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Drug Hypersensitivity Reactions (DHR): types

HLA II Non bullous diseases (MPE, DRESS, AGEP) Th2 CD4 IL4 IFN γ Th1 Th0, CD8 Th17 HLA I Bullous diseases (FDE, SJS/TEN) Th1 CD8 IFN ɣ Perforine Granzyme B

Non Immediate Allergic Drug Reactions (NIADRs) IV a Maculopapular exanthems (MPE) Fixed Drug eruptions (FDE) IV b Drug Rush with Eosinophilia and Systemic Symptoms (DRESS/DHIS) IFNγ, TNFα IL-5, eotaxin IV c Steven Johnson Syndrome Toxic Epidermal Necrolysis (SJS/TEN) IV d Acute Generalized Exanthematous Pustolosis (AGEP) Perforin/ Granzyme B CXCL-8, GM-CSF

Drug Hypersensitivity Reactions (DHR): timing

Factors predisposing to T cell mediated drug allergy Shiohara, Clin Rev All Immunol 2007; 33: 124 Genetic factors Environmental factors Epstein Bar virus (EBV) Herpes Simplex virus (HSV) Human herpes virus 6 (HHV 6) Cytomegalovirus (CMV) Varicella-Zoster virus (VZV) Human Immunodeficiency Virus (HIV) Mycoplasma Pneumoniae

The severity and clinical course of drug allergy can be influenced by viral infections that occur before, concurrent with, or subsequent to drug allergy Shiohara, Clin Rev Allergy Immunol, 2014

Role of virus infections in NIADRs Mild Severe Maculo Papular Exantems (MPE) Drug Induced Hypersensitivity Syndrome (DHIS-DRESS) Fixed Drug Eruptions (FDE) Steven Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN)

Maculo-Papular Exantems (MPE) 75% of drug hypersensitivity reactions Frequently observed as adverse reactions to beta lactams Classyfing them by morphology is difficult and physician too frequently use the generic term of rash

Drug maculopapular exanthems Drago, Br J Dermatol 2002:147:255 112 patients, 7 patterns Virus Drugs Macular Bacteria Undiagnosed Parasites Maculo-papular Papular 36 32 % Maculopapular with petechiae Erytematovescicular 5 25 Erytematopustular 2 Urticarial

Aminopennicillins : 60% Sulphametossazole: 43%

Amoxicillin-induced exanthema in mononucleosis Renn, Br J Dermatol 2002;147:1166 Rashes in mononucleosis: 14-23% Rashes to amoxicillin: 5-10% Rashes in mononucleosis following intake of amoxicillin 70% in adults 100% in children

Viral induced Th1 responses enhance allergic diseases Dahl, Nature Immunology 2004;3:337 1. Lower respiratory tract infection with influenza A in mice 2. Allergic sensitization and challenge with hemocyanin (KLH) 3. Study of BAL fluid Cells in BAL fluid Influenza A viral infection, which induces IFN γ production, enhanced allergic reaction to KLH and promoted T responses Effect of IFN-γ neutralization

Fixed Drug Eruptions (FDE) Small number of circumscribed, round erythematous macules and plaques with dusky centers on the skin and/or mucoses Lesions start exactly the same site with each administration of the causative drug New FDE lesions often develop at the site of viral infection such as HSV and previously traumatized or inflamed skin

Direct evidence for IFN production by effector-memory-type intraepidermal T Cells (TRM) residing at an effector site of immunopathology in FDE Mizukawa, Am J of Path 2002; 161: 1337 5 pt.s with FDE to drugs and history of herpetic lesions before Drug challenge after Before and after drug challenge Biopsy specimens RT-PCR for IFN ɣ in situ Isolation of intraepidermal T cells from the FDE lesions Drug challenge active CD8+ TRM cells and IFN γ production

Viral induced Th1 responses enhance allergic diseases Dahl, Nature Immunology 2004;3:337 Infection (danger signal) NIADRs: pathogenesis T cell activation (depending on the virus, virulence, dose, genetic susceptibility) Risk of drug allergic reactions T eff 1. Activation of drug specific T cells 2. Drug-virus cross reactions 3. Pharmacological interaction with Immuno receptors (p-i concept) T reg

Pharmacological interaction of drugs with antigen specific immune receptors: the p - i concept Pichler, Curr Opin Allergy Clin Immunol 2002; 2: 301 PECULIARITIES OF NIADRs p-i model 1. Dose dependence Not HLA restricted 2. hapten Allergic tests not useful model 3. Prior exposure not necessary HLA restricted

Drug hypersensitivity: diagnostic work up Kowalski, Allergy 2011;66:818 Immediate Prick test Delayed Patch test and/or IDT read after 24-48 h IDT Lymphocyte trasformation test (LTT) Challenge Challenge

Virus-immune system interactions points in allergic reactions to drugs Torres, J Investig Clin Immunol 2009; 19: 80

Potential involvement of dendritic cells in delayed-type hypersensitivity reactions to b-lactams Rodriguez-Pena, JACI 2006; 118: 949 9 patients with maculopapular exanthema and sensitized to amoxicillin 8 contol subjects Phenotypic analysis of dendritic cells before and after culturing with amoxicillin Amoxicillin drove DCs to a phenotypic and functional semimature status, inducing a T- cell proliferation response

Amoxicillin-induced exanthema in mononucleosis: allergy or transient immunostimulation? Jappe, Allergy 2007; 62: 1474 41 pt.s with drug eruptions following the intake of beta lactams 8 with mononucleosis at the time of drug eruption After 3 months allergologic work up Two of amoxicilin patch test positive pt.s remain positive in a follow up visit at 2 yrs Persistence of the delayedtype reactions to amoxicillin

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Shiohara, Br J Dermatol 2007; 156:1045 3 weeks-3 months after drug exposure Symptoms persisted longer than 2 wk after drug cessation At least one abnormalities of WBC - leukocytosis > 11.000 /mmc - atypical lymphocytosis (> 5%) - eosinophilia (> 1.500/mmc) Liver abnormalities (GOT/GPT > 100 U/l) Enlarged lymph nodes Long term sequelae: type1 diabetes, autoimmune thyroiditis, systemic sclerosis

Common culprit drugs DRESS Steven-Johnson Syndrome Carbamazepine Phenytoin Phenobarbital Mexiletine Dapson Salazosulfapyridine Allopurinol Minocycline Sulphonamides Penicillins Cephalosporins Erythromycin Phenobarbital Carbamazepine Diazoxyde NSAIDs Patients with DRESS or SJS often show unexplained cross-reactivity to multiple drugs with different structures, including to those used after the onset of symptoms

Differences in immunological alterations and underlying viral infections in two well-defined severe drug eruptions Hirahara, Clin Exp Derm 2010:35:863 Groups of pt.s: SJS/TEN 9, DRESS 19 Determinations: Serum lymphocytes, serum cytochine levels

Carbamazepine-induced DIHS: case report Aihara, Br J Dermatol 2003: 149: 165 Patient 14 yrs, DHIS to carbamazepin

Herpesviruses reactivation in DRESS Kano, Br J Dermatol 2006:155:301 4 pt.s. with DRESS Determinations of PCR/sierological anticorpal titles for EBV HHV6, HHV7, CMV Immunodepression cause viral reactivation Viral reactivation cause immunostimulation

Herpes virus reactivation

The dynamics of herpesvirus reactivations during and after severe drug eruptions: their relation to the clinical phenotype and therapeutic outcome Ishida, Allergy 2014: 69: 798 Groups of pt.sdhis (12) SJS 16 TEN 10 SJS/TEN overlap 2 DHIS/DRESS 34 Controls 23 Determinations Blood samples (days) 1-10, 11-30, 31-100, 101-300 Virus DNA loads for EBV, CMV, HHV6 Frequencies of patients with increased EBV DNA loads

The dynamics of herpesvirus reactivations during and after severe drug eruptions: their relation to the clinical phenotype and therapeutic outcome Ishida, Allergy 2014: 69: 798 SJS may develop in patients who are not capable of adequately mounting effective immune responses to the reactivating EBV

Severe drug allergic reactions and viral infections Takahashi, J Immunol 2009:182:8071 Drug allergy Immuno depression Virus reactivation Risk of allergy to multiple drugs T cell activation T reg Prolongation or worsening of clinical picture

Conclusions Viral infections and genetic predisposition are important risk factors to T cell mediated drug allergic reactions INFECTIONS THAT OCCUR BEFORE DRUG ALLERGY cause T cell activation and increase the risk of allergic or pharmacologic reactions INFECTIONS THAT OCCUR AFTER DRUG ALLERGY are frequently caused by herpesvirus reactivation. These virus are most likely additional factors involved in pathogenesis and clinical manifestations of severe drug eruptions

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