(BQ) Part 1 book Recent advances in dermatology presents the following contents: Human genome mapping - Relevance to dermatology, relevance to dermatology, neonatal dermatoses an update, aquatic animal bites and stings - an update; drug hypersensitivity syndrome,....
Recent Advances in DERMATOLOGY DISCLAIMER As medicine is an everyday-changing science with newer researches and refined clinical experiences, and also in view of the possibility of human error, neither the editors nor the authors/ nor the publisher warrant that the informations contained in the book is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information presented in this work Recent Advances in DERMATOLOGY Volume Editor-in-Chief Sanjay Ghosh Medical Director Institute of Allergic and Immunologic Skin Diseases, Kolkata Associate Editors Dinesh Hawelia Consultant Dermatologist Institute of Allergic and Immunologic Skin Diseases AMRI Hospitals, Salt Lake, Kolkata Susmit Haldar Consultant Dermatologist Calcutta Skin Institute Institute of Allergic and Immunologic Skin Diseases, Kolkata Assistant Editors Manas Sen, Nilendu Sarma, Sanjib Chowdhuri, Sudip Kumar Ghosh Consultant Dermatologists Institute of Allergic and Immunologic Skin Diseases, Kolkata JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi Published by Jitendar P Vij Jaypee Brothers Medical Publishers (P) Ltd EMCA House, 23/23B Ansari Road, Daryaganj New Delhi 110 002, India Phones: +91-11-23272143, +91-11-23272703, +91-11-23282021, +91-11-23245672 Fax: +91-11-23276490, +91-11-23245683 e-mail: jaypee@jaypee brothers.com Visit our website: www.jaypeebrothers.com Branches 2/B, Akruti Society, Jodhpur Gam Road Satellite, Ahmedabad 380 015 Phones: +91-079-26926233, Rel: +91-079-32988717, Fax: +91-079-26927094 e-mail: jpamdvd@rediffmail.com 202 Batavia Chambers, Kumara Krupa Road, Kumara Park East, Bangalore 560 001, Phones: +91-80-22285971, +91-80-22382956, Rel: +91-80-32714073, Fax: +91-80-22281761 e-mail: jaypeemedpubbgl@eth.net 282 IIIrd Floor, Khaleel Shirazi Estate, Fountain Plaza Pantheon Road, Chennai 600 008 , Phones: +91-44-28193265, +91-44-28194897, Rel: +91-44-32972089, Fax: +91-44-28193231 e-mail: jpchen@eth.net 4-2-1067/1-3, 1st Floor, Balaji Building, Ramkote Cross Road Hyderabad 500 095, Phones: +91-40-66610020, +91-40-24758498, Rel:+91-40-32940929, Fax:+91-40-24758499, e-mail: jpmedpub@rediffmail.com No 41/3098, B & B1, Kuruvi Building, St Vincent Road Kochi 682 018, Kerala, Phones: +91-0484-4036109, +91-0484 2395739, +91-0484 2395740 1-A Indian Mirror Street, Wellington Square Kolkata 700 013, Phones: +91-33-22451926, +91-33-22276404, +91-33-22276415, Rel: +91-33-32901926 Fax: +91-33-22456075, e-mail: jpbcal@dataone.in 106 Amit Industrial Estate, 61 Dr SS Rao Road Near MGM Hospital, Parel, Mumbai 400 012, Phones: +91-22-24124863, +91-22-24104532, Rel: +91-22-32926896 Fax: +91-22-24160828, e-mail: jpmedpub@bom7.vsnl.net.in “KAMALPUSHPA” 38, Reshimbag, Opp Mohota Science College, Umred Road Nagpur 440 009 (MS) Phones: Rel: 3245220, Fax: 0712-2704275 e-mail: jaypeenagpur@dataone.in Recent Advances in Dermatology—Volume © 2007, Sanjay Ghosh All rights reserved No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the editor and the publisher This book has been published in good faith that the material provided by contributors is original Every effort is made to ensure accuracy of material, but the publisher, printer and editor will not be held responsible for any inadvertent error(s) In case of any dispute, all legal matters are to be settled under Delhi jurisdiction only First Edition: 2007 ISBN 81-8061-896-X Typeset at Printed at JPBMP typesetting unit Replika To all the present dermatologists of India, whose dedication and contribution are leading Indian dermatology scenario towards a brighter future CONTRIBUTORS Aparna Palit Assistant Professor Department of Dermatology, Venereology and Leprology BLDEA’s SBMP Medical College, Hospital and Research Centre Bijapur-586 103, Karnataka Arun C Inamadar Professor and Head Department of Dermatology, Venereology and Leprology BLDEA’s SBMP Medical College, Hospital and Research Centre Bijapur-586 103, Karnataka Asok Gangopadhyay Prof and Head, Department of Dermatology RKM Seva Pratisthan and Vivekananda Institute of Medical Sciences, Kolkata 7, Bawali Mondal Road, Kolkata-700026 Balkrishna Nikam Senior Resident Department of Dermatology, BYL Nair Hospital and TN Medical College Mumbai Central, Mumbai-400 008 Bibhuti Saha Associate Professor and Head, Department of Tropical Medicine School of Tropical Medicine Kolkata Deepak Vedamurthy W-176, Park Road, Anna Nagar West Extn Chennai-600 101 G Raghu Rama Rao Prof and HOD of Dermatology Andhra Medical College Visakhapatnam-530 001 HR Jerajani Prof and HOD, Dept of Dermatology LTM Medical College and General Hospital, Sion Mumbai-400 022 KK Raja Babu Prof and HOD (Retd.) Consultant Dermatologist A-62, Road No 12 Film Nagar, Jubilee Hills Hyderabad Maya Vedamurthy Consultant Dermatologist W-171, Park Road, Anna Nagar West Extn Chennai-600 101 Meghana Phiske Lecturer, Dept of Dermatology LTM Medical College and General Hospital, Sion Mumbai-400 022 Nanda Kishore B Prof and Head, Department of Dermatology, Venereology and Leprology Father Muller Medical College Kankanady, Mangalore-575 002 Niti Khunger Associate Professor Department of Skin and STD VM Medical College and Hospital New Delhi viii Patrick Yesudian Visiting Consultant, Apollo Hospitals Prof of Dermatology (Retd.) Madras Medical College 10, Ritherdon Avenue Vepery, Chennai-600 007 Rajiv Joshi Consultant Dermatologist 14, Jay Mahal, A Road Churchgate, Mumbai-400 020 Rashmi Sarkar Consultant Dermatologist Department of Dermatology and Venereology Safdarjung Hospital New Delhi-1100 29 Samar Ranjan Pal Consultant Rheumatologist Sri Aurobindo Seva Kendra Gariahat, Kolkata Sangeeta Amladi Prof and Head Department of Dermatology TN Medical College and BYL Nair Hospital Dr AL Nair Road Mumbai Central Mumbai-400 008 Sandipan Dhar Associate Professor Pediatric Dermatology Division Institute of Child Health Kolkata Recent Advances in Dermatology Seema Sainani Consultant Dermatologist 201, Ramvithal Smrutisadan Plot no 8, 19th Road, Khan West Mumbai Soumya Panda Consultant Dermatologist, Belle Vue Clinic Ashok-Swapna 122/4, Dr JR Dhar Road Kolkata-700 028 Sujata Sengupta Assistant Professor Department of Dermatology RKM Seva Pratisthan and Vivekananda Institute 1050/1, Survey Park Kolkata-700 075 Sukumar Associate Professor Department of Dermatology Venereology and Leprology Father Muller Medical College Kankanady, Mangalore-575 002 Surojit Kumar Biswas Assistant Professor Department of Dermatology Midnapore Medical College Paschim Midnapore, West Bengal VR Janaki Professor and HOD (Retd.) Madras Medical College Flat No 3, Sri Rama Bhavan New No 19, Third Street Abhiramapuram, Chennai-600 018 FOREWORD Recent Advances in Dermatology, Volume is in the offing with a totally new set of topics in which great amount of advances and research has been made in the recent years Authors of this volume are different from those of the Volume of Recent Advances in Dermatology, which was published in 2004 The topics like Human Genome Mapping, The Th1-Th2 Paradigm in Dermatology, Paraneoplastic Pemphigus, Role of Biological Agents in Management of Psoriosis and APAS are really fascinating The other interesting subjects discussed are Acute Skin Failure, Psoriatic Arthritis, Cutaneous Manifestations of HIV Infection, etc The title has also included few topics on Dermatosurgery and Cosmetology, e.g update in Vitiligo Surgery and Chemical Peeling This excellent endeavor will definitely find place in the bookshelves of both senior and junior dermatologists including postgraduate students in this speciality I must express my personal gratitude to all the contributors for their expertise and labor for writing their articles Dr Sanjay Ghosh, Editor-in-Chief, of this volume should be specially congratulated for his commitment, endurance and academic aptitude for bringing out such a nice volume like the first one, which is really a hard task to perform I also congratulate his team of associate and assistant editors for their valuable support in this project Prof SK Panja Professor & HOD (Retd.) SSKM & National Medical College Kolkata Recent Advances in Paraneoplastic Pemphigus (PNP) 127 40 De Saint Paul G, Albes B, Bayle P, et al Cutaneous T-cell lymphoma, cutaneous hyperpigmentation and paraneoplastic pemphigus Ann Dermatol Venereol 2002 Jun-Jul;129(6-7):896-900 41 Schaeppi H, Bauer JW, Hametner R, et al A localized variant of paraneoplastic pemphigus: Acantholysis associated with malignant melanoma Br J Dermatol 2001 Jun; 144(6): 1249-54 42 Kaplan I, Hodak E, Ackerman L, et al Neoplasms associated with paraneoplastic pemphigus: A review with emphasis on non-hematologic malignancy and oral mucosal manifestations Oral Oncol 2004 Jul; 40(6): 55362 43 Verrini A, Cannata G, Cozzani E, et al A patient with immunological features of paraneoplastic pemphigus in the absence of a detectable malignancy Acta Derm Venereol 2002; 82(5): 382-4 44 Jansen T, Plewig G, Anhalt GJ, et al Paraneoplastic pemphigus with clinical features of erosive lichen planus associated with Castleman’s tumor Dermatology 1995; 190(3):245-50 45 Palleschi GM, Giomi B Herpetiformis pemphigus and lung carcinoma: A case of paraneoplastic pemphigus.Acta Derm Venereol 2002; 82(4): 304-5 46 Mutasim D, Pelc N, Anhalt G Paraneoplastic pemphigus Dermatologic Clinics July 1993; vol 119(3): 473-81 47 Meyers S, Varley G, Meisler D, et al Conjunctival involvement in paraneoplastic pemphigus American Journal of Ophthalmology November1992; 114:621-4 48 Kim S.C, Chang S.N, Lee J.J, et al Localized mucosal involvement and severe pulmonary involvement in young patient with PNP associated with caste, Br J Dermatol 1998;138: 667-71 49 Thomas Habif.Vesicular and bullous diseases.In: Thomas Habiff,Ed Clinical Dermatology, colour guide to diagnosis and therapy Philadelphia: Mosby, 4th edition 2004: 547-86 50 Contact Dermatitis and drug eruptions In: Richard B Odom, William D James, Timothy G Berger, (Eds) Andrew’s Diseases of the skin Clinical Dermatology Philadelphia: W B Saunders Company, 9th Edition, 2000: 95-145 51 Viral Diseases In: Richard B Odom, William D James, Timothy G Berger, EDS Andrew’s Diseases of the skin Clinical Dermatology Philadelphia: W B Saunders Company, 9th Edition, 2000: 473-525 52 Chronic blistering dermatoses In: Richard B Odom, William D James, Timothy G Berger, (Eds) Andrew’s Diseases of the skin Clinical Dermatology Philadelphia: W B Saunders Company, 9th Edition, 2000: 574-605 53 Rybojad M, Leblanc T, Flageul B, Bernard P Paraneoplastic pemphigus in a child with a T-cell lymphoblastic lymphoma Br J Dermatol 1993 Apr; 128(4): 418-22 54 Lemon M.A., Weston W.L., Huff J.C Childhood paraneoplastic pemphigus associated with Castleman’s tumor Br J of Dermatol Jan-June1997; 136:115-7 55 Vun YY, Lun K, Strutton G et al.Use of biosynthetic dressings in paraneoplastic pemphigus Australas J Dermatol 2004 May; 45(2):133-5 56 Coelho S, Reis JP, Tellechea O, et al Paraneoplastic pemphigus with clinical features of lichen planus associated with low-grade B cell lymphoma Int J Dermatol 2005 May;44(5):366-71 57 Gergely L, Varoczy L, Vadasz G, et al Successful treatment of B cell chronic lymphocytic leukemia-associated severe paraneoplastic pemphigus with cyclosporin A Acta Haematol 2003;109(4):202-5 128 Recent Advances in Dermatology 58 Hohwy T, Bang K, Steiniche T, et al Alemtuzumab-induced remission of both severe paraneoplastic pemphigus and leukaemic bone marrow infiltration in a case of treatment-resistant B-cell chronic lymphocytic leukaemia.Eur J Haematol 2004 Sep;73(3):206-9 59 J.V.Williams, J.G Marks, E.M Billingsley Use of mycophenolate mofetil in the treatment of paraneoplastic pemphigus Br J Dermatol 2000, 142: 506-8 60 Chin AC, Stich D, White FV, Radhakrishnan J, Holterman MJ Paraneoplastic pemphigus and bronchiolitis obliterans associated with a mediastinal mass: A rare case of Castleman’s disease with respiratory failure requiring lung transplantation J Pediatr Surg 2001 Dec; 36(12): E22 Arun C Inamadar, Aparna Palit Drug Hypersensitivity Syndrome Drug hypersensitivity syndrome (DHS) is a unique subtype currently added to the category of severe cutaneous adverse drug reactioins (CADR) The distinctive feature of this entity is the predominant systemic involvement The first report of this disorder was about half a century back when a patient on therapy with phenytoin developed exfoliative dermatitis, pyrexia and features of hepatitis.1 Subsequently, several other drugs have been found to cause this disorder Though it affects a relatively small proportion of individuals, the associated morbidity and mortality has roused a major concern among clinicians Multiple organ involvement and variable clinical picture are seen and may cause diagnostic confusion Milder cases are self-limiting; but a chronic, relapsing course is common in the presence of significant systemic involvement Recently much attention has been paid in unraveling the mystery of pathogenesis of DHS Role of drug-induced hypogammaglobulinemia and viral reactivation is being investigated in many centers Different trials on in vitro tests to recognize the susceptibility to develop DHS are going on These may bring a ray of hope in the diagnosis and management of this severe disorder with unpredictable course DEFINITION AND NOMENCLATURE DHS has been defined as the clinical triad of fever, skin rash and internal organ involvement due to drug exposure.2 Since its first Recent Advances in Dermatology 130 description, the nomenclature of DHS has been changed frequently Initially it was named as dapsone syndrome (sulphone syndrome) and anticonvulsant hypersensitivity syndrome according to the commonest causative drugs It may simulate many other febrile conditions associated with skin rash and different descriptive names were given accordingly; few of these are febrile mucocutaneous syndrome, graft-vs-host-like illness, Kawasaki-like illness, mononucleosis-like illness, etc Based on the dense dermal lymphocytic infiltrate observed histoopathologically, earlier, DHS used to be termed synonymously with pseudolymphoma Recently, two different acronyms have been proposed, namely; DRESS (Drug reaction with eosinophilia and systemic symptoms)5 and DIDMOHS (Drug-induced delayed multi organ hypersensitivity Syndrome).6 These were aimed to overcome the ambiguity and inconsistencies in designating DHS, as well as to emphasize its distinctive clinical picture Though the conflict regarding nomenclature continues,the consistent clinical observations in DHS merit it to label as a distinctive syndrome (Fig 8.1) EPIDEMIOLOGY Frequency of DHS ranges from in 100 to in 10,000 drug exposures.3 In a 7-year prospective study, annual incidence rate of Fig 8.1: Drug hypersensitivity syndrome Drug Hypersensitivity Syndrome 131 Table 8.1 : Drug causing DHS3,4,6,8-16 Group Anticonvulsants Sulphonamides Antibiotics Antiretroviral Antitubercular Antifungal Antineoplastic Antihypertensive Antiarrhythmic NSAID Oral hypoglycemic Miscellaneous Drugs • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Phenytoin Carbamazepine Phenobarbitone Lamotrigine Sodium valproate Felbamate Dapsone Sulfasalazine Sulfamethoxazole Minocycline Moxifloxacin Cefaclor Abacavir Nevirapine INH Terbinafine Procarbazine Atenolol Captopril Mexiletine Diltiazem Phenylbutazone, Celecoxib Chlorpropamide Allopurinol Azathioprine Trimethoprim Codeine phosphate Spironolactone Bupropion 0.9/100,000 has been estimated among a West-Indian population.7 Like other severe CADRs it is commoner among women.3 Different groups of drugs which can initiate the condition are listed in Table 8.1.3,4,6,8-16 Though exposure to the culprit drug is necessary, a wide array of genetic and acquired factors modulate the occurrence and course of DHS, confirming the multifactorial pathogenesis A slow acetylator phenotype is a predisposing factor to develop DHS as compared to fast acetylators 17 CLINICAL FEATURES DHS occurs during first course of the causative drug but not with the first dose The clinical hallmark of this syndrome is the long Recent Advances in Dermatology 132 Table 8.2 : Clinical features of DHS System Signs and symptoms Mucocutaneous • • • • • • • • • • Hepatic Renal Reticuloendothelial and Hematological Pulmonary Cardiovascular Gastrointestinal Endocrine and exocrine Genitourinary Musculoskeletal Neurological Pruritus Maculopapular, pustular rash Exfoliative dermatitis Target and vesiculo-bullous lesions Oral aphthae Pharyngitis Conjunctivitis Hepatitis and jaundice Fulminant hepatic necrosis Nephritis, proteinuria, hematuria • Generalized lymphadenopathy • • • • • • • Hepato-splenomegaly Neutrophilia, eosinophilia Atypical lymphocytosis Hemolytic anemia Pancytopenia Pneumonitis Restrictive pulmonary dysfunction • • • • • • • • • • • • Hypotension Myocarditis Colitis Pancreatitis Thyroiditis Parotitis Orchitis Arthralgia and arthritis Myositis Rhabdomyolysis Headache Meningitis interval (1-8 weeks) between introduction of the drug and onset of symptoms The onset is rapid with fever, facial or periorbital edema, tender lymphadenitis and skin rash; gradually manifestations of multisystem involvement become evident (Table 8.2) Hepatic, renal and hematological involvements are the commonest Cutaneous involvement may be severe enough to give rise to erythroderma (Fig 8.1) At other times skin involvement is subtle and transient Asymptomatic organ involvements (changes in liver function tests, proteinuria, microscopic hematuria and hypercytosis of cerebrospinal fluid) are often recognized 3,4 Predilection for organ Drug Hypersensitivity Syndrome 133 involvement has been observed with some of the drugs.3 Prominent mucocutaneous involvement is seen with lamotrigine, whereas these are minor in case of abacavir Severe gastrointestinal manifestations may be seen with carbamazepine, abacavir and azathioprine; the latter causes pancreatitis also Pneumonitis is a feature of minocycline induced DHS Trimethoprim causes meningeal involvement and headache Azathioprine and abacavir induce hypotension Constitutional symptom like backache is commonly seen with abacavir and trimethoprim PATHOGENESIS Exact pathogenesis of DHS is yet unknown It is multifactorial and interplay of genetic, metabolic and immunological factors foreruns the onset Multiple episodes of DHS to different aromatic anticonvulsants in an individual, and familial occurrence of Chart 8.1 : Metabolic pathways for drugs Phase I (Oxidation, reduction, hydrolysis) Occurs at liver and skin DRUG Cyt P450 and mixed function oxidases REACTIVE DRUG METABOLITE Phase II Conjugation (glutathione, Detoxification by sulfate, glycine) glutathione S, Acetylation epoxide hydrolase Methylation N-acetyltransferase Occurs at liver and partly in skin INACTIVE DRUG METABOLITE Table 8.3: Important reactive drug metabolites3 Drug Anticonvulsants Lamotrigine Minocycline Abacavir Sulfamethoxazole Trimethoprim Reactive drug metabolite Arene oxide Arene oxide, nitrosamine Iminoquinone Cyclopropyl amine Hydroxylamine, nitrosamine Quinone iminemetride 134 Recent Advances in Dermatology detoxification defects of different drugs (e.g sulfonamides, anticonvulsants) prove the role of the altered pharmacogenetics.3 Susceptibility to develop DHS due to the use of antiretroviral abacavir has been proved in individuals with HLA-B*5701.18 Defects in the normal metabolic pathways of drugs (Chart 8.1), e.g absence or variable activities of drug metabolizing enzymes like Cyt P-450, N-acetyltransferase, glutathione-S, cause accumulation of the reactive drug metabolites (RDM) in the system Exact metabolic pathways and the resultant toxic RDMs are yet to be fully recognized in many a drug causing DHS; only in a few these have been recognized till date (Table 8.3) Different factors like old age, chronic liver disease, renal impairment, concurrent use of other drugs (hepatic enzyme inducer/inhibitor) and smoking influence the accumulation of RDM Though accumulation of RDM is necessary for initiation of DHS, this is unlikely to be the sole factor About 50 percent of the population is slow acetylator,20 but all not develop DHS Other exogenous and endogenous trigger factors influencing the occurrence of DHS are oxidizing stressors like sunburn, radiotherapy, viral infections and immunological alterations as seen in systemic lupus erythematosus and lymphoma.3 Role of viral infections in the pathogenesis of DHS has been confirmed by several authors In Human Immunodeficiency Virus (HIV) infection, there is an acquired deficiency of glutathione-S, causing accumulation of RDM in body.3 Kano et al21 have studied the role of human herpes virus-6 (HHV-6) in patients with DHS due to anticonvulsants Several anticonvulsants are known to cause a transient selective or panhypogammaglobulinemia as well as decreased circulating B cell count few weeks after starting the therapy.21,22 This hypogammaglobulinemia produces a congenial environment for reactivation of herpes groups of viruses.23 There are reports of DHS occurring in association with cytomegalovirus and Epstein-Barr virus infection.23,24 The mechanism by which viral infections modify the occurrence and course of DHS is not known Some authors believe that viral infection may alter the drug metabolism and induce the synthesis of RDM.23 A massive expansion of HHV-6 specific and nonspecific bystander CD8+ and CD4+ T cells in response to this reactivation is the most likely cause for gradual multiorgan involvement seen in DHS 21 Drug Hypersensitivity Syndrome 135 Chart 8.2: Initiation of immunological events in DHS Reactive drug metabolites Hapten hypothesis Danger hypothesis Binding to tissue macromolecule Oxidative cell damage Complete antigen Release of cytokines Initiation of immune response Warning signal to the immune system regarding cellular stress and damage Elimination of potentially damaged cells Immunological events induced by the RDM are poorly characterized Hapten hypothesis and Danger hypothesis3 have been postulated to explain the initial events (Chart 8.2) in inducing specific T-cell response The cytokine profile is dynamic, characteristic of both TH1 and TH2 types of response, which may change over time during the evolution of the disease.3 Elevated levels of interleukin5 (IL-5) and 6, the TH2 type of cytokines are seen in the early stage, of which IL-5 is responsible for the intense eosinophilia associated with DHS.3,25 Presence of TH1 cytokines are detected in presence of vesiculo-bullous lesions, Coombs-positive hemolytic anemia, organspecific changes like thyroiditis and granulomatous tissue infiltrate.3 Preexisting infective or inflammatory disorders involving specific organs (pulmonary tuberculosis, bronchial asthma, nephritis) enhance the local toxic effects of RDM, by means of producing local danger signals.3 Hence, such intercurrent illnesses may influence the localization and extent of organ involvement in DHS COURSE AND PROGNOSIS Mild cases generally resolve when the causative drug is identified and rapidly withdrawn Moderate to severely affected cases run a 136 Recent Advances in Dermatology prolonged course with slow resolution and recurrence Severity of clinical pictures intensifies with each recurrence Skin rash and hepatitis may persist for weeks to months.26 Rapid tapering of systemic corticosteroid, one of the effective therapeutic agents for DHS results in reappearance of symptoms Reactivation of HHV-6 may be the factor accountable for chronicity and recurrence of DHS,26 and this may be promoted by systemic corticosteroid therapy.26 Systemic involvement may be potentially fatal and DHS carries a mortality rate ranging from 10 percent 26 to 38 percent.21 Hepatic involvement is the commonest cause of death.27 Severe complications like encephalitis and fulminant type diabetes mellitus may be present in DHS associated with HHV-6 reactivation.28 DIAGNOSIS Sudden onset clinical triad of fever, skin rash and visceral involvement occurring within to weeks of starting a drug makes DHS to stand apart from other drug reactions and is usually unmistakable by an experienced dermatologist There is no goldstandard for investigating DHS Complete blood count may reveal eosinophilia (90%),16 atypical lymphocytosis (40%),16 and neutrophilia Routine urinalysis, liver function tests, renal function tests and chest X-ray are to be performed in all patients with DHS to assess the extent of visceral involvement Estimation of blood level of eosinophil cationic protein, which has been found to be high in acute stage of the disease, is helpful in monitoring the patients 29 In cases of anticonvulsant hypersensitivity syndrome, in vitro lymphocyte toxicity assay helps in confirmation of the causative agent as well as in identifying other drugs carrying the potential risk of causing DHS.30 Patch tests with anticonvulsants and other drugs like spironolactone have been found to be useful in pin-pointing the culprit drug.13,14 Biopsy from the skin lesions show nonspecific findings 27 Lymphocytic infiltrate, intermixed with eosinophils at the papillary dermis is the usual finding However, it is denser than in other drug reactions Occasionally, mycosis fungoides-like histopathological picture with epidermotropism may be found.27 In the series of patients with anticonvulsant syndrome reported by Galindo et al13 most frequent histopathological finding was that of typical erythema multiforme Drug Hypersensitivity Syndrome 137 Role of hypogammaglobulinemia and reactivation of HHV-6 are the most discussed aspects in the pathogenesis of DHS in recent years.21,22 Significant increases in anti-HHV-6 IgG antibodies is a helpful evidence for HHV-6 related cases of DHS 21 More specific tests to indicate such association are a rising HHV-6 antibody titer (4-fold), real-time PCR for quantification of HHV-6 DNA and viral culture.22 Tests like estimation of pancreatic, cardiac and muscle enzymes, lumbar puncture and imaging procedures like echocardiography are to be undertaken in presence of symptoms and signs pertaining to particular organ involvement DIFFERENTIAL DIAGNOSIS In the initial stage, fever and subtle skin rash of DHS may be mistaken as viral exanthema or maculopapular drug rash Fever and skin rash with subsequent exfoliation, constitutional symptoms, lymphadenopathy and hepatic involvement may simulate infectious mononucleosis, Kawasaki disease and Still’s disease.27 In the presence of pustular, target and vesiculo-bullous lesions, DHS has to be differentiated from acute generalized exanthematous pustulosis and Stevens-Johnson syndrome respectively.27 MANAGEMENT Prompt recognition of this life-threatening condition and immediate withdrawal of all drugs with a potential for causing DHS are the initial anchors of management Mild cutaneous lesions should be managed symptomatically with emollients and topical corticosteroids Meticulous management with fluid and electrolyte balance is needed for patients with erythroderma Systemic corticosteroids inhibit cellular transcription of many cytokines, especially IL-5, the predominant cytokine found in DHS.25 Hence, when used in adequate dosage (0.5-1 mg/kg), it results in symptomatic improvement as well as reduction in laboratory values.26 A gradual tapering is recommended to prevent recurrence of symptoms However, long-term effect of steroid on the course of DHS is unpredictable and relapses are frequent 26 Interferon-γ, which reduces IL-5 mRNA, has been proposed as a therapeutic modality in cases of DHS with chronic course.25 Current recommendation is 138 Recent Advances in Dermatology to restrict the use of systemic corticosteroids only in patients of DHS with life-threatening visceral involvements like interstitial pneumonitis or nephritis 25 There are reports of use of intravenous immunoglobulin (IVIG) in patients with DHS Kano et al21 have used IVIG containing high titers of HHV-6 IgG in two of the patients with DHS in their series The results were encouraging and the authors have attributed this partly to the anti-HHV-6 antibodies used in the preparation Mostella et al31 have used a combination of systemic corticosteroids and IVIG in a patient with anticonvulsant-induced DHS resulting in complete recovery Harman et al32 have reported effective treatment of a persistent case of DHS with ciclosporin A high doses of Nacetylcysteine has been suggested to be beneficial in anticonvulsantinduced DHS, by accelerating the elimination of the causative drug.27 Siblings and first degree relatives of the patients are to be warned about the increased likelihood (as high as in 4)33 of developing reaction to the same drugs and family-counseling constitutes an important part of the management PREVENTION OF RECURRENCE Patients should be provided with a discharge sheet bearing clear instruction about the drugs to be avoided in future, which includes the causative as well as the related drugs Cross sensitivities between the aromatic anticonvulsants, phenytoin, phenobarbital and carbamazepine are as high as 80 percent.34 Hence, the drug regime of these patients are to be substituted with nonaromatic anticonvulsants Sodium valproate is the best tolerated drug and incidence of DHS with this is rare.8,13 However, patients developing DHS due to aromatic anticonvulsants as well as sodium valproate has been reported.13 There are possibilities of cross reactivity between other chemically related drugs (e.g, 6-mercaptopurine in azathioprineinduced cases and tetracycline in minocycline-induced cases).3 Prophylactic drug desensitization can be practised with some anticonvulsants like lamotrigine, to reduce the risk of DHS.3 The treatment is commenced at a lower dose followed by gradual escalation to the optimum therapeutic dosage The initial subtherapeutic dose, being below the required threshold level, is inadequate to initiate the reaction Moreover, the gradual increase of the dose induces adaptive immunological and metabolic changes, Drug Hypersensitivity Syndrome 139 so that the individual is protected from the adverse effects of the RDM In patients with past experience of DHS due to lamotrigine, rechallenge with a slow escalating dose has been found to be helpful because of desensitization.35 This method can be considered in situations when choosing a suitable alternative anticonvulsant becomes difficult Lymphocyte toxicity assays, though not widely available, may be helpful to identify the patients at risk of developing reaction to a particular drug 30 FUTURE PERSPECTIVES There is a significant improvement in the understanding of DHS in recent years; still at times, it poses an etiological, pathogenic and therapeutic puzzle Multicentric epidemiological studies on DHS may further help to understand the genetic susceptibility, population-based variation in occurrence and clinical pattern of this disorder Large controlled, randomized trials may help in determining the efficacy of the available in vitro diagnostic tests and these can be refined further to increase their sensitivity and specificity Till date only definitive therapeutic modality available for DHS is withdrawal of the causative drug With better understanding of the pathogenic mechanisms, definitive therapeutic modalities can be worked out REFERENCES Chaiken BH, Goldberg BI, Segal JP Dilantin sensitivity: Report of a case of hepatitis with jaundice, pyrexia and exfoliative dermatitis N Eng J Med 1950;242:897-8 Shear NH, Spielberg SP Anticonvulsant hypersensitivity syndrome: in vitro assessment of risk J Clin Invest 1988;82:1826-32 Sullivan JR, Shear NH The drug hypersensitivity syndrome What is the pathogenesis? 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Br J Dermatol 2000;142:203-9 20 Wolkenstein P, Charue D, Laurent P, et al Metabolic predisposition to cutaneous adverse drug reactions Role in toxic epidermal necrolysis caused by sulfonamides and anticonvulsants Arch Dermatol 1995;131:544-51 21 Kano Y, Inaoka M, Shiohara T Association between anticonvulsant hypersensitivity syndrome and human herpes virus-6 reactivation and hypogammaglobulinemia Arch Dermatol 2004;140:183-8 22 Wong GAE, Shear NH Is a drug alone sufficient to cause the drug hypersensitivity syndrome? Arch Dermatol 2004;140:226-30 23 Descamps V, Mahe E, Houhou N, et al Drug-induced hypersensitivity syndrome associated with Epstein Barr virus infection Br J Dermatol 2003;148:1032-4 24 Satoh A, Ikai T, Miwa H, et al Acute promyelocytic leukemia with druginduced hypersensitivity syndrome associated with Epstein-Barr virus infection Intern Med 2004;43:74-8 25 Choquet-Kastylevsky G, Intrator L, Chenal C, et al Increased levels of interleukin are associated with the generation of eosinophilia in druginduced hypersensitivity syndrome Br J Dermatol 1998;139:1026-32 Drug Hypersensitivity Syndrome 141 26 Ghislain PD, Roujeau JC Treatment of severe drug reactions: Stevens-Johnson syndrome, Toxic Epidermal Necrolysis and Hypersensitivity syndrome Dermatol Online J 2002;8:5 27 Simonart TT Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): An update Dermatology 2003;206:353-6 28 Hashimoto K, Yasukawa M, Tohyama M Human herpesvirus and drug allergy Curr Opin Allergy Clin Immunol 2003;3:255-60 29 Allam JP, Paus T, Reichel C, et al DRESS syndrome associated with carbamazepine and phenytoin (abstract) Eur J Dermatol 2004;14:339-42 30 Bavdekar SB, Muranjan MN, Gogtay NJ, et al Anticonvulsant hypersensitivity syndrome: lymphocyte toxicity assay for the confirmation of diagnosis and risk assessment Ann Pharmacother 2004;38:1648-50 31 Mostella J, Pieroni R, Jones R, et al Anticonvulsant hypersensitivity syndrome: treatment with corticosteroids and intravenous immunoglobulin (Abstract) South Med J 2004;97:319-21 32 Harman KE, Morris SD, Higgins DM Persistent anticonvulsant hypesensitivity syndrome responding to ciclosporin Clin Exp Dermatol 2003;28:364-5 33 Shear NH, Knowles SR, Sullivan JR, et al Cutaneous reaction to drugs In: Freedberg IM, Eisen AZ, Klaus W, et al, (Eds) Fitzpatrick’s Dermatology in General Medicine Vol.1, 6th edn New York: McGraw-Hill; 2003 1330-7 34 Kleier RS, Breneman DL, Boiko S Generalized pustulation as a manifestation of the anticonvulsant hypersensitivity syndrome Arch Dermatol 1991; 127:1361-4 35 Tavernok SJ, Newton ER, Brown SW Rechallenge with lamotrigine after initial rash Epilepsia 1994;35 (suppl 7):72 ... 23/23B Ansari Road, Daryaganj New Delhi 11 0 002, India Phones: + 91- 11- 2327 214 3, + 91- 11- 23272703, + 91- 11- 232820 21, + 91- 11- 23245672 Fax: + 91- 11- 23276490, + 91- 11- 23245683 e-mail: jaypee@jaypee brothers.com... + 91- 0484-403 610 9, + 91- 0484 2395739, + 91- 0484 2395740 1- A Indian Mirror Street, Wellington Square Kolkata 700 013 , Phones: + 91- 33-224 519 26, + 91- 33-22276404, + 91- 33-22276 415 , Rel: + 91- 33-329 019 26 Fax: + 91- 33-22456075,... + 91- 44-2 819 3265, + 91- 44-2 819 4897, Rel: + 91- 44-32972089, Fax: + 91- 44-2 819 32 31 e-mail: jpchen@eth.net 4-2 -10 67 /1- 3, 1st Floor, Balaji Building, Ramkote Cross Road Hyderabad 500 095, Phones: + 91- 40-66 610 020,