Drug Induced Hypersensitivity and the HLA Complex

Drug-induced hypersensitivity reactions are of major concern and present a burden for national healthcare systems due to their often severe nature, high rate of hospital admissions and high mortality. They manifest with a wide range of symptoms and signs, and can be initiated by a wide range of structurally diverse chemical compounds. The pathophysiological mechanisms underlying hypersensitivity reactions are not well understood, but it is thought that they are immune mediated. MHC region on Chromosome 6 contains many genes with immune function. Classical MHC molecules are highly polymorphic cell surface glycoproteins whose function is to present peptide antigens to T cells. In addition to conferring protection from some diseases, HLA alleles are also associated with an increased risk of other diseases, including drug-induced hypersensitivity. Pharmacogenetic approach to predict the risk of drug-induced hypersensitivity has been established for several drugs. We will discuss the progress of hypersensitivity pharmacogenetics over the last few years and focus on current efforts of the international community to develop consortia which aim to standardize disease phenotypes and to identify affected individuals through international collaborations. In addition, we will discuss the clinical utility of HLA typing as predictive or diagnostic testing for drug-induced hypersensitivity.

[1]  P. Gasparini,et al.  Fixed drug eruptions with feprazone are linked to HLA-B22. , 1997, Journal of the American Academy of Dermatology.

[2]  P. Demoly,et al.  Variability in the clinical pattern of cutaneous side‐effects of drugs with systemic symptoms: does a DRESS syndrome really exist? , 2006, The British journal of dermatology.

[3]  S. Spielberg,et al.  Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk. , 1988, The Journal of clinical investigation.

[4]  S. Belknap,et al.  Serious Adverse Cutaneous and Hepatic Toxicities Associated With Nevirapine Use by Non–HIV-Infected Individuals , 2004, Journal of acquired immune deficiency syndromes.

[5]  Carbamazepine Hypersensitivity Syndrome Triggered by a Human Herpes Virus Reactivation in a Genetically Predisposed Patient , 2009, International Archives of Allergy and Immunology.

[6]  D. Goldfain,et al.  [Hepatitis caused by clometacin (Dupéran). Retrospective study of 30 cases. A model of autoimmune drug-induced hepatitis?]. , 1989, Gastroenterologie clinique et biologique.

[7]  L. Naldi,et al.  A European study of HLA-B in Stevens–Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs , 2008, Pharmacogenetics and genomics.

[8]  S. Lewitzky,et al.  OC-035 Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a diagnostic test accuracy meta-analysis , 2010, Gut.

[9]  William M. Lee,et al.  Hepatic Findings in Long-Term Clinical Trials of Ximelagatran , 2005, Drug safety.

[10]  C. Joshi,et al.  Association of HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome among Indians. , 2009, Indian journal of dermatology, venereology and leprology.

[11]  T. Takekoshi,et al.  Detection of human herpesvirus-6 transcripts in carbamazepine-induced hypersensitivity syndrome by in situ hybridization. , 2009, Journal of dermatological science.

[12]  M. Pirmohamed,et al.  Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients , 2004, BMJ : British Medical Journal.

[13]  I. Dunham,et al.  DNA sequence and analysis of human chromosome 9 , 2003, Nature.

[14]  A. Romano,et al.  Cross-reactivity among drugs: clinical problems. , 2005, Toxicology.

[15]  M. Pirmohamed,et al.  Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity. , 2004, Pharmacogenetics.

[16]  M. Pirmohamed,et al.  Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury. , 2010, Journal of hepatology.

[17]  T. Shiohara,et al.  Association between anticonvulsant hypersensitivity syndrome and human herpesvirus 6 reactivation and hypogammaglobulinemia. , 2004, Archives of dermatology.

[18]  C. K. Lee,et al.  Cutaneous adverse drug reactions seen in a tertiary hospital in Johor, Malaysia , 2010, International journal of dermatology.

[19]  M. Mockenhaupt,et al.  Variability in the clinical pattern of cutaneous side‐effects of drugs with systemic symptoms: does a DRESS syndrome really exist? , 2007, The British journal of dermatology.

[20]  C. Sotozono,et al.  HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis. , 2008, Pharmacogenomics.

[21]  M. Pirmohamed,et al.  Serious carbamazepine-induced hypersensitivity reactions associated with the HSP70 gene cluster , 2006, Pharmacogenetics and genomics.

[22]  D. Dieterich,et al.  Drug-induced liver injury associated with the use of nonnucleoside reverse-transcriptase inhibitors. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[23]  T. Zuberbier,et al.  Pharmacovigilance of drug allergy and hypersensitivity using the ENDA–DAHD database and the GA2LEN platform. The Galenda project , 2009, Allergy.

[24]  H. Takagi,et al.  Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case–control study , 2008, The Pharmacogenomics Journal.

[25]  M. Pirmohamed,et al.  Adverse Drug Reactions in Hospital In-Patients: A Prospective Analysis of 3695 Patient-Episodes , 2009, PloS one.

[26]  J. Mills,et al.  Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. , 1984, Annals of internal medicine.

[27]  P. Kwan,et al.  Association between HLA‐B*1502 Allele and Antiepileptic Drug‐Induced Cutaneous Reactions in Han Chinese , 2007, Epilepsia.

[28]  M. Blanes,et al.  Erythema multiforme to amoxicillin with concurrent infection by Epstein-Barr virus. , 2006, Allergologia et immunopathologia.

[29]  T. Shibasaki,et al.  Drug-induced hypersensitivity nephritis: lymphocyte stimulation testing and renal biopsy in 10 cases. , 1990, American journal of nephrology.

[30]  Yuan-Tsong Chen,et al.  HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[31]  K. Smith,et al.  Increased drug reactions in HIV‐1‐positive patients: a possible explanation based on patterns of immune dysregulation seen in HIV‐1 disease * , 1997, Clinical and experimental dermatology.

[32]  H. Yazaki,et al.  HLA-Cw8 primarily associated with hypersensitivity to nevirapine. , 2007, AIDS.

[33]  Yusuke Nakamura,et al.  HLA-B*3505 allele is a strong predictor for nevirapine-induced skin adverse drug reactions in HIV-infected Thai patients , 2009, Pharmacogenetics and genomics.

[34]  F. Marincola,et al.  HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[35]  K. Shianna,et al.  Host determinants of HIV-1 control in African Americans. , 2010, The Journal of infectious diseases.

[36]  T. Shiohara,et al.  A Complex Interaction Between Drug Allergy and Viral Infection , 2007, Clinical reviews in allergy & immunology.

[37]  U. Akar,et al.  Fixed drug eruption induced by trimethoprim-sulfamethoxazole: evidence for a link to HLA-A30 B13 Cw6 haplotype. , 2001, Journal of the American Academy of Dermatology.

[38]  M. Schumacher,et al.  A marker for Stevens-Johnson syndrome …: ethnicity matters , 2006, The Pharmacogenomics Journal.

[39]  A Jawaid,et al.  Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis , 2008, The Pharmacogenomics Journal.

[40]  David Nolan,et al.  Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. , 2008, Immunity.

[41]  Seung-Hyun Kim,et al.  What do we know about the genetics of aspirin intolerance? , 2008, Journal of clinical pharmacy and therapeutics.

[42]  M. Carrington,et al.  Influence of HLA Class I and HLA-KIR Compound Genotypes on HIV-2 Infection and Markers of Disease Progression in a Manjako Community in West Africa , 2010, Journal of Virology.

[43]  C. Suh,et al.  The human leucocyte antigen‐DRB1*1302‐DQB1*0609‐DPB1*0201 haplotype may be a strong genetic marker for aspirin‐induced urticaria , 2005, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[44]  S. Jee,et al.  Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions , 2006, Pharmacogenetics and genomics.

[45]  S. Mallal,et al.  HLA-B*5701 screening for hypersensitivity to abacavir. , 2008, The New England journal of medicine.

[46]  J. Roujeau.  Clinical heterogeneity of drug hypersensitivity. , 2005, Toxicology.

[47]  J. Roujeau,et al.  HLA phenotypes and bullous cutaneous reactions to drugs. , 2008, Tissue antigens.

[48]  N. Arsenovic,et al.  Fatal carbamazepine induced fulminant eosinophilic (hypersensitivity) myocarditis: emphasis on anatomical and histological characteristics, mechanisms and genetics of drug hypersensitivity and differential diagnosis. , 2010, Journal of forensic and legal medicine.

[49]  S. Tiamkao,et al.  Association between HLA‐B*1502 and carbamazepine‐induced severe cutaneous adverse drug reactions in a Thai population , 2010, Epilepsia.

[50]  C. Hsiao,et al.  Oxcarbazepine‐induced Stevens–Johnson syndrome in a patient with HLA‐B*1502 genotype , 2009, Journal of the European Academy of Dermatology and Venereology : JEADV.

[51]  C. Rondón,et al.  Monitoring non‐immediate allergic reactions to iodine contrast media , 2008, Clinical and experimental immunology.

[52]  S. Spielberg,et al.  In Vitro Assessment of Risk , 1988 .

[53]  T. Shiohara,et al.  Drug-induced Hypersensitivity Syndrome(DIHS): A Reaction Induced by a Complex Interplay among Herpesviruses and Antiviral and Antidrug Immune Responses. , 2006, Allergology international : official journal of the Japanese Society of Allergology.

[54]  A. Hovnanian,et al.  HLA-DRB1*01 associated with cutaneous hypersensitivity induced by nevirapine and efavirenz , 2008, AIDS.

[55]  D. Burns,et al.  Genetic association studies to detect adverse drug reactions: abacavir hypersensitivity as an example. , 2009, Pharmacogenomics.

[56]  C. Melief,et al.  Lymphocyte transformation in vitro. V. Thymidine incorporation into unstimulated lymphocytes. , 1973, Experimental cell research.

[57]  W R Mayr,et al.  An update to HLA Nomenclature, 2010 , 2010, Bone Marrow Transplantation.

[58]  Jacques Fellay,et al.  The HCP5 single-nucleotide polymorphism: a simple screening tool for prediction of hypersensitivity reaction to abacavir. , 2008, The Journal of infectious diseases.

[59]  C. Carcassi,et al.  HLA-dependent hypersensitivity to nevirapine in Sardinian HIV patients , 2006, AIDS.

[60]  Gen Tamiya,et al.  Complete sequence and gene map of a human major histocompatibility complex , 1999 .

[61]  R. Stern,et al.  Cutaneous disease and drug reactions in HIV infection. , 1993, The New England journal of medicine.

[62]  G. Aithal,et al.  Preempting and preventing drug-induced liver injury , 2010, Nature Genetics.

[63]  C. Day,et al.  Genetic association studies in drug-induced liver injury. , 2009, Seminars in liver disease.

[64]  W. Prasithsirikul,et al.  HLA-Cw*04 allele associated with nevirapine-induced rash in HIV-infected Thai patients , 2009, AIDS research and therapy.

[65]  D. Thorburn,et al.  Epidemiological risk factors for hypersensitivity reactions to abacavir * , 2003, HIV medicine.

[66]  A. Flahault,et al.  Prospective evaluation of risk factors of cutaneous drug reactions to sulfonamides in patients with AIDS. , 2002, Journal of the American Academy of Dermatology.

[67]  R. N. Macsween,et al.  Co-amoxiclav jaundice: clinical and histological features and HLA class II association , 2000, Gut.

[68]  S. Tiamkao,et al.  Strong association between HLA-B*5801 and allopurinol-induced Stevens–Johnson syndrome and toxic epidermal necrolysis in a Thai population , 2009, Pharmacogenetics and genomics.

[69]  G. Koren,et al.  Patch Testing for the Diagnosis of Anticonvulsant Hypersensitivity Syndrome , 2009, Drug safety.

[70]  M. Pirmohamed,et al.  HLA-B locus in Caucasian patients with carbamazepine hypersensitivity. , 2006, Pharmacogenomics.

[71]  P. Corey,et al.  Incidence of Adverse Drug Reactions in Hospitalized Patients , 2012 .

[72]  B. Crickx,et al.  Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms. , 2001, Archives of dermatology.

[73]  P. Schellekens,et al.  Lymphocyte transformation in vitro. I. Tissue culture conditions and quantitative measurements. , 1968, Clinical and experimental immunology.

[74]  I. Dunham,et al.  The DNA sequence and analysis of human chromosome 6 , 2003, Nature.

[75]  A. Romano,et al.  Delayed hypersensitivity to aminopenicillins is related to major histocompatibility complex genes. , 1998, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[76]  H. Merk,et al.  Delayed-type hypersensitivity reaction to paraphenylenediamine is mediated by 2 different pathways of antigen recognition by specific αβ+ human T-cell clones , 2002 .

[77]  W. Pichler,et al.  Delayed Drug Hypersensitivity Reactions , 2003, Annals of Internal Medicine.

[78]  C. Moore,et al.  Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts , 2005, AIDS.

[79]  T. Carrillo,et al.  Association of HLA-DR11 with the anaphylactoid reaction caused by nonsteroidal anti-inflammatory drugs. , 1999, The Journal of allergy and clinical immunology.

[80]  K. Suphapeetiporn,et al.  Carbamazepine and phenytoin induced Stevens‐Johnson syndrome is associated with HLA‐B*1502 allele in Thai population , 2008, Epilepsia.

[81]  H. Jick,et al.  Risk of cholestatic liver disease associated with flucloxacillin and flucloxacillin prescribing habits in the UK: cohort study using data from the UK General Practice Research Database. , 2005, British journal of clinical pharmacology.

[82]  F. Berenbaum,et al.  Lumiracoxib in the management of osteoarthritis and acute pain , 2007, Expert opinion on pharmacotherapy.

[83]  P. Weidle,et al.  Nevirapine-induced Stevens-Johnson syndrome in a mother and son. , 2005, AIDS.

[84]  Clive E. Bowman,et al.  Genetic variations in HLA-B region and hypersensitivity reactions to abacavir , 2002, The Lancet.

[85]  S. Mallal,et al.  High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[86]  F. Collins,et al.  Potential etiologic and functional implications of genome-wide association loci for human diseases and traits , 2009, Proceedings of the National Academy of Sciences.

[87]  J. Roujeau,et al.  Genetic susceptibility to toxic epidermal necrolysis. , 1987, Archives of dermatology.

[88]  Lin He,et al.  Harvesting Candidate Genes Responsible for Serious Adverse Drug Reactions from a Chemical-Protein Interactome , 2009, PLoS Comput. Biol..

[89]  C. Moore,et al.  Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir , 2002, The Lancet.

[90]  C. Sempoux,et al.  HLA association of amoxicillin-clavulanate--induced hepatitis. , 1999, Gastroenterology.

[91]  R. Tamagawa‐Mineoka,et al.  DRESS syndrome caused by teicoplanin and vancomycin, associated with reactivation of human herpesvirus‐6 , 2007, International journal of dermatology.

[92]  M. Nelson,et al.  High-resolution HLA genotyping and severe cutaneous adverse reactions in lamotrigine-treated patients , 2009, Pharmacogenetics and genomics.

[93]  W. Pichler,et al.  Delayed drug hypersensitivity reactions – new concepts , 2007, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[94]  S. Caillat-Zucman,et al.  Prospective screening for human leukocyte antigen-B*5701 avoids abacavir hypersensitivity reaction in the ethnically mixed French HIV population. , 2007, Journal of acquired immune deficiency syndromes.

[95]  Y. Yamakawa,et al.  Carbamazepine‐induced hypersensitivity syndrome associated with transient hypogammaglobulinaemia and reactivation of human herpesvirus 6 infection demonstrated by real‐time quantitative polymerase chain reaction , 2003, The British journal of dermatology.

[96]  H. Merk,et al.  Delayed-type hypersensitivity reaction to paraphenylenediamine is mediated by 2 different pathways of antigen recognition by specific alphabeta human T-cell clones. , 2002, The Journal of allergy and clinical immunology.

[97]  S. Sood,et al.  Carbamazepine and fatal eosinophilic myocarditis. , 1997, The New England journal of medicine.

[98]  T. Greenough,et al.  High-dose nevirapine: safety, pharmacokinetics, and antiviral effect in patients with human immunodeficiency virus infection. , 1995, The Journal of infectious diseases.

[99]  N. Shear,et al.  Mechanisms of drug reactions: the metabolic track. , 1996, Seminars in cutaneous medicine and surgery.

[100]  M. Blanca,et al.  Nonimmediate allergic reactions induced by drugs: pathogenesis and diagnostic tests. , 2009, Journal of investigational allergology & clinical immunology.

[101]  A. Roses,et al.  Association of genetic variations in HLA-B region with hypersensitivity to abacavir in some, but not all, populations. , 2004, Pharmacogenomics.

[102]  M. Daly,et al.  HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin , 2009, Nature Genetics.

[103]  Complete sequence and gene map of a human major histocompatibility complex. The MHC sequencing consortium. , 1999, Nature.

[104]  M. Tohyama,et al.  Occupational Trichloroethylene Hypersensitivity Syndrome with Human Herpesvirus-6 and Cytomegalovirus Reactivation , 2010, Dermatology.

[105]  Yuan-Tsong Chen,et al.  A marker for Stevens–Johnson syndrome , 2004 .

[106]  B. Sachs,et al.  Amoxicillin‐induced exanthema in young adults with infectious mononucleosis: demonstration of drug‐specific lymphocyte reactivity , 2002, The British journal of dermatology.

[107]  S. Knowles,et al.  Utility of patch testing in patients with hypersensitivity syndromes associated with abacavir. , 2002, AIDS.

[108]  K. Arndt,et al.  Drug-induced cutaneous reactions. A report from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975 to 1982. , 1986, JAMA.

[109]  L. K. Ely,et al.  Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition , 2009, The Journal of experimental medicine.

[110]  J. Muglia,et al.  Anticonvulsant hypersensitivity syndrome. , 1995, Archives of internal medicine.

[111]  S. Leng,et al.  HLA-B*1301 as a Biomarker for Genetic Susceptibility to Hypersensitivity Dermatitis Induced by Trichloroethylene among Workers in China , 2007, Environmental health perspectives.

[112]  M. Karakaş,et al.  The anticonvulsant hypersensitivity syndrome , 2003, Journal of the European Academy of Dermatology and Venereology : JEADV.

[113]  H. Hashizume,et al.  Drug-induced hypersensitivity syndrome associated with cytomegalovirus reactivation: immunological characterization of pathogenic T cells. , 2005, Acta dermato-venereologica.

[114]  Shui-Tein Chen,et al.  HLA-B*1502-bound peptides: implications for the pathogenesis of carbamazepine-induced Stevens-Johnson syndrome. , 2007, The Journal of allergy and clinical immunology.

[115]  J. González-Domínguez,et al.  Association of HLA-DR5 with mucocutaneous lesions in patients with rheumatoid arthritis receiving gold sodium thiomalate. , 1994, The Journal of rheumatology.