particular patient situation and the many drugs, generally well tolerated without a repeat reacmaterials, and agents potentially involved are tion. Whereas slow injection of incremental challenging [20]. A meticulous workup, includ- doses of drugs and premedication with H1 antiing all exposures prior to onset of a reaction may histamines may reduce mild reactions by histabe relevant, and complete documentation is mine-releasing agents, there is no evidence for essential. Interdisciplinary approaches including premedication with antihistamines or corticostecooperation with the anesthetist and surgeon may roids to prevent IgE-mediated events. help to identify a relevant differential diagnosis or may reveal not documented exposures and interventions or hidden allergens. Anesthetic References record, patient charts, details of any surgical or 1. Mirone C, Preziosi D, Mascheri A, Micarelli G, other perioperative exposures (disinfectants, Farioli L, Balossi LG, et al. Identification of risk faclocal anesthetic sprays/gels, dyes, cements), and tors of severe hypersensitivity reactions in general anaesthesia. Clin Mol Allergy. 2015;13(1):11. details of the procedure (e.g., catheters, stents) 2. Volcheck GW, Mertes PM. Local and general anesare mandatory to establish the test plan [4]. thetics immediate hypersensitivity reactions. Immunol Drugs the patient was not exposed to should Allergy Clin North Am. 2014;34:525–46. not be tested, as preemptive testing is not consid- 3. Carter MC, Metcalfe DD, Matito A, Escribano L, Butterfield JH, Schwartz LB, et al. Adverse reactions ered cost-effective and equivocal, and false- to drugs and biologics in patients with clonal mast positive skin test reactions may occur. cell disorders: a work group report of the mast cells In patients with a past history of a perioperadisorder committee, American Academy of Allergy, tive incident, all drugs recorded in the anesthetic Asthma & Immunology. J Allergy Clin Immunol. 2019;143(3):880–93. procedure should be investigated to identify a

214 4. Garvey LH, Ebo DG, Mertes PM, Dewachter P, Garcez T, Kopac P, et al. An EAACI position paper on the investigation of perioperative immediate hypersensitivity reactions. Allergy. 2019;74(10):1872–84. 5. Kannan JA, Bernstein JA. Perioperative anaphylaxis: diagnosis, evaluation, and management. Immunol Allergy Clin North Am. 2015;35(2):321–34. 6. Laguna JJ, Archilla J, Dona I, Corominas M, Gastaminza G, Mayorga C, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Clin Immunol. 2018;28(4):216–32. 7. Scherer Hofmeier K, Bircher AJ. Toxidermies péri- et postopératoires. In: Milpied-Homsi B, editor. Progrès en Dermato-Allergologie. Progrès en Dermato- Allergologie, vol. 26. Arcueil France: John Libbey Eurotext; 2020. p. 109–20. 8. Ebo DG, Faber M, Elst J, Van Gasse AL, Bridts CH, Mertens C, et al. In vitro diagnosis of immediate drug hypersensitivity during anesthesia: a review of the literature. J Allergy Clin Immunol Pract. 2018;6(4):1176–84. 9. Scolaro RJ, Crilly HM, Maycock EJ, McAleer PT, Nicholls KA, Rose MA, The R, et al. Australian and New Zealand Anaesthetic allergy group perioperative anaphylaxis investigation guidelines. Anaesth Intensive Care. 2017;45(5):543–55. 10. Garvey LH, Ebo DG, Krøigaard M, Savic S, Clarke R, Cooke P, et al. The use of drug provocation testing in the investigation of suspected immediate perioperative allergic reactions: current status. Br J Anaesth. 2019;123(1):e126–e34. 11. Dewachter P, Kopac P, Laguna JJ, Mertes PM, Sabato V, Volcheck GW, et al. Anaesthetic management of patients with pre-existing allergic conditions: a narrative review. Br J Anaesth. 2019;123(1):e65–81.

A. J. Bircher and K. Brockow 12. Trautmann A, Goebeler M, Stoevesandt J. Twenty years’ experience with anaphylaxis-like reactions to local anesthetics: genuine allergy is rare. J Allergy Clin Immunol Pract. 2018;6(6):2051–8. 13. Bircher AJ, Surber C. Allergic contact dermatitis from acylamide local anesthetics. Contact Dermatitis. 1999;40(5):292–3. 14. Kindler CH, Bircher AJ. Anaphylactoid reactions to protamine. Anesthesiology. 1996;85(5):1209–10. 15. Krautheim AB, Jermann TH, Bircher AJ. Chlorhexidine anaphylaxis: case report and review of the literature. Contact Dermatitis. 2004;50(3):113–6. 16. Listyo A, Scherer Hofmeier K, Bandschapp O, Erb T, Hasler C-C, Bircher AJ. Severe anaphylactic shock due to ethylene oxide in a patient with myelomeningocele: successful exposure prevention and pretreatment with omalizumab. AA Case Rep. 2014;2(1):3–6. 17. Scherer K, Studer W, Figueiredo V, Bircher AJ. Anaphylaxis to isosulfan blue and cross-reactivity to patent blue V: case report and review of the nomenclature of vital blue dyes. Ann Allergy Asthma Immunol. 2006;96(3):497–500. 18. Scherer K, Harr T, Bach S, Bircher AJ. The role of iodine in hypersensitivity reactions to radio contrast media. Clin Exp Allergy. 2010;40(3):468–75. 19. Gilgen-Anner Y, Heim M, Ledermann H-P, Bircher AJ. Iodide mumps after contrast media imaging: a rare adverse effect to iodine. Ann Allergy Asthma Immunol. 2007;99(1):93–8. 20. Brockow K. Dilemmas of allergy diagnosis in perioperative anaphylaxis. Allergy. 2014;69(1398–9995 (Electronic)):1265–6.

Muscle Relaxants

24

Paul Michel Mertes and Charles Tacquard

Key Points • Muscle relaxants are one of the main causes of perioperative anaphylaxis. • These reactions are still associated with a significant mortality with an estimated mortality rate of 4%, despite adequate resuscitation. • These reactions often occur just after anesthetic induction and involve skin, respiratory, and cardiovascular signs. The management of these reactions relies on the administration of intravenous epinephrine and vascular filling. • The primary mechanism of anaphylaxis of muscle relaxants is IgE-mediated, although both IgG-mediated and non-immune reactions are possible. • The allergy assessment relies on biological markers of mast cell and basophil activation, skin tests, specific IgE, and cellular assays.

24.1 Introduction Despite the rapid increase in allergic reactions due to antibiotics or to emerging allergens like dyes or chlorhexidine, immediate hypersensitivity reactions (IHR) to muscle relaxants (neuP. M. Mertes (*) · C. Tacquard Service d’anesthésie-réanimation chirurgicale, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg Cedex, France e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2022 A. J. Bircher et al. (eds.), Cutaneous Drug Hypersensitivity, https://doi.org/10.1007/978-3-030-82743-4_24

romuscular blocking agents, NMBAs) remain one of the leading causes of perioperative anaphylaxis. Fifty to sixty percent of these reactions are IgE-mediated. The incidence of perioperative IHR ranges from 1/1250 to 1/18,600 procedures depending on studies and countries. Among these reactions, NMBAs account for a variable share with significant differences observed between countries. In France, the incidence of allergic reactions to NMBAs is estimated at 184.0/million anesthetics (139.3– 229.7) with a higher risk for women (250.9/ million anesthetics). In the United Kingdom, Belgium, Spain, Australia, and New Zealand, NMBA-related allergic reactions are also reported with a high frequency, whereas they are less frequent in the United States, Sweden, and Denmark [1]. Several reports suggest that certain NMBAs such as suxamethonium and rocuronium seem to be associated with an increased risk of allergic reactions, while others like cis-atracurium exhibit a lower risk [2]. A recent study from the French pharmacovigilance database also described an increase in the incidence rate of IgE-mediated reactions to suxamethonium, rocuronium, and atracurium [3]. Mortality due to NMBAs is estimated at 4.1% in France and 4% in the United Kingdom despite an adequate resuscitation [4].

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24.2 Clinical Manifestations

24.2.3 Cardiovascular Signs

Symptoms of hypersensitivity reactions to NMBAs classically appear during or just after anesthesia induction, only a few minutes after drug injection. This short delay between drug exposure and the onset of the first clinical signs is related to the massive injection of antigens directly into the bloodstream. Recent series showed that immune-mediated IHR (IgE- or IgG-mediated) to NMBAs might be more severe than non-immune IHR with a high proportion of grade III reactions according to the Ring and Messmer classification.

Cardiovascular signs are frequently reported during NMBA-related IHR. They are responsible for the severity of the reaction. The most frequently reported signs are:

24.2.1 Skin Appearance of urticaria, diffuse cutaneous erythema, or mucosal edema following drug injection is a major argument in favor of an IHR. However, epidemiological studies on perioperative anaphylaxis showed that cutaneous signs are lacking in more than 50% of cases, especially when reactions are severe. Indeed, during severe shock skin perfusion is severely impaired, and cutaneous signs can only appear after resuscitation when the arterial pressure is restored.

24.2.2 Respiratory During NMBA-related IHR, patients are anesthetized and under mechanical ventilation. Therefore, subjective signs such as dyspnea cannot be expressed. Respiratory signs of IHR during anesthesia, depending on the reaction severity, include: –– Increased airway pressure, especially peak pressure due to bronchospasm. –– Difficulties to insufflate. Ventilation can be compromised in severe bronchospasm. –– Hypoxia with low oxygen saturation.

–– –– –– ––

Cardiovascular collapse Tachycardia Arrhythmia Bradycardia

In some cases, sudden cardiac arrest is the only sign of anaphylactic shock. During anesthesia, end-tidal CO2 (ETCO2) is systematically monitored and provides new information. A decrease of ETCO2 during anesthesia classically reflects a decrease in cardiac output. However, experimental data suggest that during anaphylactic shock, low ETCO2 might be due to a severe impairment of adaptive compartment perfusion (muscle, gastrointestinal tract, and skin) resulting in a low PaCO2. A low ETCO2 has recently been suggested as a marker of severity in anaphylaxis.

24.2.4 Other Signs Gastrointestinal signs are rare during perioperative anaphylaxis. Subjective signs cannot be reported due to anesthesia. Vomiting or diarrhea is rarely reported. Likewise, neurological signs are lacking because of the concomitant injection of hypnotics and opioids with NMBA.

24.3 Mechanisms NMBA-related IHR can occur through several immunological mechanisms. The reaction can be either immune-mediated or non-immune- mediated. The mechanism cannot be assumed based on the clinical signs. The allergic workup is therefore essential to identify the underlying mechanism and the culprit agent.

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a

b

CH3 O O

CH3 O

CH3

N

H3C

+

N

H3C HO

H2C

c

O H 3C

H3C

N+ CH3

O

O N+ O O

H3C O

O

CH3

O

O

H3C

N+

O

CH3

CH3

CH3

CH3

O O

O N+

O

H3C

CH3

O H 3C

O

CH3

Fig. 24.1 Chemical structure of the main neuromuscular blocking agents used in clinical practice. (a) Rocuronium (non-depolarizing steroidal relaxants). (b) Cis-atracurium

(non-depolarizing benzylisoquinolinium relaxant). (c) Suxamethonium (depolarizing relaxant)

24.3.1 Immediate Immune-Mediated Hypersensitivity Reactions

patients showed a T-cell proliferative response, indicating that dendritic cells have the capacity to present NMBA-related epitopes that are recognized by T cells [5]. Structure-activity studies established that quaternary and tertiary ammonium ions are part of the complementary allergenic sites on NMBAs (Fig. 24.1). Two substituted ammonium ions are found in every NMBA which explains the cross- reactivity between different NMBAs observed with skin testing and IgE antibodies in most patients.

24.3.1.1 IgE Pathway The first reported mechanism was a Type I reaction from the Gell and Coombs classification involving IgE-dependent activation of basophils and mast cells. When activated, these cells massively release preformed or produced pharmacologically active mediators (histamine, tryptase, platelet-activating factor) which are responsible for clinical symptoms. The mechanism of sensitization to NMBA is still debated. According to the classical immunological dogma, low molecular weight products such as NMBAs require conjugation of the native drug or its degradation product with a carrier protein in order to induce production of specific antibodies. However, NMBAs exhibit very low protein binding. Alternative mechanisms have been suggested, such as a possible direct interaction in a covalent or non-covalent manner with the major-histocompatibility-complex (MHC)peptide complex on the surface of dendritic cells as proposed in the case of delayed reactions. Experiments conducted on NMBA-pulsed monocyte- derived dendritic cells from allergic

24.3.1.2 O rigin of NMBA-Specific IgE Antibodies and Influence of Environmental Factors A substantial proportion of patients allergic to NMBAs have never been previously exposed to NMBAs. These observations prompted a search for environmental factors that could play a role in cross-sensitizing patients. Tertiary and quaternary ammonium groups are found in a large variety of substances such as cosmetics and disinfectants. An epidemiological study comparing hairdressers and backers showed that hairdressers had a 4.6-fold higher frequency of positive specific IgE against quaternary ammo-

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nium, demonstrating increased sensitization over time in subjects with professional exposure to cosmetics. However, the clinical significance of this sensitization still needs to be demonstrated. Another possible sensitizing agent is pholcodine, an opioid antitussive agent (with a morpholino side chain) containing a quaternary ammonium epitope. Its use varies between countries, and some reports suggest that a relation may exist between pholcodine consumption in the general population and the rate of sensitization against substituted ammonium ions. These observations together with the high rate of sensitization against quaternary ammonium and hypersensitivity reactions observed in Norway, a country where pholcodine was widely used, when compared with the low rate of sensitization and reactions reported in Sweden, a country where pholcodine has long been withdrawn from the market, led Scandinavian authors to formulate the “pholcodine hypothesis.” This hypothesis suggests that a high consumption of pholcodine could induce IgE sensitization to quaternary ammonium resulting in an increased frequency of IgE-mediated NMBA-induced anaphylaxis. The decrease in the incidence of NMBA-related allergic reactions following pholcodine withdrawal in Norway reinforced this hypothesis. Pholcodine is still available in several European countries, and a prospective case-control study (ALPHO) has been conducted in France since 2014 in order to investigate the link between pholcodine exposure and NMBA sensitization [6].

24.3.1.3 IgG Pathway More recently, another pathway of immediate immune-mediated hypersensitivity reactions through IgG sensitization has been proposed. The reaction could result from bonding between the IgG-antigen complex and FcγR receptors (mainly FcγRIIA). Such reactions could require a higher amount of antigen and antibodies to be clinically relevant. This mechanism may involve basophils and macrophages but also neutrophils. It is suggested that IgG-mediated reactions could be involved in up to 20% of all perioperative IHR.

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24.3.1.4 Delayed Immune-Mediated Hypersensitivity Reactions These reactions are very rare with NMBAs, and only a few cases of delayed allergic reactions to NMBA have been reported. In 2002, Pichler et al. described a delayed hypersensitivity to suxamethonium, driven by an oligoclonal T helper cell 1-skewed CD4+ memory T-cell population, expressing the skin homing receptors CLA and CCR4. This is the first report of NMBA-specific TCL.

24.3.2 Non-immune-Mediated Hypersensitivity Reactions These reactions account for 20 to 40% of all perioperative hypersensitivity reactions according to countries and series. Among all possible pathways for non-immune IHR, different mechanisms have been described: –– Direct non-specific histamine release. This would concern atracurium and mivacurium in particular. –– Activation of the complement system. –– Activation of the contact phase (Factor XII). –– Cross-reactions with extra-neuromuscular nicotinic or muscarinic receptors which are responsible for a peripheral autonomic and ganglionic effect. All NMBAs can trigger these reactions although to a highly variable extent which may not be seen at clinical doses. –– Direct mast cell activation through the MRGPRX2 receptor. NMBAs were recently shown to directly activate mast cells through this receptor, inducing release of mast cell mediators. This receptor represents a new therapeutic target for NMBA-related anaphylaxis.

24.4 Diagnostic Methods Avoiding re-exposure to the culprit agent during a subsequent anesthesia is essential. Since the mechanism of the reaction cannot be clinically deduced, subsequent investigations are primarily aimed at identifying allergic IgE-mediated reac-

24 Muscle Relaxants

tions for which there is an identifiable culprit agent and a risk of recurrence on re-exposure. The patient must be referred for an allergy evaluation in order to establish a safe anesthesia protocol.

24.4.1 Tryptase and Histamine Measurement The diagnosis of perioperative hypersensitivity reaction relies on clinical symptoms with a concordant timeline and increased plasma level of mediators secreted by mast cells and basophils (histamine or tryptase). Tryptase is mainly released by activated mast cells. With a plasma half-life of 90–120 min, the optimal timing for blood sampling is around 30 min to 2 h after the reaction. The plasma concentration of tryptase is correlated with the severity of the reaction and may be normal in low-grade reactions. The standard threshold to support the diagnosis of a perioperative IgE-mediated reaction is set at 25 μg/L although recent studies suggest that this threshold could be lowered. The most recent guidelines note that an increase of more than 2 + 1.2 × basal tryptase is clinically relevant. During unexplained cardiac arrest, a tryptase level higher than 7.35 μg/L is considered a strong argument in favor of an allergic reaction with good sensitivity and specificity [7]. Histamine is released by activated basophils and mast cells. Due to its short half-life, the histamine peak concentration occurs a few minutes after allergen exposure. Histamine should thus be sampled as soon as possible, and blood samples should be cooled immediately to 4 °C to avoid false positives. Not all guidelines recommend measurement of histamine plasma levels due to the complexity of this analysis. However, it can still be useful, especially in mild to moderate reactions or when blood is sampled early after the reaction. Pregnancy and the use of a high dose of heparin are associated with false negatives. In these situations, histamine measurement is not relevant.

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24.4.2 Skin Tests Skin tests are the gold standard to investigate perioperative IHR in order to identify the culprit agent. The results must be interpreted in light of the detailed clinical data provided by the attending anesthesiologist with the exact timing of drug administration and the reaction. Copies of the anesthesia record and blood sample results are helpful. These tests should be performed at least 4–6 weeks after the reaction. Indeed, because of the post-reaction refractory period, the risk of a false-negative result is high before 4 weeks, and only positive tests can be considered. A second delayed assessment should be performed when the first assessment was performed before 4 weeks. Skin tests should be performed in specialized facilities with trained physicians and following specific protocols. Resuscitation equipment must be available and the staff must be trained to use it. The patient must give informed consent to these tests. Table 24.1 shows recommended concentrations for skin prick tests and intradermal tests with their positivity criteria. Skin tests must be accompanied by a positive control test (with codeine) and a negative control test (saline) to determine the ability of patient’s skin to react to histamine. Cross-sensitization is common between NMBAs: in the last French epidemiological survey on perioperative anaphylaxis, 48.9% of patients allergic to one NMBA were sensitized to at least one other NMBA [2]. Only 4.3% of them were sensitized to all NMBAs, making the investigation of cross-sensitization crucial for further anesthesia. In case of NMBA-related allergic reactions, every available NMBA must be tested. In a recent study, Chiriac et al. reported a negative predictive value of 96% (95% CI 88.3– 99.9%) for skin tests to NMBA. In their series of 92 patients allergic to at least one NMBA and having experienced a subsequent anesthesia, only one patient experienced a new reaction to an NMBA [8]. The allergic assessment is therefore a reliable way to establish which NMBA could be used for further anesthesia.

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Table 24.1 Maximal concentration normally non-reactive and positivity criteria for SPT and IDT [9] NMBAs Conc (mg/mL) Atracurium 10 Cis-atracurium 2 Mivacurium 2 Rocuronium 10 Suxamethonium 50 Vecuronium 4

Dilution fluid NaCl 0.9% NaCl 0.9% NaCl 0.9% NaCl 0.9% NaCl 0.9% Water for injection

Stability 8 h 24 h 24 h 24 h – 24 h

SPT Dilution 1/10 Undiluted 1/10 Undiluted 1/5 Undiluted

Cmax (mg/mL) 1 2 0.2 10 10 4

IDT Dilution 1/1000 1/100 1/1000 1/200 1/500 1/10

Cmax (μg/L) 10 20 2 50 100 400

Positive SPT: Wheal diameter at least 3 mm greater than that of the negative control or at least half that of the positive control 20 min after injection Positive IDT: Wheal-and-flare response with a wheal diameter at least twice that of the injection wheal 20 min after injection NMBAs neuromuscular blocking agents, SPT skin prick tests, IDT intradermal tests

24.4.3 Specific IgE Assays Specific IgE assays cannot be used to predict anaphylaxis because quaternary ammonium-specific antibodies are found in 3 to 10% of the general population with no previous history of anesthesia, thus limiting the positive predictive value in the general population. However, quaternary ammonium-specific IgE assays can be of interest to diagnose IgE-mediated reaction to NMBAs, in combination with skin tests or in patients with dermographism, extensive atopic skin lesions, or non-reactive skin where skin tests are uninterpretable. Measurements can be performed either during the reaction or during the allergy workup. Several techniques are available: the quaternary ammonium-specific (QAS) test and P-aminophenylphosphorylcholine radioimmunoassay (PAPPC-RIA) are the most sensitive (around 80%) but are not commercially available, and comparison between laboratories is difficult. A commercial test (ImmunoCAP C260) is available worldwide and approximates the results of QAS and PAPPC-RIA but is less specific.

24.4.4 Cellular Tests Cellular assays can be helpful when the clinical history is significant and skin tests are negative or uninterpretable. They can be used in particular to assess cross-reactivity in order to define which NMBA to use during further anesthesia. The basophil activation test (BAT) is gaining popular-

ity, whereas leukotriene or histamine release tests have been progressively abandoned due to their lack of reproducibility. The appearance or upregulation of activation/degranulation markers (CD203c, CD63) on the surface of basophils after antigen exposure is monitored by flow cytometry. BAT can be used either to identify the culprit agent or to assess cross-sensitivity between NMBAs. BAT using unstandardized allergens should be performed in experienced laboratories. Indeed, non-responders or potential cytotoxicity of the drug may give rise to false- negative and/or false-positive results.

24.4.5 Provocation Tests NMBAs cause paralysis of all muscles, including respiratory muscles. Therefore, a challenge test with NMBA is associated with a high risk of respiratory complications. NMBA challenge has been tested for research at infra-clinical doses, but these results should be interpreted with caution because of the possible risk of false negatives due to an insufficient dose.

24.5 Management of NMBA- Related Hypersensitivity Reactions The management of perioperative immediate hypersensitivity reactions differs slightly from other clinical situations because patients are

24 Muscle Relaxants Table 24.2 Doses of epinephrine according to the severity grade Severity grade Grade I Grade II Grade III Grade IV

Epinephrine doses – 10–20 μg every 1–2 min 100–200 μg every 1–2 min 1–2 mg every 1–2 min

already fully monitored, with a venous access and, in most cases, intubation. Anesthesiologists are trained to recognize and treat these reactions. The treatment is well codified and should be adapted to symptoms, reaction severity, and comorbidities. The goal of treatment is to restore suitable vital functions and avoid complications. The standard treatment of perioperative immediate hypersensitivity reactions is well codified [9]:

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–– Methylene blue (1.5–3 mg/kg) intravenously over 15 min has been suggested in patients with persistent hemodynamic instability despite adequate treatment by epinephrine. –– Extracorporeal life support has been successfully used in isolated cases of anaphylactic shock. However, there is currently no strong evidence in favor of its beneficial effect. This technique should therefore be reserved for situations where professional skills and equipment are immediately available.

Sugammadex is a γ-dextrin designed to selectively bind steroidal NMBAs (vecuronium and rocuronium), allowing rapid reversal of the neuromuscular blockade. By encapsulating rocuronium, sugammadex has been suggested as a possible treatment for rocuronium-induced anaphylaxis, –– All suspected agents must be withdrawn. A and several case reports described significant new injection of the suspected NMBA or improvement of clinical signs of anaphylaxis after another one, even from a different pharmaco- the use of sugammadex. However, other case logical class, is strictly forbidden until allergic series showed a lack of effect. assessment. The use of sugammadex in rocuronium-induced –– Aggressive fluid resuscitation using anaphylaxis is controversial, and several reports 20–30 mL/kg of crystalloids as fast as possi- cast doubt on its efficacy. First, molecular models ble, relayed if necessary by colloids (if they showed that despite encapsulation, the determiare not suspected to be responsible for the nants of hypersensitivity may remain accessible to reaction). Fluid management should be binding with specific IgE. Moreover, in flow adapted to the hemodynamic response. cytometry, sugammadex was unable to prevent –– Epinephrine is the main treatment for anaphy- basophil activation when it was added after basolaxis. Doses of epinephrine should be adapted phil activation with rocuronium. Some cases even to the severity to reduce the risk of epinephrine- reported a worsening of clinical signs after sugamrelated complications (arrhythmia, myocardial madex. Indeed, several confirmed cases of allergic infarction, or stress cardiomyopathy). The reactions to clinical doses of sugammadex have intravenous route should be preferred due to the recently been reported. The incidence of sugammahigh frequency of available intravenous access. dex-induced anaphylactic reactions in Japan was Recommended doses of epinephrine according estimated at about 29 per million uses [10]. to severity grade are represented in Table 24.2. If the use of sugammadex is considered, it should only be used as a rescue treatment when However, the existence of refractory cases to all other treatments have failed. The benefit/risk epinephrine and other specific situations have led ratio remains to be evaluated. to the proposal of new therapeutic measures: –– For patients on ß-blockers, the dose of epinephrine should be increased. If not sufficient, glucagon can be administered 1–2 mg intravenously every 5 min followed by a continuous infusion at 5–15 μg/min if necessary.

24.6 Conclusion IHR to NMBA is rare in anesthesia but is still associated with significant morbidity and mortality. A prompt recognition of clinical

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signs is essential to initiate the appropriate treatment as soon as possible. A thorough allergy assessment is mandatory to identify the culprit agent. Close collaboration between anesthetists and allergists is necessary to establish a safe anesthesia protocol for further anesthesia.

References 1. Mertes PM, Volcheck GW, Garvey LH, et al. Epidemiology of perioperative anaphylaxis. Presse Med. 2016;45(9):758–67. 2. Tacquard C, Collange O, Gomis P, et al. Anaesthetic hypersensitivity reactions in France between 2011 and 2012: the 10th GERAP epidemiologic survey. Acta Anaesthesiol Scand. 2017;61(3):290–9. 3. Petitpain N, Argoullon L, Masmoudi K, et al. Neuromuscular blocking agents induced anaphylaxis: results and trends of a French Pharmacovigilance survey from 2000 to 2012. Allergy. 2018;73(11):2224–33.

P. M. Mertes and C. Tacquard 4. Kemp HI, Cook TM, Thomas M, et al. UK anaesthetists’ perspectives and experiences of severe perioperative anaphylaxis: NAP6 baseline survey. Br J Anaesth. 2017;119(1):132–9. 5. Pichler WJ, Hausmann O. Classification of drug hypersensitivity into allergic, p-i, and pseudo-allergic forms. Int Arch Allergy Immunol. 2016;171(3–4):166–79. 6. Florvaag E, Johansson SG. The pholcodine story. Immunol Allergy Clin North Am. 2009;29(3):419–27. 7. Reitter M, Petitpain N, Latarche C, et al. Fatal anaphylaxis with neuromuscular blocking agents: a risk factor and management analysis. Allergy. 2014;69(7):954–9. 8. Chiriac AM, Tacquard C, Fadhel NB, et al. Safety of subsequent general anaesthesia in patients allergic to neuromuscular blocking agents: value of allergy skin testing. Br J Anaesth. 2018;120(6):1437–40. 9. Mertes PM, Malinovsky JM, Jouffroy L, et al. Reducing the risk of anaphylaxis during anesthesia: 2011 updated guidelines for clinical practice. J Investig Allergol Clin Immunol. 2011;21(6):442–53. 10. Takazawa T, Mitsuhata H, Mertes PM. Sugammadex and rocuronium-induced anaphylaxis. J Anesth. 2015;30(2):290–7.

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Anticoagulants Kathrin Scherer Hofmeier

25.1 Introduction Anticoagulants and antithrombotic drugs belong to the most frequently prescribed drugs overall. They inhibit coagulation by various different mechanisms [1], interacting with the coagulation cascade, platelet function, or the fibrinolytic system. In a more narrow sense, anticoagulants prevent or reduce the plasmatic coagulation of blood by prolonging the clotting time. Based on their mode of action, the following groups of anticoagulants and platelet inhibitors are distinguished: • Indirect anticoagulants without direct effect on the plasmatic coagulation system: –– Vitamin K antagonists/coumarins –– Heparins and derivatives Unfractionated heparin/high molecular weight heparin (HMWH) K. Scherer Hofmeier (*) Dermatology and Allergology Cantonal Hospital Aarau and Medical Faculty, University of Basel, Basel, Switzerland e-mail: [email protected]

© Springer Nature Switzerland AG 2022 A. J. Bircher et al. (eds.), Cutaneous Drug Hypersensitivity, https://doi.org/10.1007/978-3-030-82743-4_25

•

• • •

Fractionated heparin/low molecular weight heparin (LMWH) Synthetic pentasaccharide inhibitors of factor Xa Heparinoids Directly acting oral anticoagulants (DOACs) –– Direct factor Xa inhibitors –– Direct factor IIa inhibitors/thrombin inhibitors Antithrombin Thrombolytic and fibrinolytic drugs Antiplatelet drugs –– Cyclooxygenase inhibitors –– P2Y12 inhibitors –– Glycoprotein (GP) IIb-IIIa receptor antagonists –– Phosphodiesterase III inhibitors and dipyridamole

Hypersensitivity to anticoagulants and platelet inhibitors mostly follows the Coombs and Gell classification (types I–IV), depending on the components of the adaptive immune system involved. Apart from those immunologically mediated hypersensitivity reactions, there are non- immunologically mediated intolerance reactions.

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25.2 Indirect Anticoagulants Without Direct Effect on the Plasmatic Coagulation System 25.2.1 Vitamin K Antagonists/ Coumarins Hypersensitivity reactions to coumarin derivatives (warfarin, acenocoumarol, phenprocoumon) are overall very rare. They include the coumarin necrosis, purple toe syndrome, as well as maculopapular, urticarial, or vesicular exanthems and DRESS (drug rash with eosinophilia and systemic symptoms) syndrome [2, 3]. For the latter reactions, hypersensitivity reactions type I (IgE) or type IV (T cells) have been suggested, although not yet proven. The prevalence of coumarin necrosis is between 0.01 and 0.1%. It is most frequent in adipose women, with breast, thighs, and buttocks as predilection sites. Lesions are initially erythematous and partly hemorrhagic and may develop into bullous, widespread dark blue areas, or ecchymosis, which are usually painful. Coumarin necrosis is thought to be caused by an imbalance between proteins C/S, which have a relatively short half-life of 6–8 h, and the pro-coagulative proteins, factors II, IX, and X, which, due to their longer half-life, may cause a hypercoagulative state [4]. It usually manifests within the first days after the start of the therapy, but has been observed during maintenance therapy and even several days after the end of therapy [5, 6]. Another very rare complication is purple toe syndrome, a bilateral purple discoloration on toes and fingers. The skin is intact and cool upon palpation. The mechanism is unclear, but some authors suggest coumarin-promoted cholesterol crystal embolization as a potential cause [7].

25.2.2 Heparins and Derivatives Heparins are a group of highly sulfated polysaccharides belonging to the glycosaminoglycan family. They include unfractionated heparin (UFH), low molecular weight heparins (LMWH), penta-

K. Scherer Hofmeier

saccharides (ultra-low molecular weight heparins), and heparinoids. Depolymerization of UFH results in LMWH, which is approximately 30% of the size of the native molecule. LMWH have better pharmacokinetic characteristics and fewer side effects than UFH. Pentasaccharides are synthetically produced and selectively inhibit factor Xa [6]. Although heparins are widely prescribed, allergic reactions are relatively rare. There is evidence for all types of hypersensitivity reactions, most commonly type IV reactions and type II reactions, very rarely also type I and type III reactions.

25.2.2.1 Cell-Mediated, Delayed-Type Hypersensitivity (DTH) to Heparins Pruritic, erythematous, infiltrated plaques are typical at the injection site of LMWH or UFH, rarely after a pentasaccharide or heparinoid, accompanied occasionally by vesicles or bullae [8]. If therapy is continued, evolution into a generalized exanthema is possible. After i.v. administration of UFH, maculopapular exanthems and recall phenomena at the site of prior local reactions after subcutaneous injections may develop. Differential diagnosis of the localized erythematous plaques includes hematoma, infectious complications, and contact dermatitis [1]. Contact dermatitis to topically applied heparin gels is possible [9]. There is a striking female predominance. Hormonal factors, longer persistence of heparins in the subcutaneous fat, or a relationship to lipase activity of heparins have been proposed as cause [10]. Generalized exanthems are rare, but can present as maculopapular or bullous exanthems, toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and symmetrical drug related intertriginous flexural exanthem (SDRIFE) [11–13]. Intradermal tests with late reading and less so patch tests seem to be sensitive diagnostic tests. Weberschock et al. [14] showed that in patients with a known type IV sensitization to LMWH, the risk of a cross-reaction to other heparins was very high (92.9%). They reported a probability of 67.1% for cross-reactivity to UFH. The lowest frequency of cross-reactions was observed for

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pentosan polysulfate (36.4%) and fondaparinux (10.4%). Fondaparinux is therefore recommended as the current best alternative in cases of DTH reactions to either UFH or LMWH.

25.2.2.2 Immediate-Type Hypersensitivity to Heparins Immediate-type hypersensitivity (ITH) reactions (type I) are very rare, and only few well- documented cases have been published [15, 16]. Positive skin tests to the causative LMWH, which appear to have a rather high sensitivity, suggest an IgE-mediated mechanism. An epidemic of anaphylactic reactions to heparins in 2008 could be related to oversulfated heparin molecules triggering activation of the contact system [17]. As in delayed-type hypersensitivity, there is extensive cross-reactivity among LMWH, but most patients can tolerate fondaparinux and some UFH [16].

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not affected. Complement activation, signs of systemic inflammation, or deposition of immunoglobulins is not found, but eosinophilia is present in approx. 13% [22]. Some patients seem to improve despite continuation of LMWH [23].

25.2.2.4 Heparinoids Danaparoid is a LMWH product that contains a mixture of glycosaminoglycans with an average weight of 6 kD, mainly heparan sulfate (84%), dermatan sulfate (12%), and chondroitin sulfate (4%), and inhibits factor Xa via antithrombin (AT) and thrombin via both AT and heparin cofactor II. It has low potential for cross-reactivity with heparin-induced antiplatelet antibodies due to its low degree of sulfation and absence of heparin. It is therefore a useful alternative in patients with HIT. However, in a retrospective literature study by Lindhoff-Last et al. [24] on 51 pregnant women with coagulation disorders and heparin 25.2.2.3 Heparin-Induced intolerance (among them 32 HIT patients), 5 Thrombocytopenia (HIT) patients developed new platelet count reductions A dreaded complication is HIT, induced by IgG under alternative treatment with danaparoid, one antibody formation against complexes of heparin of which was proven to be due to danaparoid and and platelet factor 4. The resulting IgG- cross-reactivity of preexisting heparin antibodheparin- PF4 complexes are prothrombotic by ies. In the other three cases, cross-reactivity could causing platelet activation, thrombin generation, not definitely be excluded. Cross-reactivity can and endothelial injury [15, 18]. Platelet levels occasionally be seen in non-HIT skin eruptions decrease by consumption and can be used as in heparin allergic patients. diagnostic indicator. HIT should be considered if the platelet count drops by 50% in the first 4–10 days of therapy in relation to the baseline 25.3 Directly Acting Oral value or below 100 G/L [19]. It occurs in approx. Anticoagulants (DOACs) 1–4% of patients treated with UFH [20]. Some patients additionally develop heparin-induced The terms non-vitamin K-antagonist or novel skin necrosis, which is clinically similar to cou- oral anticoagulants (NOACs) are used synonymarin necrosis and occurs at or distal from the mously. They include thrombin inhibitors and injection site. This situation may be complicated factor Xa inhibitors. Hypersensitivity reactions to by systemic involvement, thrombocytopenia, and DOACs are rare, especially regarding the frethromboembolism. quent use of these drugs. The same antigen-antibody complexes are likely also responsible for rare cases of leukocytoclastic vasculitis [21]. Another rare, maybe 25.3.1 Direct Factor Xa Inhibitors underdiagnosed complication is bullous hemorrhagic dermatosis where very superficial, tense, Direct inhibitors of factor Xa (e.g., rivaroxaban, hemorrhagic blisters without surrounding inflam- apixaban, edoxaban) inhibit the active site and/or mation appear independently from the injection the substrate binding sites of factor Xa and thus site of the LMWH. Deeper layers of the skin are have an anticoagulatory effect. Hypersensitivity

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occurs in approx. 0.1–1% according to the package insert (accessed 08/2020). Carli et al. identified 29 cases of hypersensitivity to NOAC in the literature since 2008, 21/29 caused by direct factor Xa inhibitors [25]. Rivaroxaban was responsible for most reactions, probably reflecting prescription practice and availability. ITH is reported only once (urticaria, angioedema, and bronchospasm) [26]. Three cases of rivaroxaban- induced thrombocytopenia [27–29] and slightly more type III reactions (leukocytoclastic vasculitis, serum sickness disease, IgA nephropathy) [30–36] were found. DTH seems to be more frequent with various clinical presentations having been reported: DRESS [37–40], maculopapular exanthem [41, 42], bullous pemphigoid-like skin eruption [43], bullous drug reaction [44], exfoliative drug reaction [34], and an AGEP-like eruption [45]. Hepatotoxicity in the sense of drug-induced liver injury (DILI) is described repeatedly [39, 46], although the general risk for DILI seems not to be elevated [47].

25.3.2 Direct Factor IIa Inhibitors/ Thrombin Inhibitors Dabigatran is a specific, reversible direct thrombin inhibitor. Being a prodrug (dabigatran etexilate), it needs to be transformed into the active form by esterases. In the RE-LY Study (randomized evaluation of long-term anticoagulation therapy), drug hypersensitivity, allergic edema, and anaphylactic reactions were reported in less than 0.1% [48]. Hypersensitivity reactions are rare, mainly maculopapular exanthems [49–52], leukocytoclastic vasculitis [36, 53, 54], and a single case of possible but unproven TEN [55]. Allergy testing has not been done as a rule. Argatroban is another synthetic, reversible thrombin inhibitor for patients with heparin allergy and HIT. In the package leaflet, exanthems, dyspnea, and cough are listed as signs for potential hypersensitivity, but no further reports are available and the reported symptoms are not clearly linked to argatroban.

Bivalirudin, lepirudin, and desirudin (recombinant hirudin preparations) are bivalent thrombin inhibitors. Type IV sensitization to hirudin [56], eczema, and maculopapular exanthems has been reported in up to 4% of patients [13]. Despite the fact of frequent induction of IgE antibodies, type I allergy occurs in less than 1% [57]. There is a single case report of a possible bivalirudin-induced anaphylaxis complicated by fatal acute stent thrombosis, without further allergy workup [58]. IgG-mediated urticaria was demonstrated after repeated application of recombinant hirudin [59].

25.4 Antiplatelet Drugs 25.4.1 Cyclooxygenase Inhibitors Side effects of COX-1 inhibitors are being discussed elsewhere in this book.

25.4.2 P2Y12 Inhibitors/ Thienopyridines Clopidogrel, ticlopidine, prasugrel, ticagrelor, and cangrelor are P2Y12 receptor antagonists, thereby inhibiting platelet activation. Hypersensitivity to clopidogrel occurs in 2–6% of patients [60, 61] and typically presents either as type IV reaction, mainly generalized or localized maculopapular exanthems, or less commonly as urticaria without angioedema [62–64], usually starting 5–10 days after initiating the drug [61]. Other cutaneous presentations include fixed drug eruption [65], pustular psoriasis [66], leukocytoclastic vasculitis [67, 68], and AGEP [69–71]. Sporadic cases are reported of Stevens- Johnson syndrome [72], aplastic anemia [73, 74], isolated neutro- and thrombocytopenia [75–78], thrombocytopenic thrombotic purpura [79], serum sickness-like reaction [80], and acute polyarthritis [81–83]. Hematologic reactions to clopidogrel have been reported less frequently than to other thienopyridine drugs [84]. In case of

25 Anticoagulants

cutaneous immediate- or delayed-type hypersensitivity, desensitization has been frequently successful, but requires interruption of therapy [85, 86]. Another option, successful in >88%, is treating with corticosteroids and antihistamines as temporary additional therapy [62, 87]. In those failing those procedures, prasugrel or ticlopidine has been successfully given, although cross- reactivity is found in close to 20% [88]. Cheema et al. [62] identified cross-reactivity to prasugrel in delayed-type hypersensitivity by means of patch testing in 7/42 clopidogrel-sensitized patients (17%), to ticlopidine in 10/42 (24%), and to both ticlopidine and prasugrel in 3/42 (7%). This is similar to other reports on cross- reactivity between clopidogrel and ticlopidine, which found clinical cross-reactivity with ticlopidine in 27% of patients with an allergic or hematologic adverse reaction to clopidogrel. The most common reaction was a rash (93%). Cross- reactivity with clopidogrel in patients who first received ticlopidine was 37% [89, 90]. In the study by Cheema [62], patch tests were positive in 81% of patients with suspected delayed-type clopidogrel hypersensitivity.

25.4.3 Glycoprotein (GP) IIb-IIIa Receptor Antagonists Abciximab, tirofiban, and eptifibatide directly and reversibly inhibit the binding of von Willebrand factor or fibrinogen binding to the activated GP IIb/IIIa receptor, thus inhibiting thrombus formation. Abciximab is the Fab fragment of a chimeric monoclonal antibody against the GP IIb-IIIa receptor. Tirofiban and Eptifibatide are short-acting, synthetic low molecular weight GP IIb-IIIa receptor antagonists. Four percent of patients receiving abciximab for the second time will develop severe thrombocytopenia [91], while others less frequently after an average of six to nine treatments. The most likely reason is IgG or IgM against the murine component of the Fab fragment of abciximab. For reasons not yet understood, between 0.5% and 1% of patients

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develop severe thrombocytopenia after the very first dose. Also, several allergic immediate-type reactions up to grade IV anaphylaxis [92–94] with positive intradermal tests, sometimes with following thrombocytopenia, have been seen. In another case and also in the cases of Iakouvou [94] and Guzzo [93], IgG-mediated anaphylaxis cannot be ruled out. In a case of Moneret-Vautrin [95], 70% activated, mainly CD8+ T cells have been found in a patient with facial swelling, thrombocytopenia, and eosinophilia. Eptifibatide and tirofiban can also cause remarkable thrombocytopenia, but only very rarely type I hypersensitivity. Tirofiban may trigger thrombocytopenia after first administration similar to abciximab [1].

25.4.4 Phosphodiesterase III Inhibitors Dipyridamole and cilostazol block phosphodiesterases, thereby accumulating cGMP and cAMP intracellularly which inhibits platelet aggregation. Few hypersensitivity reactions are known. DRESS (drug rash with eosinophilia and systemic symptoms) syndrome was observed under therapy with cilostazol and carbamazepine, which healed after discontinuation and was reproduced by provocation tests with both individual substances at 4-week intervals. Since cilostazol and carbamazepine are not structurally related, a cross-reaction is not to be assumed, but rather “multiple drug hypersensitivity” [96]. The same medication plus omeprazole triggered fatal toxic epidermal necrolysis in a 78-year-old patient [97]. A number of immediate-type symptoms have been reported under therapy with dipyridamole. Since dipyridamole is marketed in fixed combination with acetylsalicylic acid, it remains unclear whether these side effects are caused by dipyridamole or more likely the other component. Salava et al. report a generalized exanthem under treatment with dipyridamole and a proof of type IV sensitization by patch test [98]. Dipyridamole has likely caused Stevens-Johnson syndrome in one patient from Taiwan [99].

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25.5 Summary

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Eur due to rivaroxaban: a rare adverse effect. Transfus J Case Rep Intern Med. 2018;5(3):000724. Apher Sci. 2020;22:102883. 44. Vernon HM, Nielsen AK, O’Bryan 28. Mima Y, Sangatsuda Y, Yasaka M, Wakugawa Y, EC. Hypersensitivity reaction after administraNagata S, Okada Y. Acute thrombocytopenia after inition of rivaroxaban (Xarelto). Am J Emerg Med. tiating anticoagulation with rivaroxaban. Intern Med. 2016;34(7):1325.e1–2. 2014;53(21):2523–7. 45. Yates J, Choudhry M, Keys G. A case report 29. Pop MK, Farokhi F, Iduna L. Drug-induced thrombo- describing a suspected rivaroxaban hypersensitivcytopenia after anticoagulation with rivaroxaban. Am ity reaction in a surgical patient. J Clin Pharm Ther. J Emerg Med. 2018;36(3):531.e1–2. 2013;38(2):159–61. 30. Sainz-Gaspar L, Pita da Veiga G, Suárez- Peñaranda JM, Vázquez-Veiga H, Sánchez-Aguilar 46. Licata A, Puccia F, Lombardo V, Serruto A, Minissale MG, Morreale I, Giannitrapani L, Soresi M, Montalto D. 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230 Leukocytoclastic Vasculitis. Case Rep Med. 2015;2015:616109. 55. Tsoumpris A, Tzimas T, Gkabrelas K, Akritidis N. Iron complex, dabigatran and toxic epidermal necrolysis syndrome: a case-report. J Clin Pharm Ther. 2013;38(2):177–8. 56. Zollner TM, Gall H, Völpel H, Kaufmann R. Type IV allergy to natural hirudin confirmed by in vitro stimulation with recombinant hirudin. Contact Dermatitis. 1996;35(1):59–60. 57. Close P, Bichler J, Kerry R, Ekman S, Bueller HR, Kienast J, Marbet GA, Schramm W, Verstraete M. Weak allergenicity of recombinant hirudin CGP 39393 (REVASC) in immunocompetent volunteers. The European Hirudin in Thrombosis Group (HIT Group). Coron Artery Dis. 1994;5(11):943–9. 58. Despotopoulos S, Roumeliotis A, Kounis NG, Tsigkas G, Hahalis G, Davlouros P. Severe allergic reaction during angioplasty culminating to fatal acute stent thrombosis: an association with Kounis syndrome. Heart Lung. 2019;48(2):138–40. https://doi. org/10.1016/j.hrtlng.2018.07.015. 59. Bircher AJ, Czendlik CH, Messmer SL, Müller P, Howald H. Acute urticaria caused by subcutaneous recombinant hirudin: evidence for an IgG-mediated hypersensitivity reaction. J Allergy Clin Immunol. 1996;98(5 Pt 1):994–6. 60. CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329–39. 61. Campbell KL, Cohn JR, Savage MP. Clopidogrel hypersensitivity: clinical challenges and options for management. Exp Rev Clin Pharmacol. 2010;3: 553–61. 62. Cheema AN, Mohammad A, Hong T, Jakubovic HR, Parmar GS, Sharieff W, Garvey MB, Kutryk MJB, Fam NP, Graham JJ, Chisholm RJ. Characterization of clopidogrel hypersensitivity reactions and management with oral steroids without clopidogrel discontinuation. J Am Coll Cardiol. 2011;58:1445–54. 63. Doshi R, Enoh A, Antonopoulos P, Sattar P. A novel, accelerated method of desensitization in a patient with a documented hypersensitivity reaction to clopidogrel. J Cardiol Cases. 2010;1(3):158–60. 64. Chopra P, Prashant V, Klaustermeyer WB. Successful use of prasugrel, an alternative antiplatelet agent, in a patient with clopidogrel allergy. Ann Allergy Asthma Immunol. 2011;107(6):541–2. 65. Ghosh SK, Bandyopadhyay D. Clopidogrel-induced fixed drug eruption. J Eur Acad Dermatol Venereol. 2009;23(10):1202–3. 66. Meissner M, Beier C, Wolter M, Kaufmann R, Gille J. Suberythrodermic pustular psoriasis induced by clopidogrel. Br J Dermatol. 2006;155(3):630. 67. Shetty RK, Madken M, Naha K, Vivek G. Leucocytoclastic vasculitis as a late complication of clopidogrel therapy. BMJ Case Rep. 2013;2013:bcr2012007861.

K. Scherer Hofmeier 68. Erpolat S, Nazli Y, Colak N, Yenidunya S. Leukocytoclastic vasculitis associated with clopidogrel. Cutan Ocul Toxicol. 2012;31(2):171–3. 69. Ulman CA, Palmer DG, Trevino JJ, Olsen TG, Krishnamurthy S, Gandhi RK. Acute generalized exanthematous pustulosis induced by clopidogrel. Int J Dermatol. 2014;53(10):461–2. 70. Ellerbroek JC, Cleveland MG. Clopidogrel-associated acute generalized exanthematous pustulosis. Cutis. 2011;87:181–5. 71. Nakamizo S, Kobayashi S, Usui T, Miyachi Y, Kabashima K. Clopidogrel induced acute generalized exanthematous pustulosis with elevated Th17 cytokine levels as determined by a drug lymphocyte stimulation test. Br J Dermatol. 2010;162(6):1402–3. 72. Jeung YJ, Lee JY, Oh MJ, Choi DC, Lee BJ. Comparison of the causes and clinical features of drug rash with eosinophilia and systemic symptoms and Stevens-Johnson syndrome. Allergy Asthma Immunol Res. 2010;2(2):123–6. 73. Trivier JM, Caron J, Mahieu M, Cambier N, Rose C. Fatal aplastic anaemia associated with clopidogrel. Lancet. 2001;357(9254):446. 74. Meyer B, Staudinger T, Lechner K. Clopidogrel and aplastic anaemia. Lancet. 2001;357(9266):1446–7. 75. Akcay A, Kanbay M, Agca E, Sezer S, Ozdemir FN. Neutropenia due to clopidogrel in a patient with end-stage renal disease. Ann Pharmacother. 2004;38(9):1538–9. 76. Suh SY, Rha SW, Kim JW, et al. Neutropenia associated with clopidogrel use in a patient with chronic renal failure who underwent percutaneous coronary and peripheral intervention. Int J Cardiol. 2006;112(3):383–5. 77. McCarthy MW, Kockler DR. Clopidogrel-associated leukopenia. Ann Pharmacother. 2003;37(2):216–9. 78. Elmi F, Peacock T, Schiavone J. Isolated profound thrombocytopenia associated with clopidogrel. J Invasive Cardiol. 2000;12(10):532–5. 79. Bennett CL, Connors JM, Carwile JM, et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med. 2000;342(24):1773–7. 80. Phillips EJ, Knowles SR, Shear NH. Serum sickness- like reaction associated with clopidogrel. Br J Clin Pharmacol. 2003;56(5):583. 81. Khan EA, Blake JW, Stamp LK. Ticlopidine as a safe alternative for clopidogrel-associated arthritis. J Rheumatol. 2009;36(4):855. 82. Boulman N, Rozenbaum M, Slobodin G, Rosner I. Acute polyarthritis associated with clopidogrel treatment. IMAJ. 2005;7(10):670. 83. Williams MF, Maloof JA. Resolution of clopidogrel- associated polyarthritis after conversion to prasugrel. Am J Health Syst Pharm. 2014;71(13):1097–100. 84. Ford MK, Cohn JR. Clopidogrel hypersensitivity: pathogenesis, presentation and diagnosis. Curr Vasc Pharmacol. 2019;17:110–2. 85. von Thiel KF, Price MJ, Valencia R, Ludington KJ, Teirstein PS, Simon RA. Clopidogrel desensitization

25 Anticoagulants after drug-eluting stent placement. J Am Coll Cardiol. 2007;50:2039–43. 86. Camara MG, Almeda FQ. Clopidogrel (Plavix) desensitization: a case series. Catheter Cardiovasc Interv. 2005;65:525–7. 87. Campbell KL, Cohn JR, Fischman DL, Walinsky P, Mallya R, Jaffrani W, Savage MP. Management of clopidogrel hypersensitivity without drug interruption. Am J Cardiol. 2011;107:812–6. 88. Siu H, Kaliyadan A, Fischman DL, Nardone E, Poll D, Savage MP. Platelets. 2016;27(8):824–7. 89. Lokhandwala JO, Best PJ, Butterfield JH, Skelding KA, Scott T, Blankenship JC, Buckley JW, Berger PB. Frequency of allergic or hematologic adverse reactions to ticlopidine among patients with allergic or hematologic adverse reactions to clopidogrel. Circ Cardiovasc Interv. 2009;2(4):348–51. 90. Makkar K, Wilensky RL, Julien MB, Herrmann HC, Spinler SA. Rash with both clopidogrel and ticlopidine in two patients following percutaneous coronary intervention with drug-eluting stents. Ann Pharmacother. 2006;40(6):1204–7. 91. Tcheng JE, Kerelakes DJ, Lincoff AM, George BS, Kleiman NS, Sane DC, et al. Abciximab readministration: results of the ReoPro Readministration Registry. Circulation. 2001;104:870–65. 92. Hawkings C, Gatenby P, McGill D. Severe hypotenson complicating primary angioplasty: allergy to abciximab. Allergy. 2003;58:688–9.

231 93. Ja G, Nichols TC. Possible anaphylactic reaction to abciximab. Catheter Cardiovasc Interv. 1999;48:71–3. 94. Iakovou Y, Mangina A, Millissari E, Cokkinos DV. Acute profound thrombocytopenia associated with anaphylactic reaction after abciximab therapy during percutaneous coronary angioplasty. Cardiology. 2001;95:215–6. 95. Moneret-Vautrin DA, Morisset M, Bignaud JM, Kanny G. T-cell mediated allergy to abciximab. Allergy. 2002;57:269–70. 96. Kang SY, Kim JY, Kim MY, Less SY, Kim MH, Kim TW, et al. Drug-induced hypersensitivity syndrome/ drug reactions with eosinophilia and systemic symptoms syndrome induced by Cilostazol and carbamazepine. J Dermatol. 2012;39:723–4. 97. Concepciòn Martin I, Fernandez de Palencia Espinoa MA, Garrido Corro B, Da la Rubioa Nieto A. Toxic epidermal necrolysis with fatal ending due to the concurrent use of carbamazepine, Cilostazol and omeprazole: a case report. Farm Hosp. 2011;35:217–8. 98. Salava A, Alanko K, Hyry H. Dipyridamole- induced eczematous drug eruption with positive patch test reaction. Contact Dermatitis. 2012;67:101–18. 99. Jao T, Tsai TH, Jeng JS. Aggrenox (Asasantin- retard)-induced Stevens-Johnson syndrome. Br J Clin Pharmacol. 2008;67:264–5.

Biological Drugs

26

Alessandra Vultaggio

Key Points • Biological agents (BA) are an important option for inflammatory and autoimmune diseases and for cancer, but their use may be complicated by adverse reactions. • Cutaneous clinical manifestations may be present in both acute and delayed events and in antidrug antibody (ADA)- and non-ADAmediated reactions. • Delayed cutaneous manifestations may be induced by target-related mechanisms of some BA. • The diagnostic tools, including in vivo and in vitro tests, are currently insufficient.

26.1 Clinical Manifestation Both acute (or immediate) and delayed reactions to biological agents (BA) can be characterized by cutaneous clinical manifestations that may vary considerably, ranging from mild to severe. Additionally, both acute and delayed events can be categorized as local or systemic.

A. Vultaggio (*) Careggi University Hospital, Immunoallergology Unit, Firenze, Italy e-mail: [email protected]

© Springer Nature Switzerland AG 2022 A. J. Bircher et al. (eds.), Cutaneous Drug Hypersensitivity, https://doi.org/10.1007/978-3-030-82743-4_26

26.1.1 Acute Infusion Reactions Acute reactions to BA, occurring during or within 1 h after the end of the infusion, include mainly systemic cutaneous symptoms such as itching, urticaria, and flushing [1]. Acute reactions may be mild, moderate, or severe and in some cases may be even life-threatening. Clinical symptoms may be diverse involving different organ systems (respiratory, skin, cardiovascular, neurological). Of note, in addition atypical symptoms may be present such as back pain. The clinical characteristics of infliximab (IFX)-induced acute infusion reactions have been analyzed, and cutaneous symptoms, together with respiratory manifestations, were the most frequent clinical features [2]. Acute infusion reactions are well described in cancer patients treated with biologicals such as anti-epidermal growth factor receptor (EGFR) and anti-CD20 monoclonal antibodies. Among anti-EGFR, cetuximab is more frequently associated with acute reactions, with reported incidence ranging from 7.6 to 33%. Clinical signs involve the heart, lung, and skin. Immediate infusion- related reactions to rituximab (anti-CD20 antibody) are quite common; in fact among biological agents, rituximab has the highest reported incidence of infusion reactions (up to 77% at the first infusion). The frequency usually decreases with subsequent infusions. Clinical presentation is characterized by fever, chills, rigor, and pain. In

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some cases, wheezing, flushing, urticaria, and pruritus do occur.

26.1.2 Delayed Infusion Reactions Delayed reactions to BA usually occur within the first 7–15 days after the drug exposure. The clinical presentation of delayed reactions may be consistent with a classic serum sickness (SS) characterized by the production of antibody to foreign immunoglobulin with formation of antigen-antibody complexes. They usually present with systemic symptoms (arthralgia, myalgia, fever) associated with cutaneous manifestations (exanthems, urticaria, and itching). The rash is usually widespread, but it may start at the site of injection. In addition to exanthematous eruption, papules, and palmar erythema, and necrotizing vasculitis of the skin may be present, sustained by inflammatory infiltrates of small blood vessels and complement deposition [3]. SS has been described for several chimeric and humanized monoclonal antibodies such as infliximab, abciximab, rituximab, omalizumab, trastuzumab, and natalizumab. Delayed injection site reactions (ISR) are quite frequent and are characterized by infiltrated plaques. Zeltser et al. have evaluated the histologic features of delayed ISR associated with etanercept, describing a superficial perivascular infiltrate mainly sustained by CD8+ T cells with few eosinophils [4]. During therapy with BA, disseminated skin reactions have been rarely reported, including exanthemas (maculopapular, eczematous, lichenoid, and granulomatous) and erythema multiforme. These types of reactions have been described in patients treated with rituximab and anti-TNFα agonists. Severe cutaneous hypersensitivity reactions, such as StevenJohnson syndrome/TEN, induced by biologicals are rare, with reports seemingly confined mainly to anticancer therapy (ibritumomab, brentuximab, and rituximab) [5]. Recently a DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome has been described during therapy with tocilizumab in a patient with adultonset Still’s disease. The term “hypersensitivity” is sometimes used to cover reactions that clearly

have no immune basis and which are otherwise not easy to classify or where the mechanism remains to be determined. Examples of such reactions which are not genuine hypersensitivities (i.e., not immune-mediated) include adverse reactions provoked by administration of agents that bind EGFR. Cetuximab and panitumumab are the two monoclonal antibodies that act as EGFR inhibitors and commonly cause a moderate to severe, dose-dependent so-called acneiform or papulopustular eruption (50–100% of treated patients). Among target-related cutaneous side effects of BA, the paradoxical induction of psoriasiform eruptions during TNF-a antagonists can be included. Palmoplantar pustulosis represents the most common clinical presentation, and it may be associated with guttate or plaque-like psoriasis. In addition to systemic manifestations, injection site reactions (ISR) should be considered among delayed events. They are induced by subcutaneously administered BA and characterized by erythema, swelling, itching, or infiltrated plaques. ISR are more commonly associated with the use of peptide pharmaceuticals such as glatiramer acetate, somatostatin analogue, enfuvirtide, anakinra, and etanercept.

26.2 Mechanisms Biologicals display some differences from pharmaceutical drugs, and adverse reactions to BA cannot be classified according to the traditional classification. An alternative classification, based on the immunological activity of biologicals, was proposed by Pichler. This classification includes five groups: (Type α) high cytokine levels, (Type β) hypersensitivity reactions and IgE, IgG, and T cell-mediated reactions, (Type δ) immune imbalance syndrome, (Type γ) cross-reactivity with native proteins, and (Type ε) non-immunologic adverse effects [6]. Alfa reactions are associated with high cytokine levels, and in most cases, high cytokine levels occur due to endogenous cell activation that is called a cytokine release reaction. Beta-type reactions are HSRs and are further defined as immediate and delayed and occur with

26 Biological Drugs

IgE, IgG, and complement or T cell involvement. One of the main features of BA is the immunogenicity, the capability to induce an immune response against the drug itself, leading to the development of antidrug antibodies (ADAs). Immune response against BA may lead to the development of antidrug antibodies (ADA). For this reason, reactions could be also divided into ADA-mediated and non-ADA-mediated reactions. Among all patients with immediate infusion reactions, a proportion of them display an ADA-mediated reaction, and a subgroup of reactive ADA-positive patients display an IgE-mediated mechanism [1]. Reactions sustained by drug-specific IgE ADA have been described for several BA, such as infliximab, cetuximab, rituximab, and tocilizumab. In post-marketing surveys, IgEmediated anaphylaxis has also been reported in a patient undergoing basiliximab therapy. Immediate-onset anaphylaxis during first exposure to cetuximab displayed that BA-specific pre-existing IgE do exist and are involved in mechanisms of reactions to BA. ADAs may be involved in the pathogenic mechanisms of cutaneous manifestations, specifically during immediate reactions, even if ADAmediated reactions may be clinically indistinguishable from not ADA-mediated reactions. Among delayed reactions the development of ADA has been more frequently associated with serum sickness-like disease and thrombosis, whereas disseminated skin reactions seem to be less associated with ADA. Among non-ADAmediated reactions, the best characterized condition is represented by cytokine release syndrome, occurring when a large number of cells are activated through different pathway. The complement (C′) activation represents the second non-ADA-mediated mechanism; the C′ may be directly activated by the drug (for aggregates or additives) or indirectly by immunocomplexes between drug and antidrug antibodies. Studies that investigate the underlying pathogenic mechanism of disseminated skin reactions are lacking. In patients with infliximab-induced erythemato-squamous exanthema, a lymphocyte

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infiltration at the dermo-epidermal junction has been reported. Torres et al. have shown the involvement of T cells (activated memory CD4+ and CD8+ T cells) in generalized maculopapular exanthema in two patients treated with infliximab, by performing skin biopsy and a lymphocyte proliferation test [7]. Even if it’s well known that type IV reactions depend upon antigen- specific TH1/TH2/TH17 lymphocytes and effector mechanisms involving the activation of cytotoxic lymphocytes, macrophages, and eosinophils, the underlying mechanisms of systemic severe cutaneous reactions to BA have rarely been investigated. Regarding target-related skin reactions induced by EGFR inhibitors, these BA deeply affect the growth of hair follicle, leading to its degeneration because EGFR is widely expressed in the skin and its activation plays an important role in the keratinocyte proliferation and differentiation and in the development of the hair follicle. The follicular degeneration triggers an inflammatory response, mainly sustained by neutrophils. In addition, some in vivo studies in mice models suggest a direct role of EGFR inhibitors in favoring leukocyte chemotaxis in the skin, by inducing chemokine expression [8]. From a pathogenic point of view, a cytokine imbalance, induced by TNF-a blocking and favoring the production of type I IFN, seems to play a key role in the induction of psoriasiform eruptions. IFN-α stimulates Th1 lymphocytes, which play a role in the pathogenesis of psoriasis. In addition to the disequilibrium favouring proinflammatory cytokines, emerging data suggest that the interleukin (IL)-23/T-helper (TH)17 axis could play an important role in the pathogenesis of psoriasiform lesions in the setting of TNF-α suppression. In fact, IL-17-expressing T cell infiltrates have been identified in TNF-α inhibitor-induced psoriatic lesions of patients with inflammatory bowel disease, and IL-12/23 antagonism with ustekinumab has been an effective treatment in these patients [9]. Table 26.1 lists both pathogenic mechanisms and clinical features of biological-induced reactions.

A. Vultaggio

236 Table 26.1 Biological agents causing adverse reactions: pathogenic mechanisms and clinical features Pathogenic mechanism Cytokine release

Onset of symptoms Acute

C′ activation

Acute

IgE-mediated

Acute

IgG-mediated

Acute

IgG-mediated

Delayed

T cell-mediated

Delayed

T cell-mediated

Delayed

Cytokine imbalance Delayed Toxicity (non-immunologic Delayed mechanism)

Symptoms Flu-like symptoms Anaphylactic symptoms Flu-like symptoms Anaphylactic symptoms Urticaria, angioedema, bronchospasm, anaphylaxis Urticaria, angioedema, bronchospasm, anaphylaxis Serum sickness Thrombosis Erythema Plaques Itching (at the site of injection) Disseminated skin reactions Psoriasiform eruption Acneiform eruption

Drug (example) Rituximab Bevacizumab, trastuzumab, infliximab, rituximab Infliximab, cetuximab, tocilizumab, rituximab TNFa-blockers TNFa-blockers Etanercept

Ibritumomab, brentuximab, rituximab TNFa-blockers Anti-EGFR

TNF tumor necrosis factor, EGFR epithelial growth factor receptor

26.3 Diagnostic Methods Even if during the last few years positive skin testing has been reported in patients with immediate hypersensitivity caused by BA such as rituximab, anti-TNFα agents, and trastuzumab, in vivo tests are not currently standardized and approved for biologics. Of note, there is an insufficient evidence to recommend appropriate drug concentration, as well as the timing to perform it. It is an obvious factor that for skin testing the time between the reaction and the evaluation is a crucial point, due to temporary unresponsiveness of the skin mast cells following massive activation during the reaction. In addition, we don’t have any negativization rate of skin testing for BA, as yet. It has been observed, at least for infliximab, a very high concordance between the detection of serum IgE and skin testing positivity, even if it is essential to perform intradermal tests, as the skin prick test is usually negative [2]. The sensitivity of skin testing is about 30%, with an estimated positive predictive value of 56%. That could appear not particularly high, but this is related to the fact that not all hypersensitivity reactions to infliximab are IgE-driven. Patch testing can be used to investigate delayed cutaneous reactions, representing

both a screening and a provocation test in the skin. However, few studies about its application for delayed hypersensitivity to BA are reported and mainly regarding interferon-induced reactions. However, controversial data are reported, and conclusive results are still lacking. The in vitro assays are especially focused on the detection of ADA. To this aim, different methods exist, but non-isotype-specific ELISA is the most frequently used, displaying good sensitivity and specificity. The co-evaluation of circulating drug levels in the case of ADA negativity is necessary to understand ADA assay’s results, ruling out false-negative results due to drug interference in the assay. ADA mainly belongs to the IgG class; however, a full assessment of immunogenicity is recommended, including the IgE isotype definition of positive samples, taking into account that IgE-mediated reactions are more severe. The detection of ADA is very useful in the diagnosis of immediate reactions to BA that are very frequently associated with ADA positivity as well as in cases of suspected SS. Among other tests, the measurement of serum tryptase may be used as a marker of mast cell activation. However, tryptase levels within normal range do not exclude IgE-mediated anaphylaxis, as described in patients with acute systemic

26 Biological Drugs

reactions to BA. The measurement of complement fractions or immunocomplexes may be supposed in the in vitro evaluation of delayed BA-induced SS reactions, but they are not routinely performed as yet. In fact, their modification in serum concentrations is transient and tends to return to normal rapidly. Finally, to date, the role of in vitro T cell analysis remains to be defined in the clinical setting for both acute and delayed BA-induced reactions, even if the presence of BA-specific T cell in the peripheral blood of treated patients who experienced hypersensitivity reactions to BA was shown [10].

26.4 Management The severity of the reaction drives the clinical management of such infusion. Cutaneous manifestations during mild to moderate immediate event, especially if not associated with ADA, may be managed by reducing the infusion rate (after a temporary interruption) and administering antihistamines and corticosteroids. In the case of skin symptoms associated with cardiovascular/respiratory involvement (severe reactions), the infusion must be stopped and rescue treatment promptly administered according to the full clinical features of the reaction. Premedication plays a role in the prevention of reactions during subsequent infusions. After an immediate reaction that occurs in the presence of ADA, in association with skin testing positivity and/or serum drug-specific IgE, desensitization represents a useful tool to repeat BA administration [1]. Regarding delayed reactions, patients displaying SS disease must be treated with steroids, and in addition, plasma exchange may be required for those most severely affected. On the other hand, premedication plays no established and secure role in exanthems or serum sickness and is often without effect. In the case of dermatosis (not severe), the clinician may try to continue BA, accompanied by corticosteroid application. In the

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case of severe disseminated events such as Stevens-Johnson/TEN, the switch to a different BA is mandatory. The use of local corticosteroids is usually sufficient in the management of ISR along with a follow-up of the lesions to assess their severity and the compliance of patients to the treatment. In fact, ISR are usually mild and disappear when the treatment is continued.

References 1. Vultaggio A, Castells MC. Hypersensitivity reactions to biologicals. Immunol Allergy Clin N Am. 2014;34:615–32. 2. Matucci A, Pratesi S, Petroni G, Nencini F, Virgili G, Milla M, Maggi E, Vultaggio A. Clin Exp Allergy. 2013;43:659–64. 3. Karmacharya P, Poudel DR, Pathak R, Donato AA, Ghimire S, Giri S, Aryal MR, Bingham CO 3rd. Rituximab-induced serum sickness: a systematic review. Semin Arthritis Rheum. 2015;45:334–40. 4. Zeltser R, Valle L, Tanck C, Holyst MM, Ritchlin C, Gaspari AA. Clinical, histological, and immunophenotypic characteristics of injection site reactions associated with etanercept: a recombinant tumor necrosis factor alpha receptor: fc fusion protein. Arch Dermatol. 2001;137:893–9. 5. Grant Peter J, Lehloenya R, Diamini S, Risma K, White KD, Konvinse KC, et al. Severe delayed cutaneous reactions and systemic reactions to drugs: a global perspective on the science and art of current practice. J Allergy Clin Immunol Pract. 2017;5:547–63. 6. Pichler W. Adverse side-effects to biological agents. Allergy. 2006;61:912–20. 7. Torres MJ, Chaves P, Doña I, Blanca-López N, Canto G, Mayorga C, et al. T-cell involvement in delayed- type reactions to infliximab. J Allergy Clin Immunol. 2011;128:1365–7. 8. Baldo BA. Adverse events to monoclonal antibodies used for cancer therapy. Focus on hypersensitivity responses. Oncoimmunology. 2013;2:e26333. 9. Tillack C, Ehmann LM, Friedrich M, Laubender RP, Papay P, Vogelsang H, et al. Anti-TNF antibody- induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-γ-expressing Th1 cells and IL-17A/IL-22- expressing Th17 cells and respond to anti-IL-12/ IL-23 antibody treatment. Gut. 2014;63:567–77. 10. Vultaggio A, Petroni G, Pratesi S, Nencini F, Cammelli D, Milla M, Prignano F, Annese V, Romagnani S, Maggi E, Matucci A. ABIRISK consortium. Clin Exp Immunol. 2016;186:364–72.

27

Corticosteroids Marie Baeck and An Goossens

27.1 Introduction 27.1.1 A Not-So-Uncommon Condition Corticosteroids (CSs), potent anti-inflammatory and immunomodulator agents used in the treatment of various inflammatory and allergic diseases, are among the most commonly used drugs, both topically and systemically. Although unexpected and paradoxical, allergic hypersensitivity to corticosteroids is a common finding, delayed- type reactions being much more frequently encountered than the immediate-type ones. The frequency of contact-allergic reactions to CSs observed ranges from 0.2% to 5% of patch-tested subjects. Longstanding dermatological diseases, because of the application of numerous CSs over a long period and/or unsupervised self-treatment with

low-potency CSs, are determining factors in the development of CS sensitivity [1–4]. Allergic reactions following systemic administration of CSs have rarely been reported in the literature and most often concerned isolated cases. In 1998, Klein-Gitelman et al. [5], in a cohort study of 213 children treated with intravenous CSs for various rheumatological conditions, estimated the rate of allergic reactions to be 0.1% (for approximately 10,000 doses of glucocorticosteroids), most being of the immediate type. Other authors have estimated the prevalence of such reactions at 0.3% [6]. About a hundred publications have reported immediate reactions following oral or parenteral administration of CSs, the allergic nature of which was not always demonstrated. The prevalence of delayed allergic hypersensitivity reactions following systemic administration of CSs [7] has not been determined.

27.2 Delayed Allergic Hypersensitivity to Corticosteroids M. Baeck (*) Department of Dermatology, Cliniques universitaires Saint-Luc, Université Catholique de Louvain, Bruxelles, Belgium e-mail: [email protected] A. Goossens Department of Dermatology, University Hospital, Katholieke Universiteit Leuven, Leuven, Belgium © Springer Nature Switzerland AG 2022 A. J. Bircher et al. (eds.), Cutaneous Drug Hypersensitivity, https://doi.org/10.1007/978-3-030-82743-4_27

27.2.1 The Skin: Main Sensitization and Elicitation Route Although sensitization and elicitation mainly occur via the skin, other routes, among them inhalation of corticosteroids, may be involved. 239

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While few patients are sensitized or do present with allergic reactions when using inhaled corticosteroids personally [8–10], exposure to them and to budesonide in particular has been found to be responsible for primary airborne sensitization and/or airborne allergic contact dermatitis in subjects not themselves treated by aerosols containing this CS, but taking care of, or living with, patients who used them regularly because of a chronic respiratory disease [11]. Raison-Peron et al. [12] were the first authors to describe connubial or consort contact dermatitis in the mother of a 3-year-old boy being treated for asthma with an aerosol containing budesonide. Moreover, Pontén [13] and later on also Corraza [14] have reported on airborne contact dermatitis from occupational exposure to such aerosols, notwithstanding the extremely low concentrations involved. This type of exposure should be routinely searched for in patients suspected of airborne contact dermatitis or with unexplained positive patch tests to budesonide. Moreover, also the conjunctival and nasal mucosa and the respiratory and digestive tract may be causal routes [3, 10, 15, 16], although a primary sensitizing contact with the surrounding skin cannot be excluded either. Not many cases of sensitization and/or allergic reactions due to ocular use of CSs have been reported in the literature. Baeck et al. observed that 6% of patients with a CS sensitization presented with allergic manifestations via this route [15], particularly to hydrocortisone, the most prescribed ophthalmic CS. Furthermore, besides CSs, multiple positive tests were also observed for other potential allergens present in ophthalmic preparations, such as topical antibiotics, antiseptics, and even vehicle components. Primary sensitization related to systemic administration of a CS, of which the intravenous route is the most common, occurs even less frequently [2, 17].

M. Baeck and A. Goossens

27.2.2 Clinical Presentation: Neither Specific Nor Spectacular The clinical signs of CS allergy are usually minor or display a completely atypical chronology. Allergy to CSs should be suspected a priori in cases of CS-sensitive diseases that respond poorly or not at all to CS treatment, become worse following the use of CSs, or reoccur rapidly after CS withdrawal [3]. Allergic contact dermatitis from CSs may present as chronic eczema, often with the eruption being more pronounced at the periphery of the treated zone (“edge effect”) (Fig. 27.1). Moreover, as there may be a long delay before diagnosis, the clinical presentation can be dom-

Fig. 27.1 Chronic eczema with the eruption more pronounced at the periphery of the treated zone

27 Corticosteroids

a

241

b

Fig. 27.2 (a) and (b) Perinasal dermatitis or clinical presentation dominated by “classical” side effects of topical corticosteroids

a

b

Fig. 27.3 (a) and (b) Eczema of the face more pronounced around the nose, lips, and eyes with locoregional dissemination, or even generalization following oral inhalation of budesonide

inated by other “classical” side effects such as cutaneous atrophy, rosacea, and perioral or perinasal dermatitis (Fig. 27.2a, b). In sensitized patients, ocular use of CSs may result in facial or periocular edema and/or eczema, conjunctivitis, burning, itching, and tearing [15], while inhaled CSs may provoke eczematous eruptions around the orifices (nostrils, nose, lips), with possible locoregional dissemination,

as well as mucosal reactions, such as stomatitis, nasal congestion, and chronic rhinitis (Fig. 27.3a, b). Moreover, bronchospasm and bronchoconstriction as well as systemic reactions have also been observed [9]. Finally, flare-up reactions at previously affected skin sites and also generalized eruptions following systemic administration of CSs have been reported [3].

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242

a

Fig. 27.4 (a) and (b) Typical “edge effect,” a ring of induration, erythema, and/or papulovesicles around the patch test site with no reaction in the center, which is due

27.2.3 The Indisputable Value of Patch Testing The anti-inflammatory properties of corticosteroids may mask the clinical signs of allergy or render them aspecific, thus rendering the skin test results difficult to interpret (Fig. 27.4a, b: typical patch tests’ edge effect). Testing with corticosteroid allergy markers in the European baseline series [18] is necessary since both budesonide and tixocortol pivalate detect 89% of the corticosteroid-sensitized patients [3]. However, it is important to test with the particular corticosteroids used as well. Patch tests remain the most adequate and effective method, with ethanol being the vehicle of choice for most molecules and with removal on Day 2 and readings up to 7 days later [19–22]. The association of intradermal tests allows additional allergy cases to be diagnosed (mainly when ethanolic preparations of the active principles are not available for skin testing), thereby avoiding false-negative skin test results [17, 19, 23–26]. Compared to patch tests, ID tests seem easier to read and become positive sooner (at least on D1 or D2), but later readings such as D7 are, in most cases, not use-

b

to the anti-inflammatory properties of corticosteroids and usually appears on early readings

ful. Local ID reactions are less intense and shorter. However, there is a significant risk of atrophy, particularly with potent corticosteroids and in suspensions. Further studies are needed to determine if such skin atrophy is transient or not and to define a standardized method with limited injected volume (0.02 ml) [27]. Hence this is actually a contraindication for routine use. Prick tests are of minor diagnostic value for diagnosing CS delayed allergic hypersensitivity, though no side effects were noted.

27.2.4 The Central Role of Halogenation and C16- Methyl Substitution and Reappraisal of the ABCD Classification Sensitized patients frequently (85%) test positively to several corticosteroids [3]. Although the existence of cross-reaction phenomena has been demonstrated by positive skin tests to synthetic corticosteroids to which a patient could never have been exposed (simply because they were not available at the time), simultaneous or subsequent sensitization can never be entirely ruled out [28].

27 Corticosteroids

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In 1989, Coopman et al. [29] classified corti- ketal/diol structure (former acetonide Group B); costeroids (CSs) into four reacting groups, A, B, and Group 3, the halogenated and C16-methylated C, and D, in function of clinical and structural molecules (former Group C and D1) that only characteristics. In 1995, Lepoittevin et al. [30] rarely produce allergy (Table 27.1). This represupported this classification and the central role sents a simplification compared to previous clasof constituents of the D-ring by means of confor- sifications [29–31]. However, some patients may mational analysis of the observed also react exclusively to budesonide (R isomer, cross-reactions. 32) along with molecules from the acetonide Later, Matura et al. [31], observing the partic- group. Indeed, budesonide is a particular moleular behavior of certain constituents of Group D cule with its acetal function being an equal mixCS esters, proposed a further subdivision into ture of two isomers (R and S), and hence its two subgroups, i.e., the stable D1 and labile D2 resemblance to both Group 1 and Group 2 moleesters. cules [30, 36]. In addition to the C16/C17 substitutions, Moreover, two subgroups of corticosteroid- Wilkinson et al. [32] considered that the A-ring sensitized patients with probably different areas was a second reactive center and that halogena- of immune recognition have been identified: tion of the CS structure (C6 and/or C9) was of Profile 1 patients, who react to molecules from critical importance in their cross-sensitivity one unique group, i.e., Group 1 for whom elecpattern. trostatic fields (molecular charge) seem imporIt was shown that a distinction needs to be tant; and Profile 2 patients who may react to the made between C16-methylated and non-entire spectrum of CSs, i.e., Group 1 and Group methylated molecules, the latter of which selec- 2 and/or Group 3 for whom steric fields (molecutively bind with arginine to form stable cyclic lar structure) are determinant, and who probably adducts and induce sensitization more often than present a global recognition of the CS skeleton. the former [33]. Indeed, positive patch test reacFor Profile 1 patients, replacement agents can tions are, with statistical evidence, much more be chosen within Group 2 and Group 3, since frequently observed to corticosteroid molecules they only react to Group 1. without C16-methyl substitution in the D ring and For Profile 2 patients, a classification, despite not halogenated in most cases, i.e., Groups A being valuable for orienting the search for a (esterified or not) and D2, than to those that are replacement molecule, cannot replace systemhalogenated and have a methyl group at C16, i.e., atic, individualized evaluation of their sensitizaGroups C and D1 [34]. tion/tolerance profile. In case corticosteroids can C16-methyl substitution interferes with the no longer be used, treatment with a calcineurin protein binding, and halogenation of the cortico- inhibitor, i.e., topical tacrolimus or pimecrolisteroid molecules plays an important role in their mus, may be a valuable alternative. Less is known about the classification and stabilization, which seems to protect them from cross-reactivity pattern of the less common sensitization properties. Based on patch test results and molecular delayed reactions following systemic administramodeling of CS, Baeck et al. were later able to tion of CSs, although this might be the same as simplify the classification of CSs into three dif- with topical use [37]. Most of the reactions ferent groups [35], i.e., Group 1, the non-methyl- observed are “systemic contact dermatitis” due to ated, most often non-halogenated molecules oral or parenteral re-exposure of sensitized indi(former Group A, D2, and budesonide), which viduals with the respective corticosteroids produce most of the allergic reactions; Group 2, previously applied topically. However, previous the halogenated molecules with a C16/C17 cis- contact sensitization does not seem to be

O

O

HO

Group 1 Characteristics No C16-methyl substitution No halogenation (in most cases) Indicative a structure

Table 27.1 Corticosteroids classification

OH

OH

O

HO

O O

O

HO

F

c

OH

b O

3 C16-methyl substitution Halogenation (except*)

2 C16/C17 cis ketal diol structure Halogenation (in most cases except*) O

OH

OH

244 M. Baeck and A. Goossens

Typical members

Budesonide Cloprednol Cortisone acetate Dichlorisone acetate Difluprednate Fludrocortisone acetate Fluorometholone Fluprednisolone acetate Hydrocortisone Hydrocortisone aceponate Hydrocortisone acetate Hydrocortisone 17-butyrate Hydrocortisone 21-butyrate Hydrocortisone hemisuccinate Isofluprednone acetate Mazipredone Medrysone Methylprednisolone aceponate Methylprednisolone acetate Methylprednisolone hemisuccinate Prednicarbate Prednisolone Prednisolone caproate Prednisolone pivalate Prednisolone sodium metasulfobenzoate Prednisolone succinate Prednisone Tixocortol pivalate Triamcinolone

Amcinonide Budesonide (R-isomer)¨ Desonide* Fluchloronide Flumoxonide Flunisolide Fluocinolone acetonide Fluocinonide Halcinonide* Triamcinolone acetonide Triamcinolone benetonide Triamcinolone diacetate Triamcinolone hexacetonide ¨ may exceptionally only cross-react with the acetonides

Alclometasone dipropionate Beclomethasone dipropionate Betamethasone Betamethasone 17-valerate Betamethasone dipropionate Betamethasone sodium phosphate Clobetasol propionate Clobetasone butyrate Cortivazol* Desoxymethasone Dexamethasone Dexamethasone acetate Dexamethasone sodium phosphate Diflucortolone valerate Diflorasone diacetate Flumethasone pivalate Fluocortin butyl Fluocortolone Fluocortolone caprylate Fluocortolone pivalate Fluprednidene acetate Halomethasone Meprednisone* Fluticasone propionate Mometasone furoate

27 Corticosteroids 245

246

mandatory for developing systemic hypersensitivity to corticosteroids [27]. Group 1 molecules, such as methylprednisolone, are mainly implicated. Moreover, most patients reacted to all three groups from the recently reappraised classification. Indeed, these patients seem to be able to react to any corticosteroid molecules, probably due to a global recognition of the corticosteroid skeleton, and therefore need a systematic, individualized evaluation of their sensitization/tolerance profile [38]. Additionally, most of the oral or intravenous commercialized corticosteroid molecules belong to Group 1; hence, it is difficult to avoid the whole group and to find alternative corticosteroids in the two other groups. Therefore, it is important to perform provocation tests with molecules that tested negatively on skin testing (in non-severe reactions), even if they belong to the same group as those responsible for the initial reaction. Some patients sensitized to CSs respond positively to skin tests with other steroids, such as sex hormones [39, 40]. Wilkinson and Beck [41] estimated the prevalence of 17-hydroxyprogesterone sensitization in patients reacting positively to hydrocortisone to be 19% to 26% and considered them to be the expression of cross-reactivity. They also considered that, in most cases, there are no clinical consequences. However, an allergy to endogenous progesterone may present as a generalized eczematous eruption that becomes worse during the premenstrual period: “autoimmune progesterone dermatitis” (AIPD) [42]. Indeed, any patient presenting symptoms compatible with AIPD should also be tested for CS allergy.

27.3 Immediate Allergic Hypersensitivity to Corticosteroids 27.3.1 Clinical Presentation: Not Specific to Corticosteroids An urticarial eruption, often generalized, is the most common expression of an immediate

M. Baeck and A. Goossens

reaction to corticosteroids [43]. Facial angioedema and edema of the eyelids may also be observed alone or associated with other symptoms [44, 45]. Moreover, shock and cardio-respiratory failure are possible as well [46, 47].

27.3.2 Diagnosis: Allergy to Excipients Needs to Be Ruled Out Immediate allergic hypersensitivity reactions can be detected by prick tests and early ID test readings (30 minutes). If the prick test is negative, ID tests at progressively higher concentrations (1/1000 and then 1/100 of the prick solution), for which the lowest non-irritant concentration needs to be defined, are carried out. The paradoxical action of cutaneous tests for delayed allergies (i.e., the competition between allergic reaction and anti-inflammatory effect) does not seem to occur in immediate skin tests. As mentioned by Nancey et al. [48], CSs are not able to either prevent or improve experimental urticaria, i.e., wheal and flare, and they even enhance histamine and codeine-induced erythema. However, this needs further confirmation [49, 50]. Allergy to additives such as sodium carboxymethylcellulose (e.g., [51]), which is a semi- synthetic hydrosoluble polymer with a high molecular weight, as well as macrogols (e.g., [52]), both used as excipients in numerous injectable CS preparations (especially intra-articular solutions), also needs to be ruled out. If the skin tests turn out to be negative in suspected cases, reintroduction could be performed with the causal CS preparation and, separately, with its vehicle components and preservative agents. Oral provocation tests remain the gold standard for confirming or refuting the patient’s hypersensitivity to a given substance, as they reproduce clinical symptoms regardless of the underlying etiological or pathogenic mechanism [53].

27 Corticosteroids

27.3.3 Pathogenesis: Poorly Understood The pathogenesis of immediate CS reactions is still poorly understood. Only a few authors have found evidence for IgE antibodies that are specific to certain CSs [43–45, 54, 55]. However, neither their absence nor negative test results rule out the possibility of an antibody-mediated allergic reaction. Pseudo-allergic reactions or idiosyncrasies similar to those observed with acetylsalicylic acid (including overproduction of leukotrienes by blocking the cyclooxygenase pathway) could explain certain immediate CS reactions [56, 57]. Other IgE-independent mechanisms involve the direct release of histamine by mast cells. Acute cardiovascular toxic reactions have also been described in patients who receive high and rapidly infused doses of CSs [58, 59]. Such reactions seem to be due to a α-adrenergic blockage and the drug’s negative inotropic effect rather than to an immunological phenomenon.

27.3.4 No Cross-Reactivity Patterns Observed

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Burgdorff [44] has described the case of a patient allergic to methylprednisolone sodium succinate who presented cross-reactions to all the agents carrying the same succinate ester. Skin tests and the reintroduction of other CSs without this particular ester or with another C21 substitution were all negative without exception. Others have confirmed the absence of cross-reactions between succinate CSs and agents carrying other esters (e.g., phosphate) or with non-esterified hydrocortisone or methylprednisolone [46, 64–69]. The opposite may also occur, such as reactions to native hydrocortisone and methylprednisolone but not to their corresponding sodium succinate salts [70, 71]. A high tolerance to halogenated betamethasone and dexamethasone in hydrocortisone- and methylprednisolone-sensitized patients has been found in several studies [62, 63, 71–74]. With regard to immediate allergic reactions, two authors failed to detect any cross-reactivity between betamethasone and dexamethasone (agents with identical chemical structure, differing only in the position of the C16-methyl group) [74, 75]. Thus, immediate hypersensitivity to CSs would seem to be a rather heterogeneous phenomenon with no particular cross-reactivity pattern observed [76, 77]. Some patients react to the steroid itself, others to a specific esterified derivative. It appears that, in contrast to other esters such as phosphates, the succinate esters of hydrocortisone and methylprednisolone are frequently involved in immediate hypersensitivity reactions, the mechanism of which is unclear. Moreover, halogenated derivatives are rarely implicated.

Few authors have studied the possibility of extending the classification described by Coopman et al. [29] and further by Baeck et al. [35] to immediate reactions. The most frequently implicated CSs are hydrocortisone and methylprednisolone, both of which belong to Group A according to the ABCD classification, within which cross-reactions may be observed [6]. Venturini et al. [60], reporting on seven cases of immediate hypersensitivity to systemic CSs, could not demonstrate the existence of cross- reactions between CSs belonging to the same group. Similarly, some patients who are allergic References to hydrocortisone and methylprednisolone M, Marot L, Nicolas JF, Pilette C, Tennstedt (esterified or not) could still tolerate predniso- 1. Baeck D, Goossens A. Allergic hypersensitivity to topilone and/or prednisone, all of which belong to cal and systemic corticosteroids: a review. Allergy. 2009;64(7):978–94. Group A [6, 61–63].

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27 Corticosteroids less allergenic than the non-methylated molecules. Contact Dermatitis. 2011;64(6):305–12. 35. Baeck M, Chemelle JA, Goossens A, Nicolas JF, Terreux R. Corticosteroid cross-reactivity: clinical and molecular modelling tools. Allergy. 2011;66(10):1367–74. 36. Isaksson M, Bruze M, Lepoittevin JP, Goossens A. Patch testing with serial dilutions of budesonide, its R and S diastereomers, and potentially cross- reacting substances. Am J Contact Dermat. 2001;12(3):170–6. 37. Ventura MT, Calogiuri GF, Muratore L, Di Leo E, Buquicchio R, Ferrannini A, et al. Cross-reactivity in cell-mediated and IgE-mediated hypersensitivity to glucocorticoids. Curr Pharm Des. 2006;12(26):3383–91. 38. Baeck M, Goossens A. Systemic contact dermatitis to corticosteroids. Allergy. 2012;67(12):1580–5. 39. Schoenmakers A, Vermorken A, Degreef H, Dooms- Goossens A. Corticosteroid or steroid allergy? Contact Dermatitis. 1992;26(3):159–62. 40. Lamb SR, Wilkinson SM. Contact allergy to progesterone and estradiol in a patient with multiple corticosteroid allergies. Dermatitis. 2004;15(2):78–81. 41. Wilkinson SM, Beck MH. The significance of positive patch tests to 17-hydroxyprogesterone. Contact Dermatitis. 1994;30(5):302–3. 42. Ingber A, Trattner A, David M. Hypersensitivity to an oestrogen-progesterone preparation and possible relationship to autoimmune progesterone dermatitis and corticosteroid hypersensitivity. J Dermatol Treat. 2009;10(2):139–40. 43. Rasanen L, Tarvainen K, Makinen-Kiljunen S. Urticaria to hydrocortisone. Allergy. 2001;56(4):352–3. 44. Burgdorff T, Venemalm L, Vogt T, Landthaler M, Stolz W. IgE-mediated anaphylactic reaction induced by succinate ester of methylprednisolone. Ann Allergy Asthma Immunol. 2002;89(4):425–8. 45. Pryse-Phillips WE, Chandra RK, Rose B. Anaphylactoid reaction to methylprednisolone pulsed therapy for multiple sclerosis. Neurology. 1984;34(8):1119–21. 46. Freedman MD, Schocket AL, Chapel N, Gerber JG. Anaphylaxis after intravenous methylprednisolone administration. JAMA. 1981;245(6):607–8. 47. King RA. A severe Anaphylactoid reaction to hydrocortisone. Lancet. 1960;276(7159):1093–4. 48. Nancey S, Freymond N, Catelain A, Cousin F, Rozieres A, Nicolas JF. Effects of local corticosteroids on acute experimental urticaria. Eur J Dermatol. 2004;14(5):323–6. 49. Cole ZA, Clough GF, Church MK. Inhibition by glucocorticoids of the mast cell-dependent weal and flare response in human skin in vivo. Br J Pharmacol. 2001;132(1):286–92.

249 50. Hammarlund A, Pipkorn U, Enerback L. Mast cells, tissue histamine and eosinophils in early- and late-phase skin reactions: effects of a single dose of prednisolone. Int Arch Allergy Appl Immunol. 1990;93(2–3):171–7. 51. Patterson DL, Yunginger JW, Dunn WF, Jones RT, Hunt LW. Anaphylaxis induced by the carboxymethylcellulose component of injectable triamcinolone acetonide suspension (Kenalog). Ann Allergy Asthma Immunol. 1995;74(2):163–6. 52. Dewachter P, Mouton-Faivre C. Anaphylaxis to macrogol 4000 after a parenteral corticoid injection. Allergy. 2005;60(5):705–6. 53. Aberer W, Bircher A, Romano A, Blanca M, Campi P, Fernandez J, et al. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy. 2003;58(9): 854–63. 54. Lauerma AH, Kiistala R, Makinen-Kiljunen S, Haahtela T. Allergic skin reaction after inhalation of budesonide. Clin Exp Allergy. 1993;23(3):232–3. 55. Aranda A, Mayorga C, Ariza A, Dona I, Blanca- Lopez N, Canto G, et al. IgE-mediated hypersensitivity reactions to methylprednisolone. Allergy. 2010;65(11):1376–80. 56. Karsh J, Yang WH. An anaphylactic reaction to intra- articular triamcinolone: a case report and review of the literature. Ann Allergy Asthma Immunol. 2003;90(2):254–8. 57. Dajani BM, Sliman NA, Shubair KS, Hamzeh YS. Bronchospasm caused by intravenous hydrocortisone sodium succinate (Solu-Cortef) in aspirin- sensitive asthmatics. J Allergy Clin Immunol. 1981;68(3):201–4. 58. Erstad BL. Severe cardiovascular adverse effects in association with acute, high-dose corticosteroid administration. DICP Annals Pharmacother. 1989;23(12):1019–23. 59. Kamm GL, Hagmeyer KO. Allergic-type reactions to corticosteroids. Ann Pharmacother. 1999;33(4):451–60. 60. Venturini M, Lobera T, del Pozo MD, Gonzalez I, Blasco A. Immediate hypersensitivity to corticosteroids. J Investig Allergol Clin Immunol. 2006;16(1):51–6. 61. Fulcher DA, Katelaris CH. Anaphylactoid reaction to intravenous hydrocortisone sodium succinate: a case report and literature review. Med J Aust. 1991;154(3):210–4. 62. Sieck JO, al-Ohaly Y, Saour J, Khan M, Henriquez H. An allergic reaction to intravenous methylprednisolone administration. Br J Clin Pract. 1990;44(12):723–5. 63. Rao KV, Andersen RC, O'Brien TJ. Successful renal transplantation in a patient with anaphylactic

250 reaction to Solu-Medrol (methylprednisolone sodium succinate). Am J Med. 1982;72(1):161–3. 64. Fernandez S, Reano M, Vives R, Borja J, Daroca P, Canto G, et al. 6-methylprednisolone-induced bronchospasm. Allergy. 1997;52(7):780–2. 65. Walker AI, Rawer HC, Sieber W, Przybilla B. Immediate-type hypersensitivity to succinylated corticosteroids. Int Arch Allergy Immunol. 2011;155(1):86–92. 66. Murrieta-Aguttes M, Michelen V, Leynadier F, Duarte-Risselin C, Halpern GM, Dry J. Systemic allergic reactions to corticosteroids. J Asthma. 1991;28(5):329–39. 67. Calogiuri GF, Muratore L, Nettis E, Ventura MT, Ferrannini A, Tursi A. Anaphylaxis to hydrocortisone hemisuccinate with cross-sensitivity to related compounds in a paediatric patient. Br J Dermatol. 2004;151(3):707–8. 68. Laine-Cessac P, Moshinaly H, Gouello JP, Geslin P, Allain P. Severe anaphylactoid reactions after intravenous corticosteroids. Report of a case and review of the literature. Therapie. 1990;45(6):505–8. 69. Peces R, Gorostidi M, Azofra J, Sanchez L, Alvarez J. Anaphylaxis following intravenous methylprednisolone sodium succinate in a renal transplant recipient. Nephron. 1991;59(3):497–8. 70. Mendelson LM, Meltzer EO, Hamburger RN. Anaphylaxis-like reactions to corticosteroid therapy. J Allergy Clin Immunol. 1974;54(3):125–31.

M. Baeck and A. Goossens 71. Mansfield LE, Ting S, Haverly RW. Anaphylaxis caused by the sodium succinate ester of hydrocortisone and methylprednisolone. J Asthma. 1986;23(2):81–3. 72. Ventura MT, Calogiuri GF, Matino MG, Dagnello M, Buquicchio R, Foti C, et al. Alternative glucocorticoids for use in cases of adverse reaction to systemic glucocorticoids: a study on 10 patients. Br J Dermatol. 2003;148(1):139–41. 73. Escribano-Rodriguez MM, Gonzalez-Pol J, Munoz- Bellido FJ, de la Calle-Toral A, Velazquez-Amor E, Conde-Hernandez J. Immediate reaction to methylprednisolone with tolerance of other corticosteroids. Allergy. 1997;52(6):677–8. 74. Erdmann SM, Abuzahra F, Merk HF, Schroeder A, Baron JM. Anaphylaxis induced by glucocorticoids. J Am Board Fam Pract. 2005;18(2):143–6. 75. Ventura MT, Sanapo F, Calogiuri GF, Satriano F. Anaphylaxis induced by intramuscular betamethasone disodium phosphate: reflections on a clinical case. Int J Immunopathol Pharmacol. 2007;20(2):387–91. 76. Patel A, Bahna SL. Immediate hypersensitivity reactions to corticosteroids. Ann Allergy Asthma Immunol. 2015;115(3):178–82.e3. 77. Otani IM, Banerji A. Immediate and delayed hypersensitivity reactions to corticosteroids: evaluation and management. Curr Allergy Asthma Rep. 2016;16(3):18.

28

Vaccines Giovanna Zanoni and Mariasole Migliorini

28.1 Introduction Vaccination is the most important public health intervention to control preventable infectious diseases. However, vaccines can cause adverse reactions, usually mild and self-limiting, while serious manifestations such as anaphylaxis are very rare. Hypersensitivity reactions can be triggered by microbial antigens or by other ingredients used in the preparation of vaccines. Patients at risk of allergic reactions deserve specialized evaluation and management [1, 2].

28.2 Clinical Manifestations 28.2.1 Injection Site Reactions After administration of parenteral vaccines, a local non-specific injection site reaction with pain, redness, swelling, and tenderness is very common [1]. This reaction is part of the immune response to injected material, and it commonly disappears in a few days. In a minority of cases, the reaction can be severe, with inflammation and

G. Zanoni (*) · M. Migliorini Green Channel Centre of the Veneto Region, Immunology Unit, University Hospital, Azienda Ospedaliera Universitaria Integrata, Verona, Verona, Italy e-mail: [email protected]

© Springer Nature Switzerland AG 2022 A. J. Bircher et al. (eds.), Cutaneous Drug Hypersensitivity, https://doi.org/10.1007/978-3-030-82743-4_28

edema extending beyond the nearest lying joint or lasting more than 72 h [3]. Rarely, vaccines can cause serious local reactions such as sterile abscess [1]. Infrequently patients can develop delayed hypersensitivity reactions to vaccines that manifest with a localized, or rarely diffuse, eczematous reaction, or persistent subcutaneous nodules at the site of vaccine injection. Various non-active vaccine components can induce delayed-type hypersensitivity, in particular adjuvants (aluminum salts) or residual production components, preservatives, or stabilizers (Table 28.1) [4].

28.2.2 Systemic Reactions Various adverse events, in particular cutaneous manifestations such as non-allergic skin rashes and delayed urticaria, sometimes accompanied by fever, malaise, or other non-specific symptoms, can occur after vaccine administration. These reactions appear several hours or a few days after vaccination, and they usually do not require diagnostic tests and do not contraindicate further vaccine administration [5, 6]. In case of rashes temporarily related to immunization, mostly occurring in children, an intercurrent viral illness should also be taken into account [7]. Known vaccine-related eruptions are varicella- like papules or vesicles that occur after varicella vaccine and morbilliform rash that appears after 251

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252 Table 28.1 Responsible components in hypersensitivity reactions to vaccines Mechanisms Type I IgE-mediated

Type III Immune complex reaction Type IV Cell-mediated

Vaccine components Tetanus, diphtheria toxoids Pneumococcal, Bordetella pertussis, influenza antigens HPV particles Residual food allergens: Gelatin (porcine or bovine), egg proteins, casein, yeast Latex Polysorbate 80 Tetanus, diphtheria toxoids Attenuated or inactivated viruses or bacteria Antibiotics: Neomycina, streptomycin, kanamycin, polymyxin B, gentamicin, chlortetraciyclin Preservatives: 2-phenoxyethanol, thimerosal, phenol Adjuvants: Aluminum salts Inactivating agent: Formaldehydea Polysorbate 80

Rare cases of immediate reactions have been reported

a

measles-containing vaccines. They typically manifest with a time interval of 3–30 days after immunization with a peak after 7–10 days, and they are related to the direct action of the live attenuated virus replication [8]. Anaphylaxis to vaccines has been reported with a frequency of 1.31/million doses [7]. Anaphylaxis is the most severe form of IgE- mediated reaction that involves vital organ systems, i.e., respiratory and/or cardiovascular system, and it is an acute, potentially life- threatening emergency. Various case definitions of anaphylaxis have been created; the most recent and easily applicable one is that updated by the European Academy of Allergy and Clinical Immunology [9]. An anaphylactic reaction to any vaccine is probable if it occurs within 1 hour and up to 4 hours after administration [10]. Anaphylaxis after vaccination represents a contraindication to the administration of the same vaccine components, although procedures for vaccine administration can be carried out in specialized settings (see below). It is important to distinguish anaphylaxis from other manifestations such as vasovagal syncope following immunization that can be mistaken for anaphylaxis. Other

conditions to be considered for differential diagnosis are seizures and hypotonic hypo-responsive episode characterized by the sudden onset of unresponsiveness, hypotonia, and pallor [5]. A cutaneous manifestation defined as discolored leg syndrome has been described in children after vaccination. It is characterized by a transient, patchy discoloration of the skin (being purple, red, blue, or pale) usually, but not mandatorily, in limbs where the vaccine was injected, although not radiating from the injection site. Swelling, petechiae, and fierce crying are often reported with discoloration. This reaction can appear usually within 48 hours (2 weeks for petechiae) after injection of combined diphtheria- tetanus- pertussis-inactivated polio and Haemophilus influenzae type b vaccine. It is considered a self-limiting vasomotor phenomenon with limited recurrence, and it does not contraindicate further injections of the same vaccines [11]. Children with mastocytosis present an increased risk of developing symptoms due to mast cell mediator release after vaccination. Therefore, in subjects with mastocytosis, it is recommended to administer vaccines in single injections avoiding co-administrations, under medical supervision for at least 30 minutes; anti-allergic premedication can be considered [12].

28.3 Mechanisms Vaccine-associated hypersensitivity due to immediate reactions to vaccine constituents is very rare but potentially life-threatening. IgE-mediated reactions can be suspected on the basis of the short time interval between vaccination and the acute onset of symptoms. Confirmation by allergy workup is recommended to identify the culprit allergens from the microorganism or other ingredients, in order to manage subsequent administrations. A complete list of all potential allergens in vaccines can be found at the website of the Institute for Vaccine Safety of the Johns Hopkins University [13]. Table 28.1 summarizes the most common triggers of hypersensitivity to vaccine components.

28 Vaccines

Hypersensitivity to tetanus and diphtheria toxoids has been rarely demonstrated and should be suspected in cases of immediate reactions to these vaccines. Toxoids are also present in small amounts as carriers of conjugated vaccines containing polysaccharide antigens, and they can cause allergic reactions as well [5]. Anecdotal reports of allergic reactions to other microbial antigens (pneumococcal, pertussis, influenza, and possibly HPV vaccines) have also been published [7, 14]. Egg allergy has been implicated as a cause of hypersensitivity reactions to vaccines, due to the small amount of egg proteins present in some products. Studies on large populations have demonstrated the safety of measles-mumps-rubella (MMR) vaccine and, more recently, also influenza vaccines for patients allergic to egg. Administration of yellow fever vaccine, due to the presence of a higher amount of residual ovalbumin, still requires additional precautions (see below). Animal gelatin is present in many food preparations and in some drugs. In some brands of vaccines, porcine or bovine gelatin is present in small quantities as a stabilizing agent. Subjects with severe allergy to animal gelatin are at risk of anaphylaxis when receiving gelatin-containing vaccines. Moreover, a case of anaphylaxis has been described after varicella zoster vaccine administration to a patient allergic to mammalian meat and sensitized to galactose-alpha-1,3- galactose [7]. Saccharomyces cerevisiae (Baker’s yeast) is the substrate used by some manufacturers to obtain HB and HPV vaccine or CRM197 carrier, and residual yeast protein can be present in the injectable preparation. Several cases of allergic reactions to vaccines where yeast has been demonstrated as the culprit allergen have been reported [4, 7]. Casein from cow’s milk can also be also used in the initial phases of vaccine production. A case series of anaphylactic reactions to vaccines containing traces of casein in children with severe milk allergy was published in 2011 [4]. In selected patients casein-free vaccines should be preferred if available.

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Natural rubber latex is a known cause of immediate hypersensitivity reactions including anaphylaxis. In some brands of vaccines, latex can be present in the vial stopper or the plunger of the syringe. Alternative vaccines with latexfree packages should be preferred in subjects with severe latex allergy, although the risk of immediate reactions in case of latex-containing vaccines has not been determined [5]. As for any patient, if a risk exists, however small, healthcare providers administering the vaccine should avoid penetrating the cap with the needle of the syringe when extracting the vaccine and be equipped to treat allergic reactions [3]. Type IV hypersensitivity reactions according to Gell and Coombs’ classification can be triggered by non-active constituents of vaccines (Table 28.1) [3]. Although these reactions do not contraindicate the use of vaccines containing these substances in sensitized subjects, because they are mostly non-serious and self-limiting manifestations such as contact allergy or rarely generalized rashes [4, 7], it is important to know them to evaluate the risk-benefit ratio of vaccination and to find an allergen-free product if available. If an alternative brand is not found, the vaccine can be administered when necessary. Deeper intramuscular injection is associated with a lower rate of these reactions [4]. The substances are declared in the manufacturer’s package insert, which should be checked during the allergological workup. They include the aptens described as follows. Trace amounts of antibiotics such as neomycin, gentamicin, kanamycin, tetracyclines, and polymyxin B used in the production process of some vaccines can cause injection site dermatitis or rarely a generalized cutaneous reaction [5]. Preservatives such as 2-phenoxyethanol, thimerosal, and phenol have been associated with local or systemic hypersensitivity reactions. Thimerosal has been removed from almost all single-dose vials of vaccines due to concerns regarding hypothesized but not proved neurological adverse reactions to mercury salts [7]. Aluminum salts (hydroxide and phosphate) are the most common adjuvants used in many inactivated vaccines. Contact allergy to a luminum

254

has been demonstrated by patch testing in children with persistent itching nodules at injection site, and the frequency of these reactions is approximately 1% [4]. Formaldehyde is used to inactivate microbial antigens during the vaccine preparation process, and it can be present in traces in some products. It can rarely trigger hypersensitivity reactions in sensitized subjects [15]. Polysorbate 80 is a small molecule present in some brands of vaccines as stabilizer; it has been implicated both in immediate (with positivity to allergy skin testing) and delayed reactions after HPV and pneumococcal vaccine injection, but very few cases have been described [4]. Hypersensitivity to vaccine antigens can also manifest with immune complex reactions (type III). Local (Arthus type) reactions involving the entire injected arm have been more frequently observed after booster doses of toxoids; systemic manifestations such as serum sickness or vasculitis have also been reported. Thrombocytopenia is a rare serious immuno-mediated adverse reaction associated with MMR vaccine. These events represent a contraindication to further doses of the same components; therefore, risk-benefit assessment should be carefully evaluated [3].

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teins and tetanus toxoid). Moreover, serum- specific IgE to vaccine antigen production is often part of the immune response, and it has a limited predictive value of an allergic reaction to a vaccine. When the culprit allergen is identified, an alternative brand free from the offending ingredient should be preferred if the patient needs additional doses. For some vaccines, serologic testing to measure antibody titers to assess the level of protection can be used to establish the need for further doses. Non-protected patients with negative skin test to the vaccine can be immunized with a full-strength dose; in case of previous history of anaphylaxis, a split dose strategy with initial 10% of the vaccine dose, followed 30 minutes later by the remaining 90% of the dose, is a more cautious option [4]. Patients with positivity to vaccine skin testing should undergo desensitization in graded doses. Increasing vaccine doses are administered every 15–30 minutes provided that there are no signs of allergic reaction (0.05 ml of 1:10 dilution and then 0.05 ml, 0.1 ml, 0.15 ml, and 0.2 ml of a 0.5 ml full-strength vaccine) [10]. Patients who have successfully undergone this protocol must still be considered allergic to the vaccine, and this procedure should be repeated in case of boosters. These vaccination approaches must only be used in a controlled 28.4 Diagnostic Methods setting where prompt treatment of anaphylaxis by experienced staff is available [4]. When an IgE-mediated reaction is suspected and In delayed reactions, patch testing, although the culprit allergen has not been identified, the not essential for therapeutic decisions, could help patient should undergo vaccine skin testing in a in identifying the culprit components and avoidsetting equipped to treat anaphylaxis. Prick test ing them if alternative apten-free brands are with full-strength vaccine followed by intrader- available. However, sensitization and contact mal test with 0.02 ml of vaccine diluted 1:100 allergy to specific components are not considered and, if negative, 1:10 dilution could follow, absolute contraindications, because the risks of although some authors describe irritant false- not being immunized outweigh problems caused positive reactions with this concentration. by delayed reactions [4]. Positive and negative control testing is recomVarious vaccine aptens for patch tests are mended. Prick test and/or IgE to specific food commercially available: aluminum chloride components present in suspected vaccines (egg hexahydrate and/or elemental aluminum, polyproteins, yeast, porcine gelatin) should be per- sorbate 80, thimerosal, formaldehyde, kanamyformed and interpreted according to current cin sulfate, polymyxin B and gentamicin, guidelines [4]. Interpretation of specific IgE test phenoxyethanol 1%, neomycin, and phenol. results needs expertise because commercially Patch tests should be removed at 48 hours and available vaccine allergens are limited (food pro- read at 72 and/or 96 hours or 1 week.

28 Vaccines

255 Clinical history of suspected hypersensitivity reaction

History consistent with nonallergic manifestations to vaccines

History consistent with immediate hypersensitivity to vaccine components

History consistent with delayed hypersensitivity to vaccine components

Additional doses of vaccine required?

Causality assessment + severity score

No Yes

No Yes

Stop

Additional doses of vaccine necessary Serologic testing for immunity No Yes

Immune Stop

Stop

Non-immune Serologic testing for immunity Immune

Immune Non-immune

Skin (prick, i.d.) test and/or Specific IgE

Patch testing

(-)

Non-immune Stop Immunization in separated single injections

(-)

Full strength vaccination under observation

(+)

(+)

Graded doses

Full strength vaccination

Vaccination with apten-free vaccine

Fig. 28.1 Algorithm for management of patients with suspected vaccine hypersensitivity

28.5 Management Concerns about possible allergic reactions to vaccines are frequently raised by parents/patients and healthcare providers; however, among adverse events following immunization (AEFI), true hypersensitivity reactions to vaccines are rare [15]. Standardized screening tools to register any situation that can represent a potential contraindication to vaccination are available [3]. An algorithm to select and manage vaccination of patients at risk of allergic reactions is proposed

in Fig. 28.1. If a vaccinee manifests any adverse event in temporal relationship to vaccination, it is important to evaluate the clinical history to identify the risk of allergic reactions, requiring a specialized evaluation before subsequent vaccinations. The main issues to be assessed in suspected allergic reactions are temporal relationship, type of reaction, brand of vaccine, risk factors if present (i.e., food allergy, severe uncontrolled asthma, mastocytosis), and need for further doses, to evaluate the risks and benefits of vaccination and communicate them to the vaccine providers.

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evaluation and management at the specialized Green Channel consultation clinic. Clin Exp Allergy. 2012 Jul;42(7):1088–96. 7. McNeil MM, Weintraub ES, Duffy J, et al. Risk of anaphylaxis after vaccination in children and adults. J Allergy Clin Immunol. 2016 Mar;137(3): 868–78. 8. Strebel PM, Papania MJ, Gastanaduy PA, Goodson References JL. Measles vaccines. In: Plotkin SA, Orenstein WA, Offit PA, editors. Plotkin’s vaccines. 7th ed. Elsevier; 2018. p. 579–618. 1. Mansoor O, World Health Organization. Regional Office for the Western Pacific. Immunization safety 9. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernandez Rivas M, et al. Anaphylaxis: guidelines surveillance: guidelines for immunization programme from the European academy of allergy and clinical managers on surveillance of adverse events followimmunology. Allergy. 2014;69:1026–45. ing immunization. 3rd ed. Geneva: World Health 10. Kelso JM, Greenhawt MJ, Li JT, et al. Adverse reacOrganization Press; 2015. tions to vaccines practice parameter 2012 update. J 2. Wood RA, Berger M, Dreskin SC, et al. Allergy Clin Immunol. 2012;130:25–43. Hypersensitivity working Group of the Clinical 11. Kemmeren JM, Vermeer-de Bondt PE, van Immunization Safety Assessment (CISA) network. der Maas NA. Discolored leg syndrome after An algorithm for treatment of patients with hypervaccination-descriptive epidemiology. Eur J Pediatr. sensitivity reactions after vaccines. Pediatrics. 2008 2009;168(1):43–50. Sep;122(3):e771–7. 3. Echeverría-Zudaire LA, Ortigosa-del Castillo L, 12. Bankova LG, Walter JE, Iyengar SR, Lorenzo ME, Hornick JL, Castells MC. Generalized bullous erupAlonso-Lebrero E, Álvarez-García FJ, Cortés- tion after routine vaccination in a child with diffuse Álvarez N, García-Sánchez N, Martorell-Aragonés cutaneous mastocytosis. J Allergy Clin Immunol A. Consensus document on the approach to children Pract. 2013 Jan;1(1):94–6. with allergic reactions after vaccination or allergy to vaccine components. Allergol Immunopathol (Madr). 13. Allergens in vaccines. Institute for Vaccine Safety, Jonhs Hopkins Bloomberg School of Public 2015 May-Jun;43(3):304–25. Health Baltimore. Updated dec 2018. http://www.vac 4. Nilsson L, Brockow K, Alm J, Cardona V, Caubet JC, cinesafety.edu/components-Allergens.htm. Accessed Gomes E, Jenmalm MC, Lau S, Netterlid E, Schwarze Feb 2019. J, Sheikh A, Storsaeter J, Skevaki C, Terreehorst I, 14. Nagao M, Fujisawa T, Ihara T, Kino Y. Highly Zanoni G. Vaccination and allergy: EAACI position increased levels of IgE antibodies to vaccine compopaper, practical aspects. Pediatr Allergy Immunol. nents in children with influenza vaccine-associated 2017 Nov;28(7):628–40. anaphylaxis. J Allergy Clin Immunol. 2016 5. Dreskin SC, Halsey NA, Kelso JM, Wood RA, Mar;137(3):861–7. Hummell DS, Edwards KM, Caubet JC, Engler RJ, Gold MS, Ponvert C, Demoly P, Sanchez-Borges 15. Caubet JC, Rudzeviciene O, Gomes E, Terreehorst I, Brockow K, Eigenmann PA. Managing a child with M, Muraro A, Li JT, Rottem M, Resenwasser possible allergy to vaccine. Pediatr Allergy Immunol. LJ. International consensus (ICON): allergic reactions 2014 Jun;25(4):394–403. to vaccines. World Allergy Organ J. 2016 Sep;9(1):32. 6. Micheletti F, Peroni D, Piacentini G, Schweiger V, Mirandola R, Chiesa E, Zanoni G. Vaccine allergy

However, the majority of people who experienced mild non-immunological manifestations can receive further doses, avoiding any delay in immunization.

Antiepileptic and Psychotropic Drugs

29

Andreas J. Bircher and Knut Brockow

Key Points • Among drugs with central nervous action, aromatic antiepileptic drugs are the most common elicitors of drug hypersensitivity reactions. • Psychotropic drugs (antidepressants, neuroleptics) rarely elicit hypersensitivity reactions. • Clinical manifestations include a vast range from maculopapular exanthem to potentially lethal toxic epidermal necrolysis and drug hypersensitivity syndrome. • Diagnosis is mainly based on history, clinical manifestations, and patch tests. • There is considerable cross-reactivity among aromatic antiepileptic drugs and rarely with tricyclic antidepressants.

A. J. Bircher (*) Allergology, Department of Dermatology, University Hospital Basel, Basel, Switzerland Faculty of Biomedicine, Università della Svizzera Italiana, Lugano, Switzerland e-mail: [email protected] K. Brockow Department of Dermatology und Allergology Biederstein, Technical University of Munich, Munich, Germany e-mail: [email protected] © Springer Nature Switzerland AG 2022 A. J. Bircher et al. (eds.), Cutaneous Drug Hypersensitivity, https://doi.org/10.1007/978-3-030-82743-4_29

29.1 Introduction According to the WHO [1], approximately 50 million adults and approximately ten million children [2] suffer from epilepsy worldwide; in the USA approximately three million adults and 0.5 million children are affected. In 40% of cases, epilepsy has an underlying central nervous system origin, whereas in 60% there is no identifiable cause. All patients with epilepsy require anticonvulsant therapy with antiepileptic drugs (AEDs) typically as long-term therapy, and approximately one-third require more than one AED; thus, a combination of two or more AEDs and permanent treatment is frequently required. Consequently, these drugs are used in patients with a wide age range from newborn to very old individuals, and treatment cannot be easily paused or changed. AEDs represent a very heterogenous group of drugs; their common denominator is their anticonvulsant activity and not their chemical structure or mechanism of action. They are grouped into three generations according to the year of respective introduction [3, 4]. There are currently 31 AEDs licensed for clinical use in total [4] for the treatment of epilepsy (Table 29.1), since the third-generation retigabine (ezogabine) has recently been withdrawn from the market. Indications for the various types of epilepsy can be found in the literature: some AEDs have orphan drug status, are indicated in children, or 257

258

are certified as add-on treatment only [5]. Other indications include chronic neuropathic pain (post-zoster, polyneuropathy), migraine, bipolar disorders, hyperactivity disorders, chorea, and chronic cough, but are frequently off-label use. The various mechanisms of action are not completely understood for most AEDs. Therefore, general deductions regarding adverse drug reactions (ADRs), particularly hypersensitivities, cannot be drawn. Over- or underdosing may occur due to interactions with food intake or due to metabolic interactions associated with the frequent use of several AEDs. Therefore, therapeutic drug monitoring of AEDs is often necessary [5]. Main adverse effects include psychotropic dysfunctions, e.g., altered perception, mood, consciousness, cognition, or behavior, or symptoms such as drowsiness, dizziness, sedation, somnolence, visual disturbances, coordination problems, as well as gastrointestinal disturbances, e.g., nausea, loss (anorexia) or increase of appetite, etc. In psychiatry, antidepressants and antipsychotics are the most frequently used psychotropic drug groups and are involved in the majority of severe adverse drug reactions [6, 7]; their most common ADRs involve again side effects on central nervous system functions.

29.2 Clinical Manifestations In a large pharmacovigilance study on AED- induced hypersensitivities, 40% involved the skin, and various exanthems were present in two-thirds of the cases. Other organs were also frequently affected (liver 17%, blood cells 13.5%, and lung 2.3%). Aromatic AEDs were significantly associated with cutaneous reactions, but not with hepatic, hematological, or pulmonary hypersensitivity reactions [8]. Manifestations such as urticaria, angioedema, and anaphylaxis, typically occurring in immediate type I reactions, appear to be exceptional. A series of children with angioedema from oxcarbazepine and a few cases of anaphylaxis, mostly in young children, and rarely bronchospasm have been reported under treatment with aromatic AED and levetiracetam [3, 9].

A. J. Bircher and K. Brockow

On the contrary, delayed occurring skin reactions ranging from uncomplicated maculopapular exanthem (MPE), fixed drug reaction (FDE), and phototoxicity (carbamazepine, phenobarbital, valproic acid) to severe cutaneous reactions including acute generalized exanthematous pustulosis (AGEP), severe cutaneous reactions (SCAR) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), as well as drug hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DHS/ DRESS) are not infrequent [10]. The latter was first described for aromatic AEDs as “anticonvulsant hypersensitivity syndrome.” Mild self-limiting MPEs are also more commonly caused by aromatic AEDs, e.g., phenobarbital, phenytoin, carbamazepine, and lamotrigine. For unknown reasons, lamotrigine appears to cause mild skin hypersensitivity reactions in 5–15% and severe variants in 3–4% of adults [11]. Switching from one to another aromatic AED can cause recurrence in 40% to 60% [3, 11–13]. The liver is also a commonly affected organ in ADR from AEDs and other psychotropic drugs [5, 14], ranging from transient serum aminotransferase increase to fulminant liver failure. There may be involvement limited to the liver, druginduced liver injury (DILI), or in the context of DHS/DRESS. It may be difficult to differentiate between toxic and immune-mediated liver injury.

29.3 Eliciting Drugs Hypersensitivity reactions from antiepileptic and psychotropic drugs are common. Particularly mild exanthems range from 1.7 to 8.8% for AEDs [12]; others report incidences as high as 3% to 16% in children and adults [3, 13]. The aromatic AEDs, particularly phenobarbital, phenytoin, primidone, carbamazepine, oxcarbazepine, eslicarbazepine, and lamotrigine (Fig. 29.1), are the most frequent elicitors of exanthems and severe hypersensitivities, including AGEP, SCAR, or DHS/DRESS [15], while most other AEDs have a risk 200,000 mg) of hydrochlorothiazide (but not of other diuretic agents) was associated with increased risk of non- melanoma skin cancer [14].

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dihydropyridines to non-dihydropyridines and vice versa following HSR to CCB [35]. Patch Furosemide also belongs to the sulfa non- testing with different CCBs should be considered antibiotic family [15]. Skin HSR caused by furo- [28, 33]. semide are uncommon (2 weeks). Lesions can occur after very short exposures, as in contact with contaminated clothing, or in cases of connubial or “by

37 Photosensitizing Drugs

proxy” dermatitis [12]. After UVA irradiation ketoprofen gives rise to stable photoproducts, namely, 3-hydroxy-ethyl-benzophenone, which explains cross-reactions with arylpropionic acid derivatives that share the benzophenone structure, namely, piketoprofen, dexketoprofen, tiaprofenic acid, and suprofen (not naproxen or ibuprofen), with benzophenone-derived UV filters, mainly oxybenzone, the UV filter octocrylene, and fenofibrate, an hypolipidemic agent that also has a common benzophenone structure and can cause systemic photosensitivity [12]. Interestingly, after systemic administration, ketoprofen does not reach significant concentrations on the skin, and, therefore, it seldom causes systemic photosensitivity. Etofenamate, another NSAID used topically, is also often responsible for allergic and photoallergic contact dermatitis, often in association with contact allergy or photoallergy to ketoprofen, probably due to concomitant sensitization [5]. Diclofenac can cause systemic photosensitivity, occasionally with photoonycholysis. With the recent introduction of topical diclofenac in a higher concentration (3%) for the treatment of actinic keratosis, several cases of photoallergic contact dermatitis to this NSAID have also been described.

37.4 Phenothiazines Systemic phenothiazines (chlorpromazine and thioridazine) are typically phototoxic, but they can also induce eczematous and lichenoid lesions with residual pigmentation [6]. Most recent cases of photoallergy to chlorpromazine have been reported due to direct skin contact with the tablets in caregivers who need to smash the tablets to give to patients with swallowing difficulties. Although highly phototoxic, when used topically some phenothiazines cause photoallergic contact dermatitis, namely, isothipendyl chlorhydrate and particularly promethazine used as topi-

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cal antipruritic/antihistaminic drugs and chlorproéthazine used in a cream for the treatment of muscle pain [1].

37.5 Anticancer Drugs Many classical anticancer drugs, namely methotrexate, dacarbazine, capecitabine, vinblastine, 6-mercaptopurin, and 5-fluoruracil, have been associated with photosensitivity, sometimes with pellagra-like reactions and occasionally with a recall phenomenon when further exposed to the drug without sun exposure. Paclitaxel and docetaxel have been associated with photosensitivity and drug-induced cutaneous lupus erythematosus. Many targeted therapies recently introduced in oncology are associated with cutaneous adverse effects, including photosensitivity. More than 50% of patients with metastatic melanoma under treatment with the BRAF inhibitor vemurafenib experienced immediate burning upon sun exposure followed by well-limited painful edema and erythema for a few days, mimicking erythropoietic porphyria. Photosensitivity extends to the long UVA spectrum and can be highly limitative but can be prevented by sun avoidance or sun protection [13], which is recommended also for other anti-melanoma drugs that are less frequently associated with photosensitivity: dabrafenib, ipilimumab, nivolumab, and pembrolizumab. The new kinase inhibitors used in oncology, particularly vandetanib, sorafenib, and imatinib, have been particularly associated with photosensitivity, in the case of imatinib often presenting as pseudoporphyria. In photodynamic therapy, photosensitizers (d-aminolevulinic acid, photofrin) are used to target tumor cells but may also be associated with unexpected photosensitivity. This is also observed in susceptible patients or when a high UVA dose is used during PUVA therapy in the treatment of cutaneous T-cell lymphoma, psoriasis, atopic dermatitis, or vitiligo.

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37.6 Other Photosensitizing Drugs

Baseline photopatch test series includes many drugs, namely, ketoprofen, etofenamate, piroxicam, benzydamine, and, in the extended series, The anti-arrhythmic amiodarone induces ery- also piketoprofen, dexketoprofen, ibuprofen, thema and, after long exposures, also a bluish- diclofenac, fenofibrate, and chlorpromazine [15]. gray hyperpigmentation in sun-exposed areas Apart from these, any other topical or systemic due to the dermal accumulation of drug metabo- drug suspected of causing photosensitivity can be lites. Other drugs used in the treatment of cardio- tested according to the general standardized provascular diseases, namely, diuretics cedures of photopatch testing and skin testing in (hydrochlorothiazide) and angiotensin receptor drug hypersensitivity [14]. antagonists (losartan, candesartan, olmesartan), In systemic photosensitivity photopatch tests can also induce phototoxic reactions [2, 4]. are often positive with piroxicam, as it involves a Pirfenidone, recently introduced in the treat- photoallergic mechanism, but other drugs (lomement of idiopathic pulmonary fibrosis, was floxacin, pirfenidone, fenofibrate) can also give reported to cause photosensitivity in about 12% positive results, although this is not frequent. It is of patients in clinical studies, usually as a mild nevertheless important to be aware that photoform and with a phototoxic pattern, but isolated toxic drugs may induce non-specific phototoxic cases suggesting photoallergy have also been false-positive tests, even if tested with the recomreported in the last years [4]. mended irradiation dose of 5 J/cm2 of UVA and at low drug concentrations, like chlorpromazine or promethazine at 0.1% pet [11]. 37.7 “Folk” Drugs In systemic photosensitivity, drug photoprovocation is also indicated. After exposing “Folk” medicines, mostly based on plant extracts the patient again to the possible culprit, several rich in photoactive furocoumarins, induce topical 2 × 2 cm squares of skin on the back are irradior, very occasionally, systemic photosensitivity. ated with increasing UV doses, usually UVA “Home-made” infusions of St. John’s wort (1–10 J/cm2), and readings performed within (Hypericum perforatum L.) to treat depression or 24–48 h. Also, the calculation of the minimal analogous preparations commercialized in some UVA/B erythema dose, when exposed to the European countries can induce severe reactions. drug and after drug withdrawal, may help identify the culprit.

37.8 Diagnosis of Drug Photosensitivity

37.9 Conclusions

With distinct clinical presentations, a variable time course, and a long list of possible culprits, drug photosensitivity may not be easily recognized. Apart from drug suspension and reintroduction with sun exposure to confirm imputability, phototests and photopatch tests can be performed to confirm a suspected culprit drug. Photopatch testing is indicated mainly for photoallergic contact dermatitis, but can also be useful in the study of systemic drug photosensitivity [5, 14]. The recommended European

Drug photosensitivity with classical photosensitizing drugs is still a frequent adverse event, even in countries with low sun exposure. For some new drugs, although premarketing tests are performed to predict their photosensitizing potential, we have to be alert to this possible unexpected adverse event. In drug photosensitivity it is important to recognize and avoid the correct culprit, as prolonged exposure may eventually be associated with enhanced skin photocarcinogenesis.

37 Photosensitizing Drugs

References 1. Gonçalo M, Giménez-Arnau AM. Drug photosensitivity. In: Katsambas A, Lotti T, Dessinioti C, editors. European handbook of dermatological treatments. 3rd ed. Berlin: Springer; 2015. p. 233–51. 2. Kim WB, Shelley AJ, Novice K, Joo J, Lim HW, Glassman SJ. Drug-induced phototoxicity: a systematic review. J Am Acad Dermatol. 2018;79(6):1069–75. 3. Monteiro AF, Rato M, Martins C. Drug-induced photosensitivity: photoallergic and phototoxic reactions. Clin Dermatol. 2016;34(5):571–81. 4. Nakao S, Hatahira H, Sasaoka S, Hasegawa S, Motooka Y, Ueda N, et al. Evaluation of drug-induced photosensitivity using the Japanese adverse drug event report (JADER) database. Biol Pharm Bull. 2017;40(12):2158–65. 5. Kerr AC, Ferguson J, Ibbotson SH, Dawe RS, Haylett AK, Rhodes LE, et al. A European multicentre photopatch test study. Br J Dermatol. 2012;166:5. 6. Ferguson J. Drug and chemical photosensitivity. 1st ed. New York: Oxford University Press; 1999. p. 155–69. 7. Grönhagen C, Fored C, Granath F, Nyberg F. Subacute cutaneous lupus erythematosus and its association with drugs: a population-based matched case-control study of 234 patients in Sweden. Br J Dermatol. 2012;167(2):296–305. 8. Haylett A, Felton S, Denning D, Rhodes L. Voriconazole-induced photosensitivity: photobiological assessment of a case series of 12 patients. Br J Dermatol. 2013;168(1):179–85.

319 9. Cowen E, Nguyen J, Miller D, Mcshane D, Arron S, Prose N, et al. Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole. J Am Acad Dermatol. 2010;62:31–7. 10. Gonçalo M, Figueiredo A, Tavares P, Fontes Ribeiro C, Teixeira F, Poiares BA. Photosensitivity to piroxicam: absence of cross reaction with tenoxicam. Contact Dermatitis. 1992;27:287–90. 11. Cardoso JC, Canelas MM, Gonçalo M, Figueiredo A. Photopatch testing with an extended series of photoallergens: a 5-year study. Contact Dermatitis. 2009;60(6):325–9. 12. Devleeschouwer V, Roelandts R, Garmyn M, Goossens A. Allergic and photoallergic contact dermatitis from ketoprofen: results of (photo) patch testing and follow-up of 42 patients. Contact Dermatitis. 2008;58:159–66. 13. Gelot P, Dutartre H, Khammari A, Boisrobert A, Schmitt C, Deybach J, et al. Vemurafenib: an unusual UVA-induced Photosensitivity. Exp Dermatol. 2013;22(4):297–8. 14. Barbaud A, Gonçalo M, Bircher A, Bruynzeel D. Guidelines for performing skin tests with drugs in the investigation of cutaneous adverse drug reactions. Contact Dermatitis. 2001;45:321–8. 15. Gonçalo M, Ferguson J, Bonevalle A, Bruynzeel D, Giménez-Arnau A, Goossens A, et al. Photopatch testing: recommendations for a European photopatch test baseline series. Contact Dermatitis. 2013;68(4):239–43.

Topically Applied Drugs

38

Liesbeth Gilissen and An Goossens

38.1 Introduction

from 14 to 55%; among 14,911 patients investigated for contact allergy in our tertiary referral Topically applied drugs may cause a variety of center, during a 25-year period between 1990 and adverse skin reactions, such as contact urticaria, 2014, 2600 subjects suffered from iatrogenic rosacea, acne, folliculitis, irritation, phototoxic contact dermatitis, i.e., 17.4% [2]. reactions, and, most commonly, allergic contact In order to diagnose the responsible agent, one dermatitis (ACD) [1]. In some cases the antigen has to perform patch tests with all ingredients of is generated by UV radiation, resulting in photo- the topical drugs used, and potentially cross- allergic contact dermatitis (PACD). Moreover, reacting chemicals may also be tested to eventufollowing sensitization to a topical drug, its per- ally search for safer alternatives. For ACD and cutaneous absorption or systemic administration PACD, the standard diagnostic method is patch may even induce a “systemic contact dermatitis”- testing and photo-patch testing (i.e., associated type reaction. ACD most often occurs in an iatro- exposure to medication and sunlight), respecgenic context; however, within the healthcare tively. If patch testing remains negative despite a sector or the pharmaceutical industry, also occu- high index of suspicion (i.e., a false-negative pational ACD may occur, often in an airborne patch test), eventually other test methods can be distribution. The actual culprits do not only con- used: repeated open application test (ROAT), use cern the pharmacologically active principles test, as well as prick or intradermal testing with (drugs) but also the vehicle components, includ- delayed readings, the latter most often in case of ing excipients, preservatives, antioxidants, emul- systemically induced drug eruptions. sifiers, and even fragrance components. The incidence of contact-allergic reactions to topical drugs varies geographically and depends 38.2 Risk Factors on local prescription and self-medication habits and on the presence of predisposing factors The incidence of ACD from topical products is which will be further described in this chapter. In influenced by several factors, such as high age the literature, the reported incidences are ranging and an impaired skin barrier, for example, in the presence of chronic dermatoses, such as stasis dermatitis, and particularly in the treatment of L. Gilissen · A. Goossens (*) wounds and leg ulcers [2]. This can be explained Department of Dermatology, University Hospitals by local inflammation and the use of occlusive KU Leuven, Leuven, Belgium bandages on damaged skin, favoring skin penee-mail: [email protected] © Springer Nature Switzerland AG 2022 A. J. Bircher et al. (eds.), Cutaneous Drug Hypersensitivity, https://doi.org/10.1007/978-3-030-82743-4_38

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tration, together with the use of multiple topical medicaments and dressings. Therefore, the most important lesion location of iatrogenic dermatitis is often on the legs. The prevalence of iatrogenic contact dermatitis does not increase with atopic dermatitis, even though such patients are often exposed to multiple topical agents. Another site at risk are the eyes, most often characterized by eyelid eczema, although conjunctivitis only may also occur. Moreover, the perianal areas have been frequently reported as affected sites; however, in our study, the more recent cases could be mostly attributed to isothiazolinone derivatives, preservative agents in wet wipes for intimate hygiene. Cosmetic dermatitis has indeed become increasingly important compared to topical pharmaceutical products for which positive patch test results have shown a descending trend over the years [2].

38.3 Topical Pharmacologically Active Agents Antibiotics, antiseptics, corticosteroids, and local anesthetics are among the most frequent contact sensitizers, though other classes may also be concerned, whereas nonsteroidal anti-inflammatory agents (NSAIDs) are particularly known for their photosensitizing properties. Sensitized subjects often present with multiple positive patch tests, due to concomitant use and/or cross-reactivity to chemically related substances. The different pharmacological classes and their cross-reaction patterns are discussed below.

38.3.1 Antibiotics Neomycin is routinely tested in the European baseline series, but sensitization rates have considerably decreased, probably because of prescription requirements. It is a marker though for other aminoglycoside antibiotics, such as gentamycin and tobramycin, with which there is a high rate of cross-reactivity. In recent years, the number of positive patch tests to clioquinol, to which there is no common exposure anymore,

Fig. 38.1 Allergic contact dermatitis from benzoyl peroxide in a preparation also containing adapalene, to treat acne

even ranges below 1%; hence, its inclusion in the baseline series is correctly questioned [3]. Other causal antibiotics are benzoyl peroxide (Fig. 38.1), polymyxin B sulfate, chloramphenicol nitrofurazone, fusidic acid, and mupirocin, all exerting a varying sensitization potential. Contact allergy from sulfonamides, such as sulfanilamide, potentially cross-reacting with paraphenylenediamine (e.g., in hair dyes), is historical as well.

38.3.2 Antiseptics At present, the most extensively used local antiseptic is povidone-iodine with positive patch test reactions to iodine being frequently observed; however, these need to be interpreted carefully, since their occlusion may also cause irritancy that could be misdiagnosed as contact allergy. Moreover, quaternary ammonium compounds, particularly cetrimonium bromide, and the biguanide compound chlorhexidine are also responsible for contact allergic reactions, the latter

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being sometimes tested in two different test preparations (Fig. 38.2). It may rarely also cause severe type I reactions, with which the chemically related compound polyaminopropyl bigua-

nide might partially cross-react. In the past, such reactions have also been described with bacitracin. Isopropanol (Fig. 38.3) is probably a rare, but sometimes relevant contact allergen, also occupationally. Mercurials, such as merbromine, are no longer used in clinical practice, because of their highly toxicological and sensitizing properties.

38.3.3 Antimycotics

Fig. 38.2 Patient with positive patch tests to both chlorhexidine compounds, i.e., diacetate and digluconate, the latter present in an antiseptic cream to which the patient reacted

a

Contact sensitization to antimycotics is uncommon, even though widely used, with imidazoles as the most reported culprit agents, i.e., miconazole, econazole, tioconazole, and isoconazole. Metronidazole used to treat rosacea has been occasionally reported as well. Cross-reactivity may occur (Fig. 38.3b), mainly within the compounds with a phenylethyl imidazole structure (except ketoconazole). When there is a need for antifungal therapy in sensitized patients, ketoconazole, clotrimazole, or bifonazole, or non-imidazole antifungals should be advised.

b

Fig. 38.3 The same patient as in Fig. 38.2, with positive patch test also to miconazole, (a) present in a cream to treat a mycotic infection, cross-reacting with econazole (b)

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38.3.4 Local Anesthetics

C16-methylated halogenated molecules, such as betamethasone, dexamethasone, mometasone, Sensitizing topical anesthetics are the esters of fluticasone, and clobetasol compounds. In the p-aminobenzoic acid (PABA), in particular, such baseline series, budesonide and tixocortol pivaas benzocaine, procaine, and tetracaine, hardly late are routinely tested as markers for contact being used anymore in topical medications for allergy and are, together, able to detect 88.5% of pruritus ani or hemorrhoids, or in anesthetic eye- the corticosteroid-allergic patients, and in some or eardrops. Benzocaine is still included in the countries also hydrocortisone-17-butyrate, baseline series, often cross-reacting to para- accounting for another 4% of the patients with phenylenediamine (PPD), as an indicator for sen- corticosteroid allergy [5]. Budesonide is no lonsitization to other “caines.” However, several ger used in skin preparations because of its high authors have suggested to rather test “caine- sensitization potential, while inhalation preparamixes” [4] that should preferentially contain tions (aerosols) only induce airborne sensitizaamide anesthetics, such as lidocaine, mepiva- tion in nurses or other subjects taking care of caine, and bupivacaine, which are much more in patients using them. Cross-reactivity occurs use nowadays, also in over-the-counter (OTC) mostly within the aforementioned groups, howproducts. Since there is lack of cross-reactivity ever, not in all cases. Therefore, for patients with between amide and ester derivatives, ACD from a positive test to one of the markers or to a spetopical anesthetics can presently be easily missed. cific corticosteroid used, it is recommended to Reactions to quinolone derivatives, such as dibu- test with an extended corticosteroid series in caine, have been observed as well. order to check for cross-sensitivity. A late patch test reading after 7–10 days is necessary in view of the anti-inflammatory properties of the drugs.

38.3.5 Corticosteroids

Contact allergy from corticosteroids has often been overlooked. Because of their intrinsic anti- inflammatory properties, the clinical features are indeed difficult to distinguish from chronic (sometimes atopic) eczema. However, when a dermatitis responds poorly or not at all to corticosteroid treatment and is more pronounced at the periphery of the treated zone, due to the so-called edge effect, contact allergy has to be considered. Their sensitization potential has been related to their chemical structure, and the most recent classification divides them into three major groups: group 1 being the non-methylated and most often non-halogenated molecules, which are the most important sensitizers, for example, hydrocortisone, methylprednisolone, and tixocortol pivalate; group 2, the halogenated molecules with a C16/C17cis-ketal/diol structure, such as budesonide (which may also cross-react with group 1), triamcinolone acetonide, amcinonide, and desonide; and group 3, the least sensitizing

38.3.6 NSAIDs Within this group, the arylpropionic acid derivative ketoprofen has been most frequently reported, responsible for ACD, but also reactions worsened by UV exposure referred to as “photo- aggravation,” and, mostly, photo-allergic contact dermatitis, often with severe clinical symptoms [6] (Fig. 38.4). Moreover, it often gives rise to multiple positive patch tests, i.e., balsam of Peru, fragrance mix I, and particularly cinnamic alcohol (present in both of them), as well as photopatch test reactions to several other chemicals, including the sunscreens benzophenone and octocrylene, the latter containing benzophenones as impurities. Indeed, the mutual benzophenone moiety, formed by photodegradation of ketoprofen, is put forward as the responsible mechanism. Also etofenamate frequently causes ACD and PACD, in the latter case often concomitant to ketoprofen; besides in the case of concomitant

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38.3.7 Other Active Principles

Fig. 38.4 Severe photo-allergic contact dermatitis following the use of ketoprofen gel

exposure, no explanation has been put forward yet. Nevertheless, the addition of both NSAIDs to the European photo-patch test series in 2013 has certainly contributed to improved detection, and for ketoprofen, prescription use—only since 2010—has led to more awareness among physicians and patients. In case a NSAID is needed, diclofenac seems a good alternative since it does not cross-react. Systemic photosensitization to piroxicam may be diagnosed by a positive patch test to thimerosal, particularly to its thiosalicylic acid part, being a photoproduct of piroxicam. Positive patch tests to bufexamac are no longer seen or certainly not relevant anymore, since it has been withdrawn from the EU market in 2010, because of its high sensitizing properties.

Focusing on eye medication, ACD from mydriatics (such as phenylephrine and atropine), and β-blockers (such as timolol and carteolol) are of special interest, the latter often giving rise to false-negative reactions, and thus sensitization is often overlooked. Antihistamines, such as diphenhydramine, are much less in use nowadays. Many other topical drugs, used to treat various diseases, may give rise to contact allergy, for example, minoxidil against hair loss, mephenesin as a muscle relaxant, nitroglycerin in topical transdermal systems for the treatment of angina pectoris, the cytostatic agent fluorouracil, and methyl aminolevulinate for the treatment of actinic keratosis [2]. Also topical immunomodulators, such as pimecrolimus and tacrolimus that suppress the pro-inflammatory cytokine production by cutaneous T and mast cells in the treatment of atopic dermatitis, and calcipotriol, a vitamin D derivative used to treat plaque psoriasis, have been reported [7, 8]. Not only drugs that require a medical prescription but also over-the-counter topical products, some of them even marketed as cosmetic products or medical devices, have to be taken into account. Moreover, also herbal remedies, claiming to contain “only natural ingredients,” which patients seem to relate to safety, often sensitize [9]. One of the commonest botanical allergens is Myroxylon pereirae (balsam of Peru), luckily, less used in pharmaceutical preparations nowadays, at least in Belgium. The same applies to tincture of benzoin, with which it cross-reacts, used to be applied on the skin as an antiseptic and degreaser to increase the adherence of adhesive tapes or bandages. On the contrary, Compositae plants such as Calendula officinalis, Chameamelum nobile, Echinacea purpurea, and Arnica montana are incorporated in various topical products, because of their wound-healing properties. Interestingly, also photo-aggravation has been reported from them. Other components of interest are essential oils, such as lavender and geranium oil used for their anti-inflammatory capacity, thyme oil used for its antibacterial properties, and propolis and tea tree oil (obtained

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from Melaleuca alternifolia), both used to treat various skin diseases such as acne, burns, and fungal infections.

38.4 Vehicle Components Vehicle components include excipients, preservatives, antioxidants, emulsifiers, and fragrance components. Frequently encountered allergens among the excipients of topical pharmaceutical products used to be wool alcohols as present in eucerin and lanolin, particularly in leg ulcer patients (Fig. 38.5). In a previous study conducted in our center regarding 17,367 consecutive patients patch tested between 1990 and 2013, 354 presented with a positive reaction to them [10]. The incidence of positive reactions has considerably decreased over the years though, which can be attributed to the use of wound dressings instead of wound-healing ointments. Other common vehicle components identified were propylene glycol, sorbitan oleate esters, and cetyl and stearyl alcohol. Preservatives encountered as contact allergens were, for example, benzoic and sorbic acids and rarely parabens at present. Contact allergy to benzalkonium chloride (as thimerosal in the past) is relevant for eye medication, in particular.

Fig. 38.5 Stasis dermatitis patient with a positive patch test to wool alcohols

Moreover, (metabi)sulfites, widely used antioxidants, frequently produce positive patch test reactions, the sensitization source of which is not always easily retrieved. Last but not least, also sensitizing fragrance ingredients are present in many topical medications.

38.5 Systemic Contact Dermatitis In some cases, patients sensitized to a topical contact allergen develop a generalized eruption when they are systemically (via oral, transmucosal, transcutaneous, parenteral, or respiratory) re- exposed to the allergen, or to a cross-reacting substance. It manifests mostly as symmetric vesicular palmar and/or plantar dermatitis, flexural dermatitis, eyelid dermatitis, maculopapular rash, or symmetrical drug-related intertriginous and flexural exanthema (SDRIFE or “baboon syndrome,” a symmetrical dermatitis involving mainly the body folds). Interestingly, also reactivation of a previous patch-tested site or flare-up of the previous dermatitis may be observed. Exceptionally, general symptoms may occur such as fever, malaise, headache, diarrhea, and vomiting.

38.6 Conclusions Various ingredients of topical drugs can cause ACD, mostly arising as a complication of a preexisting, often eczematous dermatitis, or wounds (e.g., leg ulcers). Therefore, whenever dermatitis does not improve despite adequate treatment, patch tests should be performed. A minority of culprits are tested in the baseline series; however, it is important to also test with the topical products itself, as well as all their ingredients. Cross- reactivity with chemical analogues and alternative treatments should be checked for. Since many vehicle compounds are also found in cosmetics, sensitized patients should be advised regarding these products as well.

38 Topically Applied Drugs

References 1. Goossens A, Medeiros S. Allergic contact dermatitis from topical medicaments. Expert Rev Dermatol. 2008;3:37–42. 2. Gilissen L, Goossens A. Frequency and trends of contact allergy to and iatrogenic contact dermatitis caused by topical drugs over a 25-year period. Contact Dermatitis. 2016;75:290–302. 3. Uter W, Spiewak R, Cooper SM, et al. Contact allergy to ingredients of topical medications: results of the European Surveillance System on Contact Allergies (ESSCA), 2009–2012. Pharmacoepidemiol Drug Saf. 2016;25:1305–12. 4. Brinca A, Cabral R, Gonçalo M. Contact allergy to local anaesthetics – value of patch testing with a caine mix in the baseline series. Contact Dermatitis. 2012;68:156–62.

327 5. Baeck M. Delayed hypersensitivity to corticosteroids in a series of 315 patients: clinical data and patch test results. Contact Dermatitis. 2009;61:163–75. 6. Kerr A, Ferguson J, Haylett AK, et al. A European multicentre photopatch test study (EMCPPTS Taskforce). Br J Dermatol. 2011;21:295. 7. Schmutz JL, Barbaud A, Tréchot P. Contact allergy with tacrolimus then pimecrolimus. Ann Dermatol Venerol. 2008;135:89. 8. Gilissen L, Huygens S, Goossens A. Allergic contact dermatitis caused by calcipotriol. Contact Dermatitis. 2018;78:139–42. 9. Gilissen L, Huygens S, Goossens A. Allergic contact dermatitis caused by topical herbal remedies: importance of patch testing with the patients’ own products. Contact Dermatitis. 2018;78:177–84. 10. Goossens A. Allergic contact dermatitis from the vehicle components of topical pharmaceutical products. Immunol Allergy Clin N Am. 2014;34:663–70.

Index

A Abciximab, 227 Acneiform, 234 Acute generalized exanthematous pustulosis (AGEP), 29, 102, 110, 138, 279 Acute interstitial nephritis, 32 Acute tubulointerstitial nephritis, 32 Additive. See Excipients Adolescents incidence, 135 recurrent ampicillin-induced MPEs, 137 Adults immediate hypersensitivity reactions, 161 Adverse drug reactions (ADR), 135, 136, 258 Allergen-specific IgE (sIgE), 112 Allergic contact dermatitis (ACD), 189, 240, 321 active principles, 325, 326 antibiotics, 322 antimycotics, 323 antiseptics, 322, 323 corticosteroids, 324 incidence, 321 local anaesthetics, 324 NSAIDs, 324, 325 risk factors, 321, 322 systemic contact dermatitis, 326 vehicle components, 326 Allergic non-cross intolerant reactions or selective reactors (SR), 142, 143 Aluminum-induced granuloma, 305 Aminoglycosides antibiotics, 189, 190 Amiodarone, 318 Amprenavir, 152 Anaphylaxis, 4, 22, 252 diagnosis of, 162 MC syndrome (see Mast cell (MC) releasing syndromes) Angioedema, 22, 281, 282 Angiotensin converting enzyme (ACE), 281 Angiotensin converting enzyme inhibitors (ACE-I), 281, 282 Angiotensin receptor blockers (ARBs), 282 Anti-acid therapy, 269 Antibiotic-induced skin rash (ASR), 136 © Springer Nature Switzerland AG 2022 A. J. Bircher et al. (eds.), Cutaneous Drug Hypersensitivity, https://doi.org/10.1007/978-3-030-82743-4

Anticancer drugs, 317 Anticoagulants antiplatelet drugs cyclooxygenase inhibitors, 226 glycoprotein (GP)-IIb-IIIa-receptor antagonists, 227 P2Y12-inhibitors/thienopyridins, 226, 227 phosphodiesterase III inhibitors, 227 DOAC direct factor Xa-inhibitors, 225, 226 heparins and derivatives cell-mediated, DTH, 224, 225 heparinoids, 225 HIT, 225 ITH, 225 pentasaccharides, 224 UFH and LMWH, 224 vitamin K antagonists/coumarins, 224 Antiepileptic drugs (AED) adverse effects, 258 anticonvulsant therapy, 257, 259 clinical manifestations, 258 cross-reactivity, 262, 263 diagnostic methods, 262–264 eliciting drugs, 258, 260, 261 management, 264, 265 mechanisms, 261 predisposing and risk factors, 261, 262 Antifungal drugs, 149 Antigen-presenting cells (APCs), 79 Antihistamines, 325 Antiinfectious drugs amphotericin B, 194 anti-herpes and anti-CMV drugs, 194, 195 antiretroviral substances - abacavir, 195 chloroquine and hydroxychloroquine, 193 dapsone–diaminodiphenylsulfone, 193 fluconazole, 194 itraconazole, 194 ketoconazole, 194 pentamidine, 193 quinine, 194 terbinafine, 194 Antimycotics, 323 329

Index

330 Antiplatelet drugs cyclooxygenase inhibitors, 226 glycoprotein (GP)-IIb-IIIa-receptor antagonists, 227 P2Y12-inhibitors/thienopyridins, 226, 227 phosphodiesterase III inhibitors, 227 Antiretroviral drugs CCR5 inhibitor, 152 fusion inhibitors, 152 integrase inhibitor, 152 non-nucleoside reverse transcriptase inhibitors, 151 nucleoside reverse transcriptase inhibitors, 150 protease inhibitors, 152 Antiretroviral substances - abacavir, 195 Antiseptics, 322, 323 Antitumor/cytostatic drugs, 298 Anti-ulcer drugs, 269 Argatroban, 226 Asparaginase, 301 Atazanavir, 152 Autoimmune hemolytic anemia (AIHA), 36 Auto-immune progesterone dermatitis (AIPD), 246 B Basophil activation tests (BAT), 112, 174, 181, 220, 270 activation markers, 96 acute phase of reaction, 95 clinical evaluation chemotherapeutic drugs, 95 clavulanic acid hypersensitivity, 94 fluoroquinolone hypersensitivity, 94, 95 diagnosis, 91 drug degradation, 96 drug metabolite, 96, 97 IgE antibodies/T-cells, 92 IgE mediated DHRs, 94 NSAIDs, 94 strength and weakness, 95, 96 test principle activation marker expression, 92 advantages, 92 allergen specific activation, 92 calcium release, 93 drug concentrations, 93 IgE-mediated mechanism, 94 non-responders, 93 results, 93 sensitivity, 93 Benzyl alcohol, 306 Beta and alpha blockers, 280, 281 β-lactam antibiotics delayed reactions, 138, 139 diagnostic tools, 139, 140 immediate reactions, 138 diagnostic tools, 139 Biological agents (BA), 236 Biopharmaceuticals, 22, 25 Budesonide, 324

C C16/C17cis-ketal/diol structure, 324 C16-methyl substitution, 242, 243, 246 Calcium channel blockers (CCB), 280 Carboplatin, 119, 120 Carboxymethylcellulose (CMC), 306, 307 Casein, 253 CCR5 inhibitor, 152 Cephalosporin allergy administration of alternative drugs, 185 aztreonam, 184 imipenem/cilastatin, 184 penicillins, 184 clinical history, 180 immediate hypersensitivity reactions chemical structures, 179 clinical features and mechanisms, 177, 180 work-up, 180–182 nonimmediate hypersensitivity reactions clinical features and mechanisms, 180 work-up, 182–184 Cetuximab, 234 Chemotherapy, 22, 25 Chemotherapy-induced alopecia (CIA), 303 Children β-lactam antibiotics, 137 delayed reactions, 138, 139 diagnostic tools, 139, 140 immediate reactions, 138 non β-lactam antibiotics, 140, 141 genetic predisposition, 137 HLA alleles, 137 incidence, 135, 136 nonsteroidal anti-inflammatory drugs, 143 classification of hypersensitivity, 141 desensitization, 144 diagnostic tests and management, 142, 143 natural history, 144 non-allergic cross-intolerant reactions, 141, 142 vaccines egg and milk allergic children, 145 gelatin and latex allergic patients, 145 immediate reaction, 145 local reactions, 144 systemic reactions, 144, 145 viral/bacterial infections, 136, 137 Cimetidine, 268 Cisplatin, 120 Complement activation-related pseudoallergy (CARPA), 289 Corticosteroids (CSs), 324 allergic reactions, 239 delayed allergic hypersensitivity ABCD classification, 242, 243, 246 classification, 244–245 clinical presentation, 240, 241

Index halogenation and C16-methyl substitution, 242, 243, 246 patch testing, 242 sensitization and elicitation route, 239, 240 immediate allergic hypersensitivity clinical presentation, 246 cross-reactivity patterns, 247 diagnosis, 246 pathogenesis, 247 Cutaneous drug hypersensitivity clinical manifestation acute infusion reactions, 233 delayed infusion reactions, 234 conventional chemotherapy, 301 diagnostic methods, 236, 237 management, 237 mechanisms, 234–236 toxic erythema, 301 Cutaneous drug hypersensitivity reaction (CDHR) diagnostics methods, 23, 25–27 management, 27 Cyanocobalamin, 294 Cyclooxygenase inhibitors, 226 Cytokine-release reactions (CRRs), 111 D Dabigatran, 226 Danaparoid, 225 Danger signs, 25, 26 late occurring reactions, 43, 44 rapidly occurring reactions, 43, 44 skin lesions, 44 systemic danger signs, 44 Darunavir, 152 Delayed hypersensitivity, 110 Delayed-onset allergic reactions, 310 Delayed-reading intradermal tests (IDT), 182–184 Delayed-type hypersensitivity (DTH), 224, 225, 308 Desensitization (DS) actin cytoskeleton remodeling, 114, 116 algorithm, 118–119 antibiotics β-lactam, 119 monoclonal antibodies(mAbs), 121, 122 platins (carboplatin, oxaliplatin, cisplatin), 119, 120 taxanes (paclitaxel and docetaxel), 120 antigen/IgE/FcεRI complex mobility, 114, 116 classical classification of, 109 contraindications, 118 definition, 109, 113 endotypes, 117 IgE, 114 mast cell activation, 114, 115 mast cell degranulation, 114, 116 mechanisms, 114 personalized protocols, 113 phenotypes, 117 progestogen hypersensitivity, 122, 123

331 risk stratification, 117 skin testing, inhibition of, 114 stratification, 117 Diclofenac, 317 Direct factor IIa-inhibitors/thrombininhibitors, 226 Direct factor Xa-inhibitors, 225, 226 Directly acting oral anticoagulants (DOAC) direct factor IIa-inhibitors/thrombininhibitors, 226 direct factor Xa-inhibitors, 225, 226 Discharge letter/certificate, 128 Docetaxel, 301 Documentation discharge letter/certificate, 128, 129 drug allergy card, 128, 129, 131 drug allergy passport, 128–130 requirements, 129, 131 Dolutegravir, 152 Drug allergy, 109 alert card, 128, 131 cardiac manifestations, 32, 33 hepatic manifestations DRESS, 30 flucloxacillin, 30, 31 immune checkpoint inhibitors, 31 LTT, 31 pathomechanism, 29, 30 HHV, 34–36 kidney injury, 31, 32 lung manifestations, 33, 34 organ manifestations, 36 passport, 128–130 Drug desensitization, 204 Drug hypersensitivity chronology, 5–7 clinical phenotype, 4 definition, 3 pathomechanisms, 7, 8 Coombs and Gell’s classification, 48, 49, 54 drug hypersensitivity syndrome (DHS), 49, 50 drug-induced liver injury (DILI), 50 skin manifestation, 51–54 severity grades classification, 5 exanthematous reactions, 5 prognosis and treatment, 4 prognostic score, 5, 6 vitamins and supplements clinical manifestation, 291, 292 cross-reactions, 293 diagnostic methods, 293 management, 293, 294 mechanisms, 292 Drug hypersensitivity syndrome (DHS), 49, 50 Drug patch tests (DPTs) clinical application, 64 concentration, 63, 64 limitations, 64 prick tests (see Drug prick tests) principle, 62, 63 Drug photoprovocation, 318

Index

332 Drug prick tests clinical application, 64 limitations, 65 principle, 64 Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, 24, 29, 30, 102, 110, 137, 234 Drug reactions, 109 Drug skin tests immediate/delayed reactions, 62 patch tests (see Drug patch tests) Drug-induced autoimmune hepatitis, 30 Drug-induced liver injury (DILI), 29, 30, 50 E Efavirenz, 151 Egg protein, 308 Elvitegravir, 152 Enfuvirtide, 152 Engerix B®, 309 Enzyme-linked immunosorbent spot (ELISpot), 174 Eosinophilic tubulointerstitial nephritis, 32 Epidemiology absolute risks, 15 drug exposure, 14, 15 measures of frequency, 12 observational studies, 11, 13 prevalence and incidence, 12, 13 risk estimates, 12 SCAR, 16, 17 Epidermal/epithelial necrolysis (TEN), 24 Epinephrine, 221 Epstein-Barr virus (EBV), 136 Etofenamate, 317 Etravirine, 151 Exanthemas, 170 AGEP, 102 clinical presentation, 99 DRESS, 102 drug induced vasculitis, 100, 101 epidermal dysmaturation, 102, 103 FDE, 101, 102 HFSR, 103 interstitial granulomatous drug eruption, 103 lichenoid drug reaction, 101 lymphomatoid drug reaction, 101 MPE, 100 paradoxical psoriasiform rash, 103 photo-allergic reactions, 100 photo-toxic reactions, 100 principle, 99, 100 RASopathic skin eruption, 103 SDRIFE, 100 skin toxicities, 103 strength and weaknesses, 105 suppurative folliculitis and perifolliculitis, 103, 104 TEN/SJS, 101, 102 urticarial drug reaction, 100

Excipients aluminum-induced granuloma, 305 antibiotics, 306 benzyl alcohol, 306 CMC, 306, 307 dyes, 307, 308 egg protein, 308 gelatin, 308 metacresol, 308 non ionic polyethoxylated surfactants, 310 povidone, 308, 309 protamine, 309 sodium benzoate, 309 sulfites, 309, 310 zinc oxide, 310 F Ferric gluconate, 289 Fixed drug eruption (FDE), 22–25, 101, 102, 138 Flucloxacillin, 30, 31 Fluoroquinolones, 314 Folic acid, 292 Folk drugs, 318 Formaldehyde, 254 Fosamprenavir, 152 Furosemide, 280 Fusion inhibitors (FI), 152 G Gabapentin-related exanthems, 261 Gadolinium-based contrast agents (GBCA) clinical manifestations, 273, 275 diagnosis, 275, 276 management, 276 mechanisms, 275 Gelatin, 308 Genetic factors, 136, 137 Glycoprotein (GP)-IIb-IIIa-receptor antagonists, 227 Graft vs. host disease (GvHD), 34 Grisefulvin, 316 H Halogenation and C16-methyl substitution, 242, 243, 246 Hand-foot syndrome (HFS), 299, 302 Hand-foot-skin reaction (HFSR), 103 Hematoxylin and eosin (H&E), 99 Hemophagocytic lymphohistiocytosis (HLH), 35 Hemophagocytic syndrome, 35 Heparin induced thrombocytopenia (HIT), 225 Heparinoids, 225 Heparins cell-mediated, DTH, 224, 225 heparinoids, 225 HIT, 225 ITH, 225

Index pentasaccharides, 224 UFH and LMWH, 224 HHV-6-B micro-RNAs (miRNA), 35 High-molecular-weight-iron dextran (HMW-ID), 287 Histamine, 219 HIV-infected patients antifungal drugs, 149 antiretroviral drugs non-nucleoside reverse transcriptase inhibitors, 151 nucleoside reverse transcriptase inhibitors, 150 anti-TB drugs, 148, 149 CCR5 inhibitor, 152 challenging management, 153 cotrimoxazole, 148 fusion inhibitors, 152 genetic predisposition, 148 integrase inhibitor, 152 maculopapular exanthema, 147 pathophysiology, 147 protease inhibitors, 152 toxoplasmic encephatilits, 149 H2 receptors antagonists (H2RA), 267 clinical manifestation, 268, 269 cross-reactivity, 271 skin tests and in vitro test, 270, 271 Human herpes virus 6 (HHV-6), 137 Human herpesvirus (HHV), 34–36 Human immunodeficiency virus (HIV), 137 Human leucocyte antigens (HLA), 79, 80, 261, 262 Hypersensitivity, 254 blood pressure agents ACE-I, 281, 282 adverse events, 279 ARBs, 282 beta and alpha blockers, 280, 281 CCB, 280 direct renin antagonists, 282 furosemide, 280 RAAS, 281 spironolactone, 282, 283 thiazide diuretics, 279 diagnostic agent adverse reactions, 273 dyes, 276, 277 RCM and GBCA, 273–276 Hypersensitivity coronary syndrome, 33 Hypersensitivity reactions (HSRs), 270, 300 atopic patients, 109 biomarkers allergen-specific IgE, 112 skin test, 112 causes, 109, 110 delayed hypersensitivity, 110 endotypes, 110 immediate hypersensitivity, 110 mediators basophil activation test, 112 granzyme B/granulysin markers, 112 HLA markers, 112

333 IL-6, 112 patch testing, 112 tryptase, 112 modified Brown classification, 110 molecular pathways cytokine-release reactions, 111 infusion related reactions, 111, 112 mixed reactions, 112 type I reactions, 110, 111 type II reactions, 111 type III reactions, 111 type IV reactions, 111 personalized and precision medicine, 109 phenotypes, 110 Hypochloridia, 269 3-hydroxy-ethyl-benzophenone, 317 I Iatrogenic contact dermatitis, 322 IgE-mediated allergy, 185 Immediate hypersensitivity, 110 Immediate hypersensitivity reactions cephalosporin allergy clinical features and mechanisms, 177, 180 work-up, 180–182 Immediate type hypersensitivity (ITH), 225 Immune checkpoint inhibitors, 31 clinical features, 156 diagnosis, 156 grading, 156 lichenoid rash, 157 maculo-papular rash, 156, 158 pruritus, 157, 158 vitiligo, 157, 158 xerosis cutis, 157, 158 management, 158 mechanisms, 155 Immune-related adverse events (irAEs), 156 Immunoassays, 92, 173, 174, 182 ImmunoCAP® system, 139 Indolent systemic mastocytosis (ISM), 163 Infectious mononucleosis (IM), 136 Infusion related reactions (IRRs), 111, 112 Injection site reactions (ISR), 25, 234 Integrase inhibitor, 152 Interferon-gamma (IFN-γ), 50 Intradermal tests (IDT), 270, 306 clinical application, 66 concentration, 66, 67 principle, 65, 66 strength and limitations, 67 Intrarenal necrotizing vasculitis, 32 In vitro diagnostics test immediate reactions basophil activation test, 174 immunoassays, 173, 174 non-immediate reactions ELISpot, 174 lymphocyte transformation test, 174

334 Iron NDIPs characteristics, 287, 288 clinical manifestations, 289 diagnosis, 290 epidemiology, 289 history, 287 HSRs, 290 iron infusions, 289 pathomechanism, 289 re-administration, 290 risk factors, 289 parenteral iron, 287 prevalence, 287 Iron sucrose, 289 K Ketoprofen, 316 L Leg ulcers, 321 Leukocytoclasia, 100, 101 Leukocytoclastic vasculitis, 32 Lichenoid rash, 157 Local anaesthetics, 324 Low-molecular-weight iron dextran (LMW-ID), 287 Low molecular weight heparins (LMWH), 224 Low reactogenic administration protocol (LRPs), 290 Lupus erythematosus (LE), 35 Lymphocyte activation test (LAT), 184, 270 Lymphocyte transformation test (LTT), 31, 174, 184 M Macrolides, 188, 189 Maculopapular exanthema (MPE), 52, 100, 147 with bullae, 23, 24 characteristic distribution patterns, 24 diagnosis, 22, 23 papules, 24 pustules, 24 severe systemic organ involvement, 24 vasculitis, 24 Maculo-papular rash, 156, 158 Major histocompatibility complex (MHC), 79, 80 Maraviroc, 152 Mast cell activation, 114, 115 degranulation, 114, 116 Mast cell (MC) releasing syndromes anaphylaxis, 162 anesthetic management, 163, 164 clinical manifestation, 161, 162 diagnostic methods, 163 drug recommendations, 164 mechanisms, 162, 163

Index systemic mastocytosis, 163 Measles-mumps-rubella (MMR) vaccine, 253 Medical intensive care unit (MICU), 122 Metacresol, 308 Monoclonal antibodies (mAbs), 121–123 (Mono)clonal MC activation syndrome (MMAS), 163 MRGPRX2 receptor, 218 Muscle relaxants cardiovascular signs, 216 cellular assays, 220 clinical manifestations, 216 delayed immune-mediated hypersensitivity reactions, 218 gastrointestinal signs, 216 immediate immune-mediated hypersensitivity reactions IgE pathway, 217 IgG pathway, 218 NMBA-specific IgE antibodies and influence of environmental factors, 217, 218 incidence, 215 mechanisms, 216 NMBA-related hypersensitivity reactions, 220, 221 non-immune-mediated hypersensitivity reactions cellular assays, 220 diagnostic methods, 218 IgE assays, 220 mechanisms, 218 provocation tests, 220 skin tests, 219, 220 tryptase and histamine measurement, 219 respiratory signs, 216 skin, 216 Myroxylon pereirae, 325 N Neomycin, 322 Neuromuscular blocking agents (NMBAs), see Muscle relaxants Nevirapine, 151 Nitroso-sulfamethoxazole (SMX-NO), 53 Non β-lactam antibiotics (NBLAs), 140, 141 Non-dextran iron preparations (NDIPs) characteristics, 287, 288 clinical manifestations, 289 diagnosis, 290 epidemiology, 289 history, 287 HSRs, 290 iron infusions, 289 pathomechanism, 289 re-administration, 290 risk factors, 289 Nonimmediate hypersensitivity reactions, cephalosporin allergy clinical features and mechanisms, 180 work-up, 182–184

Index Non ionic polyethoxylated surfactants, 310 Non-nucleoside reverse transcriptase inhibitors (NNRTIs), 151 Non-steroidal anti-inflammatory drugs (NSAIDs), 94, 211 allergic non-cross intolerant reactions or selective reactors, 142, 143 chemical structure, 200, 204 classification of hypersensitivity, 141 clinical manifestation, 197–199 NSAIDs-exacerbated cutaneous disease (NECD), 197 NSAIDs-induced induced urticaria/angioedema (NIUA), 198 single NSAIDs-induced delayed hypersensitivity reactions (SNIDHR), 199 single NSAIDs-induced urticaria/angioedema or anaphylaxis (SINUAA), 198 cross-reactions, 204 desensitization, 144 diagnostic methods, 200 clinical pattern, 201 cross-reactivity, 203 culprit drug, 203 diagnostic algorithm, 201, 202 hypersensitivity/tolerance, 201 in vitro cell activation tests, 203 skin symptoms, 201 skin/in vitro test, 203 type A adverse reactions, 201 diagnostic tests and management, 142, 143 management, 199, 200, 204 mechanisms, 199, 200 natural history, 144 non-allergic cross-intolerant reactions, 141, 142 non-irritating tests, 203 NSAID-exacerbated respiratory diseases (N-ERD), 199 NSAIDs-exacerbated cutaneous disease (NECD), 197 NSAIDs-induced induced urticaria/angioedema (NIUA), 198 Nucleoside reverse transcriptase inhibitors (NRTIs), 150 O Oral provocation test (OPT), 270 Oxaliplatin, 119, 120 P Paclitaxel, 301 Palmoplantar pustulosis, 234 p-aminobenzoic acid (PABA), 324 Panitumumab, 234 Parenteral iron, 287 Penicillin protein haptenation, 170 Penicillins (PEN) clinical manifestation, 169, 170 cross reaction, 175

335 diagnostic approach clinical history, 172 drug provocation test, 175 in vitro diagnostics, 173, 174 skin test, 172, 173 lymphocyte subpopulations, 171 mechanisms, 170 immediate reactions, 171 non-immediate reactions, 171 Penicilloyl antigenic determinant, 170 Pentasaccharides, 224 Periinterventional hypersensitivity additives, 212 anticoagulants drugs, 211 antiseptics and sterilizers, 212 blue dyes, 212 clinical manifestation, 207, 208 cross-reactivity, 213 diagnostic methods, 209 hemostatic drugs, 211 hypnotics, 210 local anesthetics, 210 management, 213 mechanisms, 208 miscellaneous drugs, 211 natural rubber latex, 210 NSAIDs, 211 opioids, 211 radio contrast media, 212 risk factors and modifying aggravating factors, 207, 208 surgical routine or emergency procedures, 207 volume expanders, 211 Pharmacologic interaction of drugs with immune receptors, 30 Phenothiazines, 317 2-phenoxyethanol, 253 Pholcodine, 218 Phosphodiesterase III inhibitors, 227 Photo-allergic contact dermatitis (PACD), 321, 324 Photoallergic reactions, 25 Photoonycholysis, 314 Photopatch testing, 318 Photosensitizing drugs anti-arrhythmic amiodarone, 318 anticancer drugs, 317 antimicrobials, 314–316 diagnosis, 318 erythema, oedema and bullae, 314 face, neck and “décolleté”, sparing, 314 “folk” drugs, 318 NSAIDs, 316, 317 phenothiazines, 317 photoonycholysis, 314 phototoxicity, 313 sun avoidance/sun protection, 313 ultraviolet, 313 Phototoxic reactions, 25

Index

336 Pirfenidone, 318 Piroxicam, 316, 318 Platins (carboplatin, oxaliplatin, cisplatin), 119, 120 Polyvinylpyrrolidone (PVP), 308, 309 Progestogen hypersensitivity (PH), 122, 123 Pro-inflammatory reactions, 31 Protamine, 309 Protease inhibitors (PI), 152 Proton pump inhibitors (PPIs) cross-reactivity, 271 development, 267 H2RA, 268–271 IgE-mediated allergy, 268 in vitro diagnostics, 270 management, 271 mechanisms, 269 OPT, 270 severe delayed drug hypersensitivity, 268 skin tests, 269, 270 Pruritus, 157, 158 Pseudo-allergic reactions/idiosyncrasies, 247 Psoriasiform rash, 103 Psoriasis, 280 Psychotropic drugs. See Antiepileptic drugs (AED) P2Y12-inhibitors/thienopyridins, 226, 227 Q Quaternary ammonium, 217–218 Quinolones, 187, 188 R Radiocontrast media (RCM), 212 clinical manifestations, 273, 275 diagnosis, 275, 276 management, 276 mechanisms, 275 RASopathic skin eruption, 103 Renin-angiotensin–aldosterone system (RAAS) blockers, 281 Resensitization, 173 Rilpivirine, 151 S Saccharomyces cerevisiae, 253, 309 Serological tests drug allergy, 70 in vitro tests, 70 serum tryptase clinical application, 70 principle, 70, 71 strength and weakness, 71 SIgE antigenic determinants, 77 carrier molecule, 76 clinical application, 75 customized immunoassays, 73–75 drug–carrier conjugates, 72

immunoassays, 72, 73 ImmunoCAP, 72, 73 solid phase and functionalization, 76, 77 strength and weakness, 76 Serum-sickness (SS), 234 Serum sickness-like disease (SSLD), 138 Serum specific IgE assay (SsIgE), 181, 182 Severe life-threatening cutaneous ADR (SCAR), 16, 17, 180 Severe cutaneous adverse reactions (SCAR), 180 Single NSAIDs-induced delayed hypersensitivity reactions (SNIDHR), 199 Single NSAIDs-induced urticaria/ angioedema or anaphylaxis (SINUAA), 198 SJS/TEN, see Stevens-Johnson syndrome/toxic epidermal necrolysis Skin prick test (SPT), 172, 187, 270 Sodium benzoate, 309 Specific Immunoglobulin E (sIgE) determination antigenic determinants, 77 carrier molecule, 76 clinical application, 75 customized immunoassays, 73–75 drug–carrier conjugates, 72 immunoassays, 72, 73 ImmunoCAP, 72, 73 solid phase and functionalization, 76, 77 strength and weakness, 76 Spironolactone, 282, 283 Steven-Johnson syndrome (SJS), 23, 52, 53, 110, 137, 138, 170, 258, 260 Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), 16, 17, 29, 30 Sulfites, 309, 310 Sulphonamide antibacterials, 315 Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), 24, 100 Systemic lupus erythematosus (SLE), 280 Systemic mastocytosis (SM), 163 T T cell costimulatory pathways, 155 T cells classification, 79, 80 clinical application, 86, 87 functional tests, 82–84 measurement of proliferation, 82, 83 mechanisms, 79, 80 phenotypic changes, 84–86 strength and weakness, 87–89 test principle, 80, 81 Tartrazine, 307 Taxanes (paclitaxel and docetaxel), 120 Tenatoprazole, 267 Tetracyclines, 314 Thiazide diuretics, 279 Thimerosal, 253 Thiosalicylic acid, 316 Thrombocytopenia, 254

Index Toxic epidermal necrolysis (TEN), 23, 52, 53, 110, 138, 170, 189, 268 Toxic epidermal necrolysis (TEN)/Stevens-Johnson syndrome (SJS), 101, 102 Toxic erythema, 301 Toxoplasmic encephatilits, 149 Tryptase, 219 Type IV hypersensitivity reactions, 253 U Unfractionated heparin (UFH), 224 Urticaria, 22, 25, 26, 301, 310 V Vaccination antibiotics, 306 clinical manifestations, injection site reactions, 251, 252 diagnostic methods, 254 egg and milk, 145 gelatin and latex, 145 immediate reactions, 145 local reactions, 144 management, 255, 256 mechanisms, 252–254

337 systemic reactions, 144, 145, 251, 252 Vanishing bile duct syndrome (VBDS), 31 Vehicle components, 326 Vitamin A, 292 Vitamin B, 291 Vitamin B9, 292 Vitamin B12, 291, 293, 294 Vitamin C (ascorbic acid), 292 Vitamin K antagonists/coumarins, 224 Vitamin K1, 292, 293 Vitamins and supplements, 291 clinical manifestation, 291, 292 cross-reactions, 293 diagnostic methods, 293 management, 293, 294 mechanism, 292 Vitiligo, 157, 158 Voriconazole, 316 X Xerosis cutis, 157, 158 Z Zinc oxide, 310