API Textbook of Medicine

Editor-in-ChiefBrothers Yash Pal Munjal

Volume 1 Jaypee

10 th EDITION

API _ Prelims _ Vol-1 for (TRADE).indd i 29-01-2015 14:22:07 The Association of Physicians of India

NOTICE The editors have checked the information provided in the book and to the best of their knowledge, it is as per the standards accepted at the time of publication. However, in view of the continuous changes in medical knowledge and the possibility of human error, there could be variance. In view of the possibility of human error by the authors, editors, or publishers of the work herein, or changes in medical knowledge, neither the authors, editors, publisher, nor any other party who has been involved in the preparation of this work, warrants that the information contained herein is in every respect accurate or complete, and they are not responsible for any errors or omissions or for the result obtained from the use of such information. Hence readers are requested to conﬁ rm information, particularly laboratory values and drug dosages from the product information sheet included in the package of each drug they plan to administer and from other sources as well, particularly in connection with new or infrequently used drugs. The editor takes no responsibility for the views expressed or the material submitted by the various contributors to this API Textbook of Medicine, Tenth Edition.

© All rights reserved. This book is protected by copyright. No part of it and CD-ROM may be reproduced in any manner or by any means, without written permission from the Editor-in-Chief. For all permissions apply to Dr Yash Pal Munjal, Editor-in-Chief, RT202, Royalton Towers, Princeton Estate, DLF Phase 5, Gurgaon, Haryana - 122002.

First Edition: 1969 Tenth Edition: 2015

ISBN 978-93-5152-415-1

Published by: Dr Yash Pal Munjal for and on behalf of The Association of Physicians of India Turf Estate # 6 & 7, Off Dr. E. Moses Road, Opp. Shakti Mills Compound, Near Mahalaxmi Station (West), Mumbai 400 011. Tel: (022) 6666 3224/2491 2218 Fax: (022) 2492 0263 e-mail: [email protected] Website: www.apiindia.org Brothers Printed, Designed and Exclusively Distributed Worldwide by: Jaypee Brothers Medical Publishers (P) Ltd.

Headquarters Jaypee Brothers Medical Publishers (P) Ltd. 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 E-mail: [email protected]

Overseas Ofﬁ ces J.P. Medical Ltd. Jaypee-Highlights Medical Publishers Inc. Jaypee Medical Inc. 83, Victoria Street, London City of Knowledge, Bld. 237, Clayton The Bourse SW1H 0HW (UK) Panama City, Panama 111, South Independence Mall East Phone: +44-20 3170 8910 Phone: +1 507-301-0496 Suite 835, Philadelphia, PA 19106, USA Fax: +44(0) 20 3008 6180 Fax: +1 507-301-0499 Phone: +1 267-519-9789 E-mail: [email protected]: [email protected] E-mail: [email protected]

Jaypee Brothers Medical Publishers (P) Ltd. Jaypee Brothers Medical Publishers (P) Ltd. 17/1-B, Babar Road, Block-B Bhotahity Shaymali, Mohammadpur Kathmandu, Nepal Dhaka-1207, Bangladesh Phone: +977-9741283608 Mobile: +08801912003485 E-mail: [email protected] E-mail: [email protected] Website: www.jaypeebrothers.com Website: www.jaypeedigital.com Inquiries for bulk sales may be solicited at: [email protected]

API _ Prelims _ Vol-1 for (TRADE).indd ii 29-01-2015 14:22:07 API Textbook of Medicine Tenth Edition

EDITOR-IN-CHIEF Yash Pal Munjal MD FICP MAMS FIAMS FACP FIACMS FRCP (Edin) Medical Director and Hon Senior Consultant, Diabetes and Life Style Disease Centre Banarsidas Chandiwala Institute of Medical Sciences, Kalkaji, New Delhi Past President of Association of Physicians of India Past Dean of Indian College of Physicians Hon Professor of Indian College of Family Physician, New Delhi, India

EXECUTIVE EDITOR Surendra K Sharma MD PhD Professor and Head Department of Medicine, All India Institute of Medical Sciences, New Delhi, India

EDITORS AK Agarwal RK Singal MD FICP FRCP (Edin) MAMS FACP FIACM FIAMS FIMSA MD FRCP FICP FACP Professor and Head, Department of General Medicine Senior Consultant and Head School of Medical Sciences and Research, Sharda University Department of Medicine Greater Noida, Uttar Pradesh Dr BL Kapur Memorial Hospital Ex-Dean, Professor and Head, Department of Medicine, PGIMER New Delhi, India Dr Ram Manohar Lohia Hospital, New Delhi, India Shyam Sundar Pritam Gupta MD FRCP FAMS FNA FSc FNASc MD (Medicine) BrothersProfessor of Medicine Senior Consultant and Head, Department of Medicine Institute of Medical Sciences Sunder Lal Jain Hospital, New Delhi, India Banaras Hindu University, Varanasi Uttar Pradesh, India Sandhya A Kamath MD FICP Subhash Varma Ex-Dean and Professor, Department of Medicine MD FICP Lokmanya Tilak Municipal Medical College and Municipal Professor and Head General Hospital, Mumbai, Maharashtra, India Department of Internal Medicine PGIMER, Chandigarh, India Milind Y Nadkar MD FICP Professor of Medicine, Chief of Rheumatology and Emergency Medicine, Seth GS Medical College and KEM Hospital Mumbai, Maharashtra, India

ASSOCIATE EDITORS Ghan Shyam Pangtey Anupam Prakash MD MD (Gen Medicine) FICP MNAMS PDCC (Hospital Management) Associate Professor, Department of Medicine PDCDM (Dialysis Medicine) Lady HardingeJaypee Medical College and Associated Hospitals Professor, Department of Medicine, Lady Hardinge Medical New Delhi, India College and Associated Hospitals, New Delhi, India

EMERITUS EDITOR Siddharth N Shah MD FICP FACP (Hon) FRCP (Edin) Post-graduate Teacher in Diabetes, University of Mumbai Consulting Physician and Diabetologist SL Raheja Hospital and All India Institute of Diabetes Saifee Hospital, Bhatia Hospital, Sir Hurkisondas Nurrotumdas Hospital Visiting Consultant, Central Railway and Western Railway Hospitals, Mumbai, Maharashtra, India

API _ Prelims _ Vol-1 for (TRADE).indd iii 29-01-2015 14:22:07 Editors-In-Chief

Late Dr RJ Vakil Late Dr KK Datey Late Dr Shantilal J Shah 1st and 2nd Edition 3rd Edition 4th Edition

Brothers

Dr GS Sainani Dr Siddharth N Shah 5th and 6th Edition 7th and 8th Edition

Jaypee

Dr Yash Pal Munjal 9th and 10th Edition

API _ Prelims _ Vol-1 for (TRADE).indd iv 29-01-2015 14:22:07 PREFACE

It is 45 years since the fi rst edition of API Textbook of Medicine was published keeping the Indian milieu in focus. Enthused by the acceptance and success of the book nine more editions were published over the years. With the dawn of the year 2015, I have the pleasure and privilege to present to you the 10th edition of API Textbook of Medicine. In the last two to three decades, Medicine has witnessed a torrential growth in the understanding of disease and its management. The disease profi le has also substantially changed along with the demography of various disorders. In the earlier edition of the book, diseases such as smallpox, poliomyelitis and guinea worm infestation were quite common and were discussed in detail. These diseases have been eradicated or their signifi cance greatly reduced due to immunisation, use of appropriate drugs and better hygienic facilities. Therefore, their presentation in the book has been reduced while newer infections such as hepatitis B, HIV, swine fl u and avian fl u have been discussed in greater detail as the new infective disorders. Along with these, various non- communicable diseases have increased in an unprecedented epidemic like manner. Therefore, this edition of the book has been designed and covers the recent trends in diagnosis and management of these disorders. The book is completely revised, updated and better illustrated. There are over 3000 pages with 1622 fi gures and 1460 tables. These large numbers of tables and fi gures have been used so that the information is easily understood and reading is facilitated. In this endeavour, many new additions have been done as compared to the previous edition. The book consists of 29 parts and each part discusses a group of disorders. In addition, 28 new chapters have also been added. 1. An entirely new part Future of Medicine, has been added. This part of the book deals with the anticipated progress in medicine which will be put to clinical use in the coming one to two decades or the advances that are being used in their early stages in clinical practice. 2. A new chapter on Disease Profi le and Epidemiology of Communicable and Non-communicable Diseases in India has been added so that the reader has an ample understanding of the diseases commonly prevalent in this part of the world. 3. During the 9th edition, a new part had been added Clinical Approach to Key Manifestations. This has been further expanded and six new chapters have been added out of which one deals with the selection of the imaging modality which will be best suited to a clinical condition. Brothers 4. Part 4 of the book on Clinical Pharmacology has been re-oriented and new authors have contributed chapters. One of the chapters deals with National Formulatory of India in the National Health System. 5. The Part 7 on Critical Care Medicine has been thoroughly revised and to put adequate emphasis on cardiac resuscitation, a separate chapter has been devoted to Advanced Cardiac Life Support System. 6. The parts of the book dealing with various life-style disorders such as diabetes mellitus and cardiovascular diseases have been re-oriented for better understanding of the newer guidelines which have emerged. 7. A chapter on life-style measures, diabetes in the elderly and prevention of cardiovascular diseases have been added and discussed. 8. In the part dealing with gastrointestinal disorders, Pancreatitis has been divided into two parts—a chapter on Acute Pancreatitis and the other on Chronic Pancreatitis have been added, while Neoplasms of the Pancreas fi nds a separate chapter. 9. Similarly, Tumours of the Liver has been discussed as a separate chapter. 10. Chronic pulmonary disorders and sleep-related pulmonary disorders are increasing in prevalence and to address these issues the chapters have been thoroughly re-written and a chapter on Pulmonary Rehabilitation has been added in this part of the book.Jaypee 11. Similarly, the management of stroke has been signifi cantly modifi ed and the chapters on Ischaemic or Haemorrhagic Stroke have been thoroughly revised and re-written. 12. A chapter on Oral Health and its relationship to systemic diseases has been presented separately. 13. For the fi rst time, Futuristic Medicine and the problems of Space Travel have been delineated and highlighted. The presentation of all disorders in a concise manner has been possible with the support, joint and collaborative effort and useful editorial guidance from all the members of my editorial team for which I am grateful to them.

API _ Prelims _ Vol-1 for (TRADE).indd v 29-01-2015 14:22:07 API _Prelims _Vol-1for(TRADE).indd vi API Textbook of Medicine vi many newthings, andIhopethatitwillbeusefulfor thereaders. thebookproves If useful, willberewarded. ourefforts has beenpresented material whichitisgoingto andthequality offer to ourreaders. The journeythough diffi I alongwithmy editorial team whowere assignedthetaskofcompiling the10theditionare excited aboutthecontent, which of theGoverning BodyofAssociation ofPhysicians ofIndia(API). task, Iamhumbledandexpress my sincere thanksto President andDrAMuruganathan, DrShashankRJoshi, andtheMembers Munjal,Dr Rama my daughter MsJaya Munjalandmy sonDrAkshay Munjalfor theirhelp. Onthecompletion ofthisonerous andmentalstrength duringthetrialsandtribulationswhilecompiling thebook.moral support Iespeciallythankmy wife I wishto thankmy andmany familyfor sacrifi theirsupport work anddedicationofourauthors. andtimelycontribution.extraordinary The quickturnaround for ofthissize theneweditionofatextbook isatribute to the I amgrateful to theexcellent group ofauthorswhohave inthe10theditionof participated to themdiligently andpainstakingly. him for allhishelp. The were editors ofvarious generous withtheirtimeandsuggestions, parts andedited thechapters allot I owe my thanksto them. NShahfor hiscontinuous Iwishtoandenthusiasticsupport, thankDrSiddharth andIamobligedto useful inputs. DrShyam Sundar, DrSubhash Varma andDrPritam Guptawere intheirhelpandsuggestionsfor forthcoming which atalltimesduringthepreparation ofthebook.support Iwishto thankDrMilind for andDrSandhya their AKamath Y Nadkar Pangtey have stood by meandhave from helpedmeincompleting thebeginningto thisproject theendandhave provided the in preparation ofthebookfor whichIamgrateful to them. Two ofmy Associate Editors, DrAnupamPrakash andDrGhanShyam busy schedule. andDrRKSingalhave DrAKAgarwal beencloselyassociated andhave provided useful inputsandsuggestions Professor Surendra KSharmahasprovided usefulguidance andhasplayed very asignificant role inplanningthebookdespite his API The various atlasesalongwiththeirexplanationsare added. pictorial This isausefulnewadditionto the10th choice questions (MCQs) withtheiranswers andafew issuesinmedicine. powerpoint presentations ofsometheimportant A CD-ROMispresented alongwiththebook. hassomeofthechapters presented It inthee-format ofthebookalongwithmultipl Textbook ofMedicine. JaypeeLet amanlearnthoroughlywhatever hemaylearn, ofhislearning. andlethisconduct beworthy

Brothers ces thisvolume theymadeto make possible. They were my API Textbook ofMedicinefor their API Textbook ofMedicine – Thirukkural Dr Yash Pal Munjal cult hastaughtus Editor-in-Chief

edition ofthe 10th Edition 29-01-2015 14:22:07 hard ted e ACKNOWLEDGEMENTS

I am happy to present to you the 10th edition of the API Textbook of Medicine in the year 2015. This is a momentous occasion, as it coincides with the platinum jubilee year of the foundation of the Association. This has been possible due to the collaborative, co-operative and untiring efforts of the editorial team and many others. Thanksgiving is always a pleasure and on the occasion of the successful completion of this gigantic task, I have the privilege to thank the members of my team who made this task possible. The help rendered by Dr Aditya Prakash Misra, Dr Anurag Saxena, Dr Vibhu Mendiratta and others is duly acknowledged. The task of proofreading and organising the manuscript was painstakingly carried out by Mr Rakesh K Gupta and Ms Seema Soni, and their respective teams. The efforts of Mr Rakesh K Gupta and his keen eye for checking manuscripts in-minute detail stand out. For this, his services need special mention. Ms Seema Soni was able to put the language correctly and in right perspective. Chief of Text-O-Graphics, Mr Atin Chatterjee, and his team were instrumental in the initial typesetting of the book. We express our appreciation and gratitude to Shri Jitendar P Vij (Group Chairman) and Mr Ankit Vij (Group President) of M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India, which is one of the largest Medical Publishers in the world, for their assistance and help. Mr Tarun Duneja (Director-Publishing) has been instrumental in getting the fi nal shape of the book. The other members of his team worked diligently and tirelessly for the fi nal production of the book. They were receptive and bore the brunt of this task willingly. They co-ordinated with the offi ce of the editorial board as a team and carried out the instructions meticulously. They deserve our appreciations and thanks. I would like to express my sincere thanks to my Secretary, Ms Pushap Lata, for having taken up the additional responsibility with due diligence and carried out all the hard work willingly and with a smile on her face at all times. Ms Beatrice Mendes assisted in all sections of the preparation of the book in the initial phases for which I thank her. Ms Archana Makhija, who joined at a later stage, but integrated the previous work and carried it forward with enthusiasm and vigour. She co-ordinated the work very effectively and effi ciently both in compiling as well as proofreading till the fi nal stages of the book. I wish to express my sincere thanks to Shri Autar Krishna (Chairman) and Shri Bhuwan Mohan (Secretary), Shri Banarsidas Chandiwala Sewa Smarak Trust Society for providing the offi ce spaceBrothers and allowing the use of infrastructure during the entire course of the publication of this assignment. Not only they provided the infrastructural support, but they also encouraged me in my task as the Editor-in-Chief of the book. The help of the editors of the parts for editing diligently and providing editorial inputs, which were very useful and timely is highly appreciated. I would like to extend our thanks on behalf of the editorial board and the authors who have been provided useful assistance by their colleagues in preparation of their respective manuscripts. Our grateful thank to our advisors, Dr A Muruganathan, Dr BB Thakur, Dr Ashok Seth, Dr Man Mohan Mehndiratta, Dr Kamlesh Tewary, Dr Manjari Tripathi, Dr Ravi Kasliwal, Dr Praveen Gulati, Dr Harsh Mahajan, Dr Vikash Bajaj and Dr NK Soni. The other distinguished teachers, who provided useful guidance in the formulation of the book, are duly acknowledged.

Dr Yash Pal Munjal Jaypee and the Editorial Board

API _ Prelims _ Vol-1 for (TRADE).indd vii 29-01-2015 14:22:07 Part/Chapter Authors Assisted By

PART 1: INTRODUCTION 2 Disease Profi le and Epidemiology of Communicable Jugal Kishore Tanu Anand and Non-communicable Diseases in India PART 2: CLINICAL APPROACH TO KEY MANIFESTATIONS 13 Syncope Pushpa Yadav Diki Palmu Theengh 15 Appropriate Ordering of Radiological Investigations Chandan J Das Ananya Panda 16 A Clinical Approach to Patients with Ascites Richa Dewan Abhilekh Srivastava 18 Approach to a Patient with Dyspnoea Praloy Chakraborty Mayuresh Chaudhari PART 3: DIAGNOSTIC IMAGING 1 Conventional Radiology Ashu Seith Bhalla Ankur Gadodia PART 4: CLINICAL PHARMACOLOGY 6 Role of National Formulary of India in National Health Jai Prakash Pooja Gupta and Care System GN Singh PART 6: MEDICAL GENETICS 9 Pharmacogenomics and Personalised Medicine C Adithan S Sureshkumar PART 7: CRITICAL CARE MEDICINE 1 Basic Considerations in Critical Care RK Mani R Aggarwal 9 Non-invasive Positive Pressure Ventilation Dhruva Chaudhry Atulya Atreja PART 9: DIABETES MELLITUS 2 Pathogenesis of Type 1 Diabetes Mellitus BrothersCarani B Sanjeevi Chengiun Sun PART 11: DERMATOLOGY 11 Sexually Transmitted Infections Yogesh S Marfatia Ankit H Bharti and Mahima Talwar 13 Leprosy Hemanta Kumar Kar Amrita Chauhan PART 12: CARDIOLOGY 10 Treatment of Heart Failure Veronica Franco Ragavendra Baliga 13 Valvular Heart Disease (ll) VK Bahl Ishwar Chandra Malav 17 Acute Coronary Syndrome—NSTEMI Ambuj Roy Shrenik Doshi 26 Disorders of the Myocardium KK Talwar Pawan Poddar PART 14: HEPATOLOGY 9 ExtrahepaticJaypee Portal Venous Obstruction Yogesh K Chawla Vijay Bodh PART 15: HAEMATOLOGY 16 Bleeding Disorders Kanjaksha Ghosh Kinjalka Ghosh 17 Platelet Disorders Prantar Chakrabarti Dibyendu De 18 Idiopathic Thrombocytopenic Purpura Cecil Ross Sanjukta Rao PARTS 16: HIV AND AIDS 6 Non-opportunistic Infections Anil Kumar Tripathi Shailendra P Verma

API _ Prelims _ Vol-1 for (TRADE).indd viii 29-01-2015 14:22:07 Part/Chapter Authors Assisted By

PART 17: INFECTIOUS DISEASES 11 Pneumococcal Infections DP Bhadoria Raghav Bansal 13 Gonococcal Infections Chander Grover Amit Dhawan 17 Diseases Caused by Gram-negative Enteric Bacilli Richa Dewan Vivek Kumar 27 Other Spirochaetal Infections: Lyme Disease and Kamlesh Tewary Amit Kumar Das Rat Bite Fever PART 18: DISORDERS OF METABOLISM 3 Lipids and Lipoprotein Metabolism Soneil Guptha Ravinder Singh Sambi 6 Porphyrias Dhanpat Kumar Kochar Abhishek Kochar 9 Inherited Disorders of Membrane Transport SK Singh Rahul Singh PART 19: NEPHROLOGY 10 Polycystic Kidney Disease and Inherited Tubular Disorders PP Varma A Jairam PART 20: NEUROLOGY 1 Neurological Disorders: Basic Consideration MV Padma Srivastava Tanu Talwar and Clinical Approach 8 Haemorrhagic Cerebrovascular Diseases MV Padma Srivastava Tanu Talwar 15 Fungal and Parasitic Diseases of the Nervous System Ashok Panagariya Bhawna Sharma 22 Demyelinating Diseases of Nervous System Man Mohan Mehndiratta Natasha Singh Gulati PART 21: ONCOLOGY 5 Principles of Radiotherapy GK Rath AK Gandhi 11 Gynaecological Malignancies BrothersPP Bapsy Vaishnavi S PART 22: PSYCHIATRIC MEDICINE 2 Organic Mental Disorders SK Khandelwal Priyanka Yadav 3 Substance Use Disorders Debasish Basu Siddharth Sarkar 5 Mood Disorders Yatan Pal Singh Balhara Siddharth Sarkar 8 Emergency Psychiatry Dipesh Bhagabati Sachin Aurora PART 23: PULMONARY MEDICINE 5 Bronchial Asthma Virendra Singh Nishtha Singh 6 Chronic Obstructive Pulmonary Disease Surendra K Sharma Sajal Ajmani PART 24: RHEUMATOLOGY 5 Gout and Other Crystal Arthritides URK Rao C Shiva Shankar 14 Mixed Connective Tissue Disease and Overlap Syndromes G Narsimulu Avinash Kusuma PART 26: POISONINGJaypee AND TOXICOLOGY 1 Poisoning: Basic Considerations and Epidemiology Narinder Pal Singh Anish Kumar 7 Drug Overdose Narinder Pal Singh Anish Kumar 9 Scorpion Sting HS Bawaskar PH Bawaskar PART 28: MISCELLANEOUS 4 Polypharmacy in Elderly Jyotirmoy Pal Tony Ete 10 Adult Immunisation AK Agarwal RK Singal

API _ Prelims _ Vol-1 for (TRADE).indd ix 29-01-2015 14:22:07 API _Prelims _Vol-1for(TRADE).indd x API Textbook of Medicine x o Part’s Name No. 6 HIVand 16. Haematology Rajat 15. Hepatology 14. Gastroenterology 13. Cardiology 12. Dermatology 11. Endocrinology 10. 9 Future ofMedicine Miscellaneous 29. Environmental Medicine 28. Poisoning and Toxicology27. Nutrition 26. Rohini Rheumatology 25. Medicine Pulmonary 24. Psychiatric Medicine 23. Oncology 22. Neurology 21. Nephrology Vinay 20. Disorders ofMetabolism 19. Diseases Infectious 18. 17. .Introduction 2. 1. .Diabetes Mellitus BoneDisorders 9. CriticalCare Medicine 8. Genetics Medical 7. Sita Immunology 6. ClinicalPharmacology 5. Diagnostic Imaging 4. 3. Clinical Appr

JaypeeAIDS oach to KeyManifestations EDITORS OF THE PARTS VOLUME 1 VOLUME 2 Brothers Vibhu Mendiratta Late Shyam Swarup Agarwal MV Padma Srivastava Editor Nikhil TandonNikhil Anil Bhansali SK Gupta SV Madhu Shyam Sundar Rajesh UpadhyayRajesh SNA Rizvi Surendra KSharma Alaka D Gurpreet Singh Wander Shashank RJoshi RK Singal Surendra KSharma Lal Rakesh Lalit Kumar Yash Pal Munjal AK Agarwal Rakesh TandonRakesh Raju Sharma Raju Narinder Pal Singh BK Sahay Randeep Guleria Randeep Naik Kumar Sakhuja Handa eshpande andBBRewari 29-01-2015 14:22:07 CONTRIBUTORS

OC Abraham MD MPH Vikas Agarwal MD DM (Clinical Immunology) DN Amarapurkar MD (Med) DM DNB Department of Medicine Unit 1 and Additional Professor Gastroenterologist and Hepatologist Infectious Diseases, Christian Medical College Department of Clinical Immunology Bombay Hospital and Medical Vellore, Tamil Nadu, India Sanjay Gandhi Post-graduate Institute of Research Centre, Jagjivanram Hospital Medical Sciences Mumbai, Maharashtra, India Philip Abraham MD DNB FCPS FICP Lucknow, Uttar Pradesh, India Consultant Gastroenterologist YK Amdekar MD DCH PD Hinduja Hospital, Mahim Amita Aggarwal MD DM Medical Director Mumbai, Maharashtra, India Professor Bai Jerbai Wadia Hospital for Children, Mumbai Department of Clinical Immunology Consultant Paediatrician SK Acharya DM Sanjay Gandhi Post-graduate Institute of Jaslok Hospital and Research Centre Professor and Head Medical Sciences Mumbai, Maharashtra, India Department of Gastroenterology Lucknow, Uttar Pradesh, India All India Institute of Medical Sciences AC Ammini MD DM (Endo) New Delhi, India Praveen Aggarwal MD DNB FICP Professor and Head Professor and Head, Department of Department of Endocrinology Prabha Adhikari MD Emergency Medicine All India Institute of Medical Sciences Professor and Head, Department of Medicine All India Institute of Medical Sciences New Delhi, India Kasturba Medical College New Delhi, India Mangaluru, Karnataka, India AC Anand MD (Medicine) DM (Gastroenterology) Ramesh Aggarwal MD (Medicine) FICP FACP FACG FAMS C Adithan MD PhD DNB (Clin Pharmacol) FAMS Assistant Professor Senior Consultant, Hepatology and Senior Professor and Head Department of Medicine Department of Clinical Pharmacology Gastroenterology Lady Hardinge Medical College and Dr Ram Indraprastha Apollo Hospital, New Delhi Jawaharlal Institute of Post-graduate Medical Manohar Lohia Hospital, New Delhi, India Education and Research Professor and Head of Department Puducherry, India Aparna Agrawal MD (Medicine) (Gastroenterology and Hepatobiliary Unit) Director Professor, Department of Medicine Army Hospital Research and Referral P Advaitham MD DM Lady Hardinge Medical College and New Delhi, India Professor, Department of Medical Associated Hospitals, New Delhi, India Gastroenterology Inder S Anand MD FRCP D Phil (Oxon.) Sri Ramachandra Medical College Gautam Ahluwalia MD (Medicine) Professor of Medicine, University of Sri Ramachandra University Professor BrothersMinnesota Medical School Chennai, Tamil Nadu, India Department of Medicine Director, Heart Failure Program Dayanand Medical College and Hospital VA Medical Center, Minneapolis MN, USA SH Advani MD DNB FICP PhD FNAMS Ludhiana, Punjab, India Director, Medical Oncology Dharamvir Singh Arya MD Jaslok Hospital and Research Centre Jamal Ahmad MD DM (Endo) FCCP(USA) Professor, Department of Pharmacology Mumbai, Maharashtra, India PhD FRCP (UK) All India Institute of Medical Sciences Professor of Endocrinology and Director New Delhi, India AK Agarwal MD FICP FRCP (Edin) MAMS FACP Rajiv Gandhi Centre for Diabetes and Naved Aslam DM (Cardiology) FIACM FIAMS FIMSA Endocrinology, Faculty of Medicine Professor and Head Aligarh Muslim University Professor, Department of Cardiology Department of General Medicine Aligarh, Uttar Pradesh, India Dayanand Medical College and Hospital School of Medical Sciences and Research Unit Hero DMC Heart Institute Mansoor Ahmed DM (Cardiology) Sharda University, Greater Noida Ludhiana, Punjab, India Medical Ofﬁ cer, Department of Cardiology Ex-Dean, Professor and Head K Govind Babu MD DM (Oncology) Department of Medicine, Post-graduate Sawai Man Singh Medical College and Associated Hospitals, Jaipur, Rajasthan, India Associate Professor, Department of Medical Institute of Medical Education and Research Oncology, Kidwai Memorial Institute of Dr Ram Manohar Lohia Hospital Vineet Ahuja MD DM MNAMS Oncology, Bengaluru, Karnataka, India New Delhi, India Professor, Department of Gastroenterology All India Institute of Medical Sciences Ajay Bahl MD DNB MB Agarwal MD MNAMS New Delhi, India Associate Professor, Department of Cardiology Haematologist and Haemato-oncologist Post-graduate Institute of Medical Education Bombay Hospital, LilavatiJaypee Hospital and Parag Aland DNB (Nuclear Med) DRM and Research, Chandigarh, India Breach Candy Hospital Junior Consultant Head, Department of Haematology Department of Nuclear Medicine VK Bahl MD DM Bombay Hospital Jaslok Hospital and Research Centre Professor and Head, Department of Cardiology Mumbai, Maharashtra, India Mumbai, Maharashtra, India All India Institute of Medical Sciences New Delhi, India Late Shyam Swarup Agarwal MD FRCP FAMS Alan F Almeida MD (Internal Medicine) FNA FNASc MNAMS (Nephrology) FISN BK Bajaj MD (Medicine) DM (Neurology) Senior Medical Consultant and Honorary Consultant Nephrologist and Transplant Professor, Department of Neurology Director (Academic and Research) Physician, Post-Doctoral Fellow of the Post-graduate Institute of Medical Education Vivekanand Polyclinic and Institute of Medical University of Missouri, Columbia (USA) and Research, Dr Ram Manohar Lohia Hospital Sciences, Lucknow, Uttar Pradesh, India Fellow, Indian Society of Nephrology New Delhi, India

API _ Prelims _ Vol-1 for (TRADE).indd xi 29-01-2015 14:22:07 API _Prelims _Vol-1for(TRADE).indd xii

xii API Textbook of Medicine MNAMS and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical Centre, ofPsychiatry Department Professor, and DrugDe-addiction Treatment Debasish Basu Scientifi Jahangeer Basha Apollo Hospitals, Bengaluru, Karnataka, India Consultant,Senior Oncology Medical PP Bapsy and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical Assistant Professor, Advanced Eye Centre Reema Bansal Mumbai, Maharashtra, India Indian College Cardiology ofInterventional General Secretary NO Bansal Gurgaon, Haryana, India and Diabetes, Medanta—The Medicity Consultant, DivisionofEndocrinology Bansal Beena Medicity, Gurgaon, Haryana, India Institute ofNeurosciences, Medanta—The Associate Consultant Atma Bansal Ram Kolkata, West Bengal, India InstituteSciences ofMedical Vivekananda Professor, ofMedicine Department Banerjee Samar Cardiologist, Howrah, West Bengal, India Consultant Senior andInterventional Amal Kumar Banerjee Kolkata, West Bengal, India College Medical RG Kar Dermatology, Venereology andLeprosy Professor andHead, of Department Debabrata Bandyopadhyay Queensland, Australia Bundaberg ofMedicine Director Hospital Rural School(Bundaberg Medical Campus) The University ofQueensland Associate Professor ofMedicine Pradeep Bambery New Delhi, India All IndiaInstituteSciences ofMedical National DrugDependence Treatment Centre Assistant Professor, ofPsychiatry Department Yatan Pal SinghBalhara Research Centre, Kochi, Kerala, India Amrita InstituteSciences ofMedical and Professor, ofGastroenterology Department V Balakrishnan Chennai, Tamil Nadu, India Dr BalajiDiabetes Care Centre Dr DiabetesV Seshiah Research Institute and Consultant andSenior Director V Balaji DNB (Cardiology) and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical ofGastroenterology Department c Pool Offi MDFRCP(UK) MD DM MD (Medicine) DM(Cardiology) MD(Medicine) MD DM MS (Ophthalmology) MD DNB MD DM cer MD MD DM MD DM(Neurology) Jaypee MD FRCP(Glas)FRACP MDDMFACC FACP FICP MDDNB(Psychiatry) MD Critical Care Medicine) (Hosp Adm) Dipesh Bhagabati andGBPant(Irwin) Hospitals, NewDelhi, India College, Medical Azad Maulana Lok Nayak Professor, ofMedicine Department Hospital, Mumbai, Maharashtra, India Wockhardt Hospital, SmtMotibenDalvi Physician,Honorary BhatiaHospital, Ashit MBhagwati Guwahati, Assam, India College Medical andHospital Gauhati Professor, ofPsychiatry Department DP Bhadoria Education andResearch, Chandigarh, India Medicine, Post-graduate Institute ofMedical Professor,Senior ofPulmonary Department Digambar Behera Raigad, Maharashtra, India HospitalandResearch CentreBawaskar HS Bawaskar Medicity, Gurgaon, Haryana, India Head, DivisionofMicrobiology, Medanta—The Usha KBaveja Mumbai, Maharashtra, India BYL NairCharitableHospital Topiwala College NationalMedical and Professor andHead, ofPaediatrics Department BBavdekarSandeep Psychiatry (N) Diplomate, AmericanBoard ofNeurology and Nadir EBharucha Jackson, Michigan, USA Medicine, Allegiance Health Consultant Diseasesand inInfectious Travel Pallavi Bhargava (C-NET), NewDelhi, India Centre for Research NutritionandMetabolic Diabetes Foundation (India)andN-DOC ResearchNutritionist andSenior Offi Swati Bhardwaj Muzaffarnagar, UttarPradesh, India ConsultantSenior Cardiologist SKD Bhardwaj Diabetes Institute, Kolkata, West Bengal, India Consultant Physician, GDHospitaland Somnath Bhar Chandigarh, India EducationMedical andResearch Endocrinology, Post-graduate Institute of Professor andHead, of Department Anil Bhansali Air Force, Agram Bengaluru, Karnataka, India Hospital andPGCollege Education ofMedical Commandant andPrincipal Command Air Vice Bhalwar MarshalRajvir New Delhi, India All IndiaInstituteSciences ofMedical ofRadiodiagnosis Department Professor Bhalla Ashu Seith FRCP (Lond) FRCP(Neurology) PhD FAMS MD (Medicine) DM(Pulmonary/ MD(Medicine) MD DM (Endocrinology) MD

MRCPIMRCPS(Glas) PhD MD MDMAMSFICR MD (Med) FICAFICPADHA MD(Med) MD MD (Bom)FAMS (India) MD DNB Brothers MD(Paed) DCH MD MPhil cer DNB (Endocrinology) AGAF Mumbai, Maharashtra, India ResearchMedical Centre, Bombay Hospital Head, ofNeuroepidemiology Department Institute Sciences, ofMedical Mumbai ofNeurology,Department Bombay Hospital Professor andHead Mumbai, Maharashtra, India College GSMedical Seth andKEMHospital ofGastroenterology Department Professor andHead Shobna Bhatia Sciences, NewDelhi, India Pharmacology, AllIndiaInstitute ofMedical Additional Professor, of Department Jagriti Bhatia Lucknow, UttarPradesh, India Institute Sciences ofMedical Sanjay Post-graduate Gandhi ofEndocrinology Department Professor andHead Eesh Bhatia and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical ofGastroenterology Department Professor andHead Deepak Kumar Bhasin New Delhi, India Medicine, Hospital Memorial DrBLKapur Consultant,Senior ofInternal Department Atul Bhasin and Hospital, Guwahati, Assam, India Haematology, College Medical Gauhati Professor, ofClinical Department Jina Bhattacharyya New Delhi, India South EastAsia RegionalOfﬁ Ofﬁ Medical Sujit KBhattacharya Sciences, Shillong, Meghalaya, India Regional Institute ofHealthandMedical Medicine, Eastern Indira Gandhi North Professor andHead, ofGeneral Department Prasanta Kumar Bhattacharya Research Centre, Mumbai, Maharashtra, India Research, Lilavati HospitalandLKMM Trust Consultant Neurophysician of andDirector M Bhattacharjee Mumbai, Maharashtra, India ResearchHospital andMedical Institute Neurology, DhirubhaiAmbani Kokilaben Consultant andHead, of Department Mohit Bhatt Sciences, NewDelhi, India Gynaecology, AllIndiaInstitute ofMedical Professor, ofObstetrics and Department Neerja Bhatla Lucknow, UttarPradesh, India Post-graduate InstituteSciences ofMedical ofEndocrinology,Department Sanjay Gandhi Professor Vijayalakshmi Bhatia PhD (Cardiology) cer, World HealthOrganization MDDNB(InternalMNAMS Medicine) MD(Internal Medicine) MD DM MD MD MD (Med) DNB(Gastroenterology) MD(Med) DM MDFNAFNAScFAMS MD (Paediatrics) MDDMFAMS FASGE ce MD (Medicine) 29-01-2015 14:22:07 Prabhash Chandra Bhattacharyya MD Mammen Chandy MD FRACP FRCPA FRCP Gourdas Choudhuri MD DM FICP FAMS FACG FRCPI Ex-Professor and Head, Department of Director, Tata Medical Centre Director and Head, Department of Medicine, Gauhati Medical College, Senior Kolkata, West Bengal, India Gastroenterology and Hepatobiliary Sciences Consultant, Department of Medicine Fortis Memorial Research Institute Down Town Hospital, Guwahati, Assam, India Mitali Chatterjee MD PhD Gurgaon, Haryana, India Professor, Department of Pharmacology Sanjeev Bhoi Institute of Post-graduate Medical Education Anumita R Chowdhury Additional Professor of Medicine and Research, Kolkata, West Bengal, India Executive Director (Research and Advocacy)

Department of Emergency Medicine Centre for Science and Environment Contributors JPN Apex Trauma Centre, All India Institute of Sarit Chatterjee MD DNB New Delhi, India Medical Sciences, New Delhi, India Consultant Physician, Assistant Professor Department of Medicine, Post-graduate MK Daga MD FCCP FICP MNAMS Aspi R Billimoria MD Institute of Medical Education and Research Director Professor, Department of Medicine, Ex-Head and Dr Ram Manohar Lohia Hospital Maulana Azad Medical College Department of Cardiology, St George’s New Delhi, India New Delhi, India Hospital and Grant Medical College, Mumbai Surendra Daga MD Cardiologist, Conwest Jain Clinic Group of Anil Chaturvedi MD Senior Consultant Cardiologist and Physician Hospitals, Mumbai, Maharashtra, India Chief Consultant, Life-style Disease and Preventive Health, Apollo Health and Life-style Kolkata, West Bengal, India Anita M Borges MD FRCPath Ltd, The Apollo Clinic, New Delhi, India Ashwin Dalal MD (Paediatrics) DM Consultant Histopathologist, Asian Institute of Oncology, SL Raheja Hospital, Mumbai Lt General Ved Chaturvedi MD DM (Medical Genetics) Head, Diagnostics Division, Centre for DNA Director, Centres of Excellence, Histopathology Chief Consultant Rheumatologist Fingerprinting and Diagnostics, Nampally SRL Diagnostics, Mumbai, Maharashtra, India Armed Forces Medical Services Research and Referral Hospital Hyderabad, Telangana, India Khadijah Breathett MD New Delhi, India PM Dalal MD FAMS The Ohio State University, Wexner Medical Consultant Neurophysician and Director of Center, Department of Internal Medicine Dhruva Chaudhry MD (Med) DNB (Med) Research, Lilavati Hospital and LKMM Trust Division of Cardiology, Columbus, Ohio, USA DM (PCCM) FICP FICCM Senior Professor and Head/Dean Faculty of Research Centre, Mumbai, Maharashtra, India Nishigandha Burute MD Medical Super-speciality Pulmonary and Debashish Danda MD (General Medicine) Fellow, Department of Medical Imaging Critical Care Medicine DM (Clinical Immunology) FRCP St. Michael’s Hospital, University of Toronto Pt BDS University of Health Sciences Professor and Head, Clinical Immunology and Toronto, ON, Canada Rohtak, Haryana, India Rheumatology, Christian Medical College and Ashok Chacko MD DM FRCP FAMS Kusumita Chaudhuri MD Hospital, Vellore, Tamil Nadu, India Director and Head, Institute of Ex-Microbiologist, Department of Ashok Kumar Das MD FAMS FICP PhD FRCP Gastroenterology and Liver Diseases, Madras Microbiology, Moolchand Hospital Professor, Department of Medicine Medical Mission, Chennai, Tamil Nadu, India New Delhi, India Pondicherry Institute of Medical Sciences Rakesh K Chadda MD FAMS FRCPsych Col Anuj Chawla MD (Physiology) Puducherry, India Professor, Department of Psychiatry, All India DNB (Physiology) MNAMS FCGP BrothersChandan J Das MD DNB MNAMS Institute of Medical Sciences, New Delhi, India Professor and Head, Department of Assistant Professor, Department of Radiology Prantar Chakrabarti MD (Med) DNB (Med) Physiology, Armed Forces Medical College All India Institute of Medical Sciences DM (Clinical Haematology) Pune, Maharashtra, India New Delhi, India Professor, Department of Haematology Rajesh Chawla MD EDIC FICCM FCCM Madhumita P Das MD Institute of Haematology and Transfusion Senior Consultant Respiratory, Critical Care Professor, Department of Medicine Medicine, Medical College and Sleep Medicine Gauhati Medical College Kolkata, West Bengal, India Indraprastha Apollo Hospital, New Delhi, India Guwahati, Assam, India Partha Pratim Chakraborty MD Yogesh K Chawla MD Shyamal Kumar Das DM Assistant Professor, Department of Medicine Director, Post-graduate Institute of Medical Professor and Head, Department of Neurology Midnapore Medical College and Hospital Education and Research, Chandigarh, India Bangur Institute of Neurosciences Paschim Medinipur, West Bengal, India Kolkata, West Bengal, India Mala Chhabra MD (Microbiology) Praloy Chakraborty MD (Medicine) Joint Director, National Centre for Disease Siddharth Kumar Das MD (Medicine) DM (Cardiology) Control, New Delhi, India Professor and Head, Department of Associate Professor, Department of Cardiology Rheumatology, King George’s Medical Vardhman Mahavir Medical College and Shibba Takkar Chhabra MD DM (Cardiology) University, Lucknow, Uttar Pradesh, India Safdarjung Hospital, New Delhi, India Assistant Professor Dayanand Medical College and Hospital Biswa B Dash MD DNB MICOG Hemraj B Chandalia MD FACP Unit Hero DMC Heart Institute Department of Obstetrics and Gynaecology Director, Endocrinology, Diabetes and JaypeeLudhiana, Punjab, India All India Institute of Medical Sciences Metabolism Jaslok Hospital and Research New Delhi, India Centre, Dr Chandalia’s Diabetes Endocrine SK Chhabra MD FCCP Nutrition Management and Research Centre Consultant, Pulmonary and Critical Surabhi Dayal MD (Skin and VD) Mumbai, Maharashtra, India Care Medicine, Head, Department of Professor, Department of Dermatology Cardiorespiratory Physiology Venereology and Leprology P Sarat Chandra MCh Vallabhbhai Patel Chest Institute Pt BDS Post-graduate Institute of Medical Professor, Department of Neurosurgery New Delhi, India Sciences, Rohtak, Haryana, India All India Institute of Medical Sciences New Delhi, India Dharma R Choudhary DM Koushik Sinha Deb MD (Psychiatry) Fellow UCLA, Faculty 1000 ILAE Director, Bone Marrow Transplant Assistant Professor, Department of Psychiatry Visiting Professor, INI, Hannover BLK Super-speciality Hospital All India Institute of Medical Sciences xiii Lower Saxony, Germany New Delhi, India Jodhpur, Rajasthan, India

API _ Prelims _ Vol-1 for (TRADE).indd xiii 29-01-2015 14:22:08 API _Prelims _Vol-1for(TRADE).indd xiv

xiv API Textbook of Medicine DNB (Dermatology) MD (London) FICS Kolkata, West Bengal, India Institute ofChildHealth ofPaediatric Dermatology Department Professor andHead Dhar Sandipan New Delhi, India Medicine, College Medical Azad Maulana ProfessorDirector andHead, of Department DewanRicha Mumbai, Maharashtra, India Government Hospitals Grant College Medical andSirJJGroup of Professor andChiefHIVUnit ofMedicine Alaka Deshpande Oncology, Mumbai, Maharashtra, India Breach Candy Hospital, Asian Institute of and Breast Diseases, PDHindujaHospital Consultant, ofSurgical Oncology Department Vinay HDeshmane Research Centre, Mumbai, Maharashtra, India Radiology,Interventional JaslokHospitaland Head, ofImagingand Department Shrinivas BDesai Research Centre, Mumbai, Maharashtra, India PD HindujaNationalHospitalandMedical ofMicrobiology Department Microbiologist Niyati Desai Mumbai, Maharashtra, India Researchand Medical Centre Paediatrician, PDHindujaNationalHospital Neelu Desai Hospital, Mumbai, Maharashtra, India Nanavati Hospital, SirHNHospitalandSaifee Consultant Haematologist BJ Wadia Hospitalfor Children, Mumbai Oncology ofPaediatric HaematologyDepartment Immunologist, Chief, DivisionofImmunology Haematologist Oncologist and Honorary Haematology Oncology Professor, ofPaediatric Department Mukesh Desai Bengaluru, Karnataka, India Neurosciences National InstituteHealthand ofMental ofNeurovirology Department Anita Desai Hospital, Mumbai, Maharashtra, India Holy Family, GuruNanakandDhanwantari Haematologist Consultant, Oncologist Medical and Avinash Deo Kanchipuram, Tamil Nadu, India InstituteSciencesMeenakshi ofMedical Sripurna Deepti Gorakhpur, UttarPradesh, India and Hospital CollegeBaba Raghav DasMedical ofMedicine Department Assistant Professor Deepshikha

MD (Medicine) MD

MD MD DNB MD (Dermatology) MD (Medicine) MD MDMAMSFIMSAFICP Jaypee MSDNBFRCS(Glas) DM (ClinicalHaematology) FRCP (London) Parul Dubey College, Kolkatta, West Bengal, India ofHaematology,Department NRSMedical Assistant Professor Tuphan Kanti Dolai Education andResearch, Chandigarh, India Leprology, Post-graduate Institute ofMedical ofDermatology,Department Venereology and Associate Professor Sunil Dogra and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical Medicine ofPulmonary Department Assistant Professor Dhooria Sahajal and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical Professor, ofHepatology Department KDhiman Radha Mumbai, Maharashtra, India Bhatia andBreach Candy Hospitals Gastroenterologist,Interventional Jaslok Centre, MotibenDalviHospital; Consultant Digestive DiseasesandEndoscopic GastroenterologistChief Interventional Pankaj Dhawan Medical College,Medical Vellore, Tamil Nadu, India Gastroenterology andHepatology, Christian Professor andHead, ofClinical Department CE Eapen New Delhi, India Jamia Hamdard (Hamdard University) Hospital AbdulHameedCentenary Hakeem SciencesMedical andResearch, Associated Preventive Cardiology, Hamdard Institute of Dean/Principal, Professor ofMedicine/ Shridhar Dwivedi Chandigarh, India EducationMedical andResearch Gastroenterology, Post-graduate Institute of Additional Professor, of Department Usha Dutta Education andResearch, Puducherry, India Jawaharlal Institute ofPost-graduate Medical Head, DivisionofClinicalHaematology Professor, ofMedicine Department Dutta Sangit Ghaziabad, UttarPradesh, India Pushpanjali Crosslay Hospital Surgeon Consultant Thoracic Tiswadi, Goa, India College Medical Goa andHospital Consultant, ofNeurology Department Tarun Kumar Dutta Guwahati, Assam, India College Medical andHospital Gauhati Professor, ofMedicine Department Roman Dutta and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical ofHepatology Department Ajay Duseja MD DM MDDMMSc(HRM) MDDNBFRCP(London) MDDMMNAMSFACG DM MS MD DM(Neurology) MDDNBDM(Gastro) MDDMFAMS FACG MD DM MD PhD (Cardiology) MD Brothers MD DNB New Delhi, India National Institute ofCholera andEnteric Diseases Assistant (ScientistD) Director Ganguly Sandipan Burdwan, West Bengal, India Dermatology, Burdwan College Medical Professor andHead, of Department Dwijendra Nath Gangopadhyay Kochin, Kerala, India HospitalandResearchLakeshore Centre Oncology ofMedical Department VP Gangadharan Mumbai, Maharashtra, India Institute Nanawati HospitalHeart Cardiologist, Professor Emeritus MJ Gandhi Division ofCardiology, Columbus, Ohio, USA Center, ofInternal Medicine Department The OhioState University Wexner Medical Veronica Franco Sciences,Medical NewDelhi, India ofMedicine,Department AllIndiaInstitute of Faraz Ahmed Farooqui Hospital,Sucheta Kriplani NewDelhi, India Lady HardingeCollege Medical andSmt Assistant Professor, ofMedicine Department Rene PEapen and Research, Kolkata, West Bengal, India Institute ofPost-graduate Education Medical Head, ofRheumatology Department Professor, ofMedicine Department Alakendu Ghosh Linder Hoehe, Cologne, Germany AerospaceGerman Center DLR Institute of Aerospace Medicine R Gerzer College, Medical Azad NewDelhi, India Surgery, GBPant HospitalandMaulana ofCardio-thoracic Department Vascular Professor Muhammad AbidGeelani Apollo Hospitals, Chennai, Tamil Nadu, India Specialist Medicine Respiratory AR Gayathri Associated Hospitals, NewDelhi, India Lady HardingeCollege Medical and Professor, ofDermatology Department Garg Taru Lucknow, UttarPradesh, India George’sKing University Medical ofNeurology Department Professor andHead Ravindra Kumar Garg New Delhi, India All IndiaInstituteSciences ofMedical Professor ofGastroenterology (Research)Sub-Dean Pramod Kumar Garg New Delhi, India All IndiaInstituteSciences ofMedical Consultant, ofNeuroradiology Department Garg Ajay (Dermatology) MD(Dermatologyand Venereology) MDFAMS FICC FICPFICE MD MD FCCP MD MD MD DNB MD PhD

MD DM MD DM MD MCh (CTVS) MD 29-01-2015 14:22:08 Kanjaksha Ghosh MD (Med) DNB (Haem) FRC Randeep Guleria MD DM (Pulmonary and Sudeep Gupta MD DM Path (Lond) FACP (USA) MRCP (Ire) MRCP (UK) FNASc Critical Care) Professor FICP FRCP (Glas) Professor and Head, Department of Pulmonary Department of Medical Oncology Director (NIIT) Medicine, All India Institute of Medical Convener, Gynaecology Oncology Working Honorary Professor (KEMH) Sciences, New Delhi, India Group, Tata Memorial Centre/Hospital Department of Haematology, KEM Hospital Mumbai, Maharashtra, India Amod Gupta MS Mumbai, Maharashtra, India Head Vaibhav Gupta MD

Manab Kumar Ghosh DCH (Cal) DTM & H (Cal) Department of Ophthalmology Consultant Contributors MD (Tropical Medicine) (Cal) Post-graduate Institute of Medical Education Department of Gastroenterology Assistant Professor and Research, Chandigarh, India Rockland Hospital, New Delhi, India Calcutta School of Tropical Medicine Ankur Gupta DM (Nephrology) YK Gupta MD Kolkata, West Bengal, India Consultant In-charge, Nephrology Services Professor and Head, Department of Uday Chand Ghoshal MD DNB DM FACG RFF Max Super-speciality Hospital, Shalimar Bagh Pharmacology, All India Institute of Medical Professor New Delhi, India Sciences, New Delhi, India Department of Gastroenterology Anu Gupta DM (Neurology) Soneil Guptha MD FACC FESC FCCP FICA Dip Sanjay Gandhi Post-graduate Institute of Department of Neurology Pharm Med Medical Sciences Post-graduate Institute of Medical Education Honorary Director Lucknow, Uttar Pradesh, India and Research, Chandigrah, India Jaipur Heart Watch Foundation Ashish Goel Jaipur, Rajasthan, India Deepak Kumar Gupta MD (Med) Associate Professor, Department of DNB (Gastroenterology) Anil Gurtoo MD Hepatology, Christian Medical College Assistant Professor Director Professor, Department of Medicine Vellore, Tamil Nadu, India Department of Gastroenterology Lady Hardinge Medical College and Hemant Gopal MD Seth GS Medical College and KEM Hospital Associated Hospitals, New Delhi, India Associate Professor, Department of Medicine Mumbai, Maharashtra, India Ashutosh Halder MD DNB DM MRCOG-I Adesh Institute of Medical Sciences and Neha Gupta DNB FNB ID Professor, Department of Reproductive Research, Adesh University Associate Consultant, Department of General Biology, All India Institute of Medical Sciences Bhatinda, Punjab, India Medicine and Infectious Diseases, PD Hinduja New Delhi, India Sankar Prasad Gorthi MD DNB Hospital, Mumbai, Maharashtra, India Rohini Handa MD DNB FAMS FICP FACR Senior Advisor Nitin Gupta MD DM FRCP (Glasgow) Department of Medicine and Neurology Consultant Senior Consultant Rheumatologist, Apollo Army Hospital Research and Referral Department of Gastroenterology Indraprastha Hospital, New Delhi, India New Delhi, India Rajiv Gandhi Cancer Institute Sanjeev Handa MD MNAMS FAAD FRCP (Edin) Ravinder Goswami MD DM FNASc FASC New Delhi, India Professor and Head Additional Professor, Department of Piyush Gupta MD MAMS FIAP Department of Dermatology, Venereology and Endocrinology and Metabolism Professor, Department of Paediatrics Leprology, Post-graduate Institute of Medical All India Institute of Medical Sciences Brothers University College of Medical Sciences Education and Research, Chandigarh, India New Delhi, India New Delhi, India CV Harinarayan MD (Int Med) DM (Endocrinology) Abhishek Goyal DM (Cardiology) Praveen Gupta MD DM FAMS FRCP (Glas) FRCP(Edin) Assistant Professor, Department of Cardiology Director and Head Director, Institute of Endocrinology Dayanand Medical College and Hospital Department of Neurology Diabetes and Osteoporosis, Sakra World Unit Hero DMC Heart Institute Fortis Memorial Research Institute Hospitals, Deverabeesanahalli, Varathur Hobili Ludhiana, Punjab, India Gurgaon, Haryana, India Marathahalli, Bengaluru, Karnataka, India RK Goyal MD Pritam Gupta MD (Medicine) NK Hase MD DNB Ex-Senior Professor and Head, Department of Senior Consultant and Head, Department of Professor and Head Medicine, Jawaharlal Nehru Medical College Medicine, Sunder Lal Jain Hospital Department of Nephrology Ajmer, Rajasthan, India New Delhi, India Seth GS Medical College and KEM Hospital Chander Grover MD DNB MNAMS Mumbai, Maharashtra, India Rajeev Gupta MD PhD Assistant Professor Consultant, Department of Medicine D Himanshu MD Department of Dermatology, Venereology Fortis Escorts Hospital, Jaipur, Rajasthan, India Unit In-charge, Department of Medicine and Leprology, University College of Chhatrapati Sahu Ji Maharaj Medical Medical Sciences and Guru Tegh Bahadur Rakesh K Gupta MD University, Lucknow, Uttar Pradesh, India Hospital University of Delhi Director and Head, Department of Radiology New Delhi, India Fortis Memorial Research Institute AK Hooda MD DM Gurgaon, Haryana, India Senior Advisor (Medicine and Nephrology) Subhasish Kamal GuhaJaypee DTM & H MD Command Hospital (Eastern Command) Associate Professor SK Gupta PhD DSc (Hon) FIACS FIPS FISER FRAMS Kolkata, West Bengal, India Department of Tropical Medicine Professor Emeritus, Delhi institute of Calcutta School of Tropical Medicine Pharmaceutical Sciences and Research G Immanuel MD PhD MAMS Kolkata, West Bengal, India Ex-Professor and Head, Department of Director, Centre for AIDS and Antiviral Pharmacology, All India Institute of Medical Research, Tuticorin, Tamil Nadu, India PD Gulati MD FAMS FAIID FICAI FIMSA Sciences, New Delhi, India Senior Honorary Consultant Arun C Inamadar MD FRCP (Edinburgh) Tirath Ram Shah Hospital, New Delhi Subash Gupta MS FRCS (Ed) FRCS (Glas) Professor and Head Ex-Head, Division of Nephrology Senior Consultant, ANG Centre for Liver and Department of Dermatology Maulana Azad Medical College and Associated Biliary Sciences, Indraprastha Apollo Hospital Sri BM Patil Medical College, BLDE University Hospitals, New Delhi, India New Delhi, India Bijapur, Karnataka, India xv

API _ Prelims _ Vol-1 for (TRADE).indd xv 29-01-2015 14:22:08 API _Prelims _Vol-1for(TRADE).indd xvi

xvi API Textbook of Medicine Kochi, Kerala, India Amrita InstituteSciences ofMedical Professor, ofEndocrinology Department RV Jayakumar Chennai, Tamil Nadu, India Indian Council Research ofMedical National Institute for Research in Tuberculosis Scientist ‘F’, ofClinicalResearch Department Former Grade) (Senior and Director Deputy MS Jawahar Mumbai, Maharashtra, India Radiologist, Imaging Jankharia Bhavin Jankharia New Delhi, India All IndiaInstituteSciences ofMedical ofRadiodiagnosis Department Manisha Jana and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical Professor, ofInternal Medicine Department Sanjay Jain New Delhi, India Medicine, LadyHardingeCollege Medical and Professor,Director of Department KJain Sachin New Delhi, India Lohia Manohar Hospital and DrRam Institute Education ofMedical andResearch ofMedicine,Department Post-graduate Assistant Professor Piyush Jain Ludhiana, Punjab, India Dayanand College Medical andHospital Associate Professor, ofMedicine Department Narender Pal Jain Gurgaon, Haryana, India Imaging, FortisResearch Memorial Institute Consultant, and ofRadiology Department Krishan KJain New Delhi, India Karnataka Trustee, ShahHospital Tirath Ram ofMedicine,Department University Manipal Afﬁ Honory DG Jain New Delhi, India All IndiaInstituteSciences ofMedical Cardiothoracic Sciences Centre Cardiovascular Radiology andInterventional Additional Professor, of Department Priya Jagia Hyderabad, Telangana,India Nizam’s InstituteSciences ofMedical Associate Professor, ofNeurology Department SA Jabeen Mumbai, Maharashtra, India College GSMedical Seth andKEMHospital Assistant Professor Itolikar Manish W Hyderabad, Telangana,India Nizam’s InstituteSciences ofMedical ofRheumatology Department Assistant Professor Vara Prasad IR MD FRCP(Edin) FRCP(Glas)FICP liate Professor

MD DNB (Radiology) MDDNB(Radiology) MD (Medicine) MD DM MD MScDLSHTM

MDDNBFRCR MDDMMNAMS FRCP MD MD MD MD FICP Jaypee MD DNB FNCCP Shashank RJoshi Nagpur, Maharashtra, India GovernmentIndira Gandhi College Medical Professor andHead, ofMedicine Department Prashant PJoshi Mumbai, Maharashtra, India Medicine, BYLNairHospital Professor andHead, ofPulmonary Department Jyotsna MJoshi Hospital, Herston Qld, Australia Medicine, Royal Brisbaneand Women’s Consultant,Senior ofRenal Department John George T Education andResearch, Chandigarh, India Medicine, Post-graduate Institute ofMedical Professor andHead, ofPulmonary Department Surinder KJindal Healthcare, Mumbai, Maharashtra, India andHinduja PD HindujaHospital(Mahim) Haematologist/Haemato-oncologist Consultant Farah Jijina Gurgaon, Haryana, India Medanta—The Medicity Nephrology and Transplant Medicine Associate Consultant, of Department Pranaw Kumar Jha Ghaziabad, UttarPradesh, India Indian Pharmacopoeia Commission Principal Scientiﬁ V Kalaiselvan Gurgaon, Haryana, India Panacea Hospital NewRise Affairs, Medical Director AnaesthesiaandSICU PN Kakar Education andResearch, Puducherry, India Jawaharlal Institute ofPost-graduate Medical Associate Professor, ofMedicine Department Tamilarasu Kadhiravan Sciences,of Medical NewDelhi, India ofPaediatrics,Department AllIndiaInstitute Additional Professor, Unit Genetics Madhulika Kabra Mumbai, Maharashtra, India Researchand Medical Centre Rheumatologist, PDHindujaNationalHospital Research,Director Consultant Physician and VR Joshi Mumbai, Maharashtra, India Director, MumbaiDietandHealthCentre Shilpa SJoshi Chapter ChairIndiaAACE of Advancement for Research inObesity) Past President, AIAARO(AllIndiaAssociation Study ofDiabetes inIndia2011) Past President, for RSSDI(Research Society the President, IndianAcademy ofDiabetes Emeritus Editor, JAPI Past President, API Joshi Clinic, Lilavati andBhatiaHospital Endocrinologist (Padma ShriAwardee 2014) FACE (USA)FRCP(GlsgandEdin) MD MD FICA MD MPharm PhD c Ofﬁ MD DMFRCPFRACP MD (Medicine) MD MDDMFICPFACP (USA) MD MD (Medicine) FAMSMD (Medicine) FCCP cer MD DNB MD Brothers FRCR FRCP FACG FAMS Madhuchanda Kar Research, NewDelhi, India graduate Institute Education ofMedical and Lohia Manohar HospitalandPost-Dr Ram SuperintendentMedical Hemanta Kumar Kar New Delhi, India All IndiaInstituteSciences ofMedical Assistant Professor Devasenathipathy Kandasamy Mumbai, Maharashtra, India Hospital and MunicipalGeneral Lokmanya CollegeTilak MunicipalMedical ofMedicine Department andProfessorEx-Dean Sandhya AKamath New Delhi, India Sciences, Guru Tegh BahadurHospital Principal, University College ofMedical Head, DivisionofNephrology Professor ofMedicine (Leicester Hospital, General UK) Commonwealth Fellow inNephrology OP Kalra Sciences, Lucknow, UttarPradesh, India Post-graduateGandhi Institute ofMedical Professor, ofNeurology, Department Sanjay J Kalita Hospital, NewDelhi, India Consultant Endocrinologist, MaharajaAgrasen Deepak Khandelwal Centre, Mumbai, Maharashtra, India Bombay Research HospitalandMedical Professor, ofNeurology Department SV Khadilkar Mumbai, Maharashtra, India Microbiology, Tata Centre Memorial Professor andHead, of Department Rohini Kelkar Hospital, Ghaziabad, UttarPradesh, India Research Associate, Pushpanjali Crosslay Gurleen Kaur Fortis Vasant Kunj, NewDelhi, India Institute and Cardiology Heart Fortis Escorts Executive andDean Director Upendra Kaul Sciences, Calicut, Kerala, India Consultant, Institute Malabar ofMedical Karunanithi Sellam Bengaluru, Karnataka, India HealthandNeurosciencesof Mental ofNeurology,Department NationalInstitute N Karthik College,Medical NewDelhi, India ofMedicine,Department Azad Maulana Professor andGastroenterologist ofMedicine Premashis Kar Kolkata, West Bengal, India Oncologist, Medical Visiting Peerless Hospital PhD (Cancer Research) (Awarded Padma ShriandDrBCRoy Award DM MD DMFAMS FACP FICPFISNFIACM

MD DPB MDDMFCSIFACC FSCAIFAMS MD MDDM(Gastroenterology) MD (Medicine) MD FICP MD MD DM

MD DNB 29-01-2015 14:22:08 SK Khandelwal MD MNAMS MRCPsych (Hon) Bindu Kulshreshtha MD DM S Lahiri Professor and Head, Department of Psychiatry Associate Professor, Endocrinology Consultant Cardiology All India Institute of Medical Sciences Post-graduate Institute of Medical Education Delhi Heart and Lung Institute, New Delhi, India New Delhi, India and Research and Dr Ram Manohar Lohia Moti Lal MD (Medicine) Hospital, New Delhi, India Sudeep Khanna MD DM Associate Professor, Department of Medicine Senior Gastroenterologist Ajay Kumar MD DM MAMS FRCP (Glasgow) Lady Hardinge Medical College and Pushpawati Singhania Research Institute for Senior Consultant, Gastroenterology and Associated Hospitals, New Delhi, India

Liver, Renal and Digestive Diseases Hepatology, Indraprastha Apollo Hospital Contributors Rakesh Lal New Delhi, India New Delhi, India Professor Vijay Kher MD DM FAMS FRCPE Arvind Kumar MD National Drug Dependence Treatment Centre Chairman, Division of Nephrology and Department of Medicine, Maulana Azad All India Institute of Medical Sciences Transplant Medicine, Medanta Kidney and Medical College and Associated Hospitals New Delhi, India Urology Institute, Medanta—The Medicity New Delhi, India Gurgaon, Haryana, India Amit Langote MD DNB (Nephrology) Jaya Kumar MD Nephrologist, The Ottawa Hospital Shilpa Khullar MD (Physiology) MHA Associate Consultant, Department of Ottawa, Ontario, Canada Assistant Professor, ESIC Dental College Respiratory Medicine, Max Hospital, Saket RD Lele MRCP (Edin) FRCP Rohini, New Delhi, India New Delhi, India Director of Nuclear Medicine and PET/CT Donald Kikta Jr MD Lalit Kumar MD DM FAMS FASc Jaslok Hospital and Research Centre and Cardiovascular Medicine, University Hospitals Professor and Head Lilawati Hospital and Research Centre Case Medical Center, Cleveland, Ohio, USA Department of Medical Oncology Mumbai, Maharashtra, India Dr Bhim Rao Ambedkar Institute of Rotary Ashok L Kirpalani MD (Medicine) Vikram R Lele MD (Med) DNB (Nuclear Med) DRM MNAMS (Nephrology) Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India Director, Department of Nuclear Medicine Professor and Head, Department of Jaslok Hospital and Research Centre Nephrology, Bombay Hospital Institute of Neeraj Kumar Mumbai, Maharashtra, India Medical Sciences, Mumbai, Maharashtra, India Department of Transplant Immunology and Yash Y Lokhandwala DM (Cardiology) Suman Kirti MD FRCP (London) FRCP (Edin) FICP Immunogenetics, All India Institute of Medical Sciences, New Delhi, India Arrhythmia Associates Senior Consultant Medicine Mumbai Quintiles Cardiac Safety Services Holy Family Hospital, New Delhi, India R Krishna Kumar MD DM FAHA Mumbai, Maharashtra, India Professor and Head Jugal Kishore MD PGDCHFWM PGDEE Netravathi M Department of Paediatric Cardiology MSc (SD MH) FIAPSM FIPHA FAMS Assistant Professor, Department of Neurology Director Professor, Department of Community Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India National Institute of Mental Health and Medicine, Maulana Azad Medical College Neurosciences, Bengaluru, Karnataka, India New Delhi, India Raj Kumar MD Kaushal Madan Professor and Head, Department of Girisha KM MD (Paediatrics) DM (Medical Genetics) Senior Consultant, Hepatologist and Professor and Head, Department of Medical Respiratory Allergy and AppliedBrothers Immunology National Centre of Respiratory Allergy, Asthma Gastroenterologist, Medanta Institute Genetics, Kasturba Medical College of Digestive and Hepatobiliary Sciences Manipal, Karnataka, India and Immunology, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, India Medanta—The Medicity Dhanpat Kumar Kochar MD DN (Vienna) Gurgaon, Haryana, India Rajat Kumar MD (Med) DNB (Med) FICP FRCP (Edin) Visiting Professor, Medical Research SV Madhu MD DM (Endocrinology) Rajasthan University of Health Sciences, Jaipur FRCP (London) FRCPC Professor, Department of Medical Oncology Professor and Head Ex-Professor and Head, Cerebral Malaria Division of Endocrinology and Metabolism Research Centre, Sarder Patel Medical College and Haematology, Cancer Care Manitoba Professor, University of Manitoba, Canada Department of Medicine, University College Bikaner, Rajasthan, India of Medical Sciences and Guru Tegh Bahadur Rakesh Kochhar MD DM Rakesh Kumar DNB PhD Hospital, New Delhi, India Professor, Department of Gastroenterology Professor and Head, Diagnostic Nuclear Rahul Mahajan MD Post-graduate Institute of Medical Education Medicine Division, Department of Nuclear Department of Dermatology and Research, Chandigarh, India Medicine, All India Institute of Medical Sciences, New Delhi, India Venereology and Leprology, Post-graduate Abraham Koshy MD DM Institute of Medical Education and Research Director, Division of Hepatology Soumitra Kumar Chandigarh, India Lakeshore Hospital and Research Centre Ltd Professor, Division of Cardiology, Department Sandeep Mahajan MD DM Maradu, Kochi, Kerala, India of Medicine, Vivekananda Institute of Medical Sciences, Kolkata, West Bengal, India Professor Prakash Kothari MD PhD Department of Nephrology, All India Institute Professor and Head, DepartmentJaypee of Sexual Uma Kumar MD of Medical Sciences, New Delhi, India Medicine, Seth GS Medical College and Professor, Department of Medicine M Mahapatra MD KEM Hospital, Mumbai, Maharashtra, India Head, Clinical Immunology and Rheumatology All India Institute of Medical Sciences Associate Professor, Department of Shyam S Kothari MD DM New Delhi, India Haematology, All India Institute of Medical Professor, Department of Cardiology Sciences, New Delhi, India All India Institute of Medical Sciences Vinod Kumar MD PK Maheshwari MD DM (Neurology) New Delhi, India Emeritus Professor, Department of Medicine St Stephen’s Hospital, New Delhi, India Professor and Head JS Kulkarni MD (Medicine) Department of Neurology, Post-graduate Associate Professor, Department of Medicine Debal Laha MD DM Department of Medicine Maharashtra Institute of Medical Education Neurologist, Lakhotia Medical Centre Sarojini Naidu Medical College xvii and Research, Pune, Maharashtra, India Howrah, West Bengal, India and Hospital, Agra, Uttar Pradesh, India

API _ Prelims _ Vol-1 for (TRADE).indd xvii 29-01-2015 14:22:08 API _Prelims _Vol-1for(TRADE).indd xviii

xviii API Textbook of Medicine (Medical Services) (Medical FICP (Ind) New Delhi, India College andSafdarjung Hospital Pharmacology, Vardhman Mahavir Medical Assistant Professor, of Department Manocha Sachin Bengaluru, Karnataka, India Cardiovascular Sciences andResearch Director, SriJayadeva Institute of ofCardiology Department Professor andHead CN Manjunath Vadodara, Gujarat, India Foods andNutrition, MSUniversity ofBaroda WHO Collaborating Centre, of Department Formerly, HeadandDirector UV Mani Corporate Park, Gurgaon, Haryana, India Sleep Medicine, Nayati Group ofHospitals, DLF Chairman, CriticalCare, Pulmonology and RK Mani Medicity, Indore, Madhya Pradesh, India Consultant Rheumatologist, Medanta—The Sourabh Malviya Sciences, NewDelhi, India Cancer Hospital, AllIndiaInstitute ofMedical Institute ofRotary Ambedkar Dr BhimRao Assistant Professor, Oncology Medical Prabhat SinghMalik and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical ofInternal Medicine Department Additional Professor Pankaj Malhotra Jaipur, Rajasthan, India CollegeSawai SinghMedical Man Hospital OncologyDivision ofMedical ProfessorSenior andHead ofMedicine Hemant Malhotra Hospital, NewDelhi, India Indian SpinalInjuriesCentre Super-speciality Consultant Senior Rheumatologist Visiting Consultant Rheumatologist, ‘A andRClinic’ AN Malaviya Puducherry, India graduate Education Medical andResearch Department, Jawaharlal Institute ofPost- Assistant Professor, DermatologyandSTD M Malathi Sciences,Medical NewDelhi, India and HumanNutrition, AllIndiaInstitute of Professor, ofGastroenterology Department Govind KMakharia Hospital, Bengaluru, Karnataka, India Consulting Physician, Multispeciality Maiya Service Medical Karnataka Ex-Professor ofMedicine M Maiya Telerad RxDx, Bengaluru, Karnataka, India PaediatricSenior Cardiologist Sunita Maheshwari MNAMS FICP FICP FAMS FNASc MDMRCP(UK)FCCP FICCM CEO FRCP(Lond) FRCP(Edin) FRCP(Glasg) PhD FICN MD MD FRCP(Lond) ACR ‘Master’ FACP MD DM MD (Pharmacology) MD FICP MD MDFRCP(London) MDDMDNB ABPABPC(USA) Jaypee Hyderabad, Telangana,India Research, Campus ApolloHealthCity Dean, ApolloInstituteSciences ofMedical and Dilip Mathai Srinagar, JammuandKashmir, India Institute Sciences ofMedical ofEndocrinology,Department Sher-i-Kashmir Additional Professor andHeadofUnit Masoodi Shariq Rashid and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical of Department Transfusion Medicine Professor andHead Neelam Marwaha Associated Hospitals, NewDelhi, India Lady HardingeCollege Medical and Assistant Professor, ofMedicine Department Shubha LaxmiMargekar College, Vadodara, Gujarat, India Venereal Diseases, SSGHospitalandMedical Head andProfessor, and ofSkin Department Yogesh SMarfatia Sciences, Belgaum, Karnataka, India Microbiology, BelgaumInstitute ofMedical Professor andHead, of Department BG Mantur Jaipur, Rajasthan, India OfﬁMedical cer, College SMSMedical Aijaz HMansoor Janakpuri, New Delhi, India Neurology, Hospital Super-speciality Janakpuri Director, Professor andHead, of Department Man MohanMehndiratta Hyderabad, Telangana,India Nizam’s InstituteSciences ofMedical Professor, ofNeurology Department AK Meena Thiruvananthapuram, Kerala, India for Sciences Medical and Technology Neurology, Sree Chitra Tirunal Institute Additional Professor, of Department PS Mathuranath Research, New Delhi, India InstituteDelhi ofPharmaceutical Sciences and Assistant Professor MathurRajani Jaipur, Rajasthan, India CollegeSawai SinghMedical Man Hospital Associate Professor, ofMedicine Department Ashwin Mathur Jodhpur, Rajasthan, India Medicine, College DrSampurnanandMedical Ex-Principal andController, Professor of and Innovation Asian Centre for Education, Medical Research and Managing Director Trustee Mathur Arvind Vellore, Tamil Nadu, India CollegeChristian Medical andHospital ofHaematology Department Professor ofClinicalHaematology Vikram Mathews DM (Endocrinology) FAMS FRCP

MD DM MDPhDFRCP(Lond) FICP BPharmMSc(DrugAssay) PhD MD MD (Medicine) DM (Cardiology) MD DM DNB DM(Neurology) MD FAMS

MD (Medicine) MD

MD DM(Neurology) Brothers Lucknow, UttarPradesh, India Institute Sciences ofMedical Immunology, Sanjay Post-graduate Gandhi Dean, Professor andHead, Clinical MisraRamnath New Delhi, India (CIM), Fortis Hospital, Vasant Kunj Endocrinology, Centre ofInternal Medicine for Diabetes, Diseasesand Metabolic Fortis-C-DOC Centre ofExcellence Anoop Misra Hospital,Ram Bagh, Karol NewDelhi, India Head, ofMedicine, Department Fortis Jessa Aditya Prakash Misra Ludhiana, Punjab, India Dayanand College Medical andHospital Professor, ofMedicine Department Vandana Midha College,Medical NewDelhi, India Venereology andLeprology, LadyHardinge Professor, ofDermatology Department Vibhu Mendiratta Chandigarh, India and Research Post-graduate InstituteEducation ofMedical ofNeurology Department Assistant Professor Manish Modi Control, NewDelhi, India Zoonosis Division, NationalCentre for Disease Additional andHead (Microbiology) Director Veena Mittal and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical andPET ofNuclearMedicine Departments Clinical Professor andHead BR Mittal Udaipur, Rajasthan, India CollegeRNT Medical andHospital ofDermatology Department Professor Asit Mittal College, NewDelhi, India GB Pant Medical Azad HospitalandMaulana ofCardiology Department Assistant Professor Amit Mittal Gurgaon, Haryana, India Diabetes, Medanta—The Medicity Chairman, DivisionofEndocrinologyand Ambrish Mithal Lucknow, UttarPradesh, India Sciencesof Medical Dean, Sanjay Post-graduate Gandhi Institute Professor andHead, ofNeurology Department UK Misra Institute Sciences, ofMedical NewDelhi, India Immunology andImmunogenetics, AllIndia Professor andHead, of Department Transplant Narinder KMehra Virginia, Charlottesville, VA, USA Vascular Neurology Fellow, University of Prachi Mehndiratta MDDRMDNBFICNMFAMS DM FAMS MD(Dermatology, Venereology, Leprosy) MD DM MD MD MD (Med) DM(Neuro) MD(Med) MD FRCP MD DM MD

MD(Dermatologyand VD) MD MD 29-01-2015 14:22:08 Alladi Mohan MD (Medicine) FAMS FRCP (Edin) Milind Y Nadkar MD FICP Jyotirmoy Pal MD FCCP (USA) FICP Professor of Medicine and Chief of Associate Professor, General Medicine Professor and Head, Department of Medicine Rheumatology, Seth GS Medical College and Institute of Post-graduate Medical Education Chief, Division of Pulmonary and Critical Care KEM Hospital, Mumbai, Maharashtra, India and Research and Seth Sukhlal Karnani Medicine, Sri Venkateswara Institute of Medical Memorial Hospital D Nagaraja DM (Neuro) DPM (Psych) MAMS Sciences, Tirupati, Andhra Pradesh, India Faculty In-Charge, Geriatric Clinic Professor Kolkata, West Bengal, India Bishav Mohan Department of Neurology

Professor, Department of Cardiology Ex-Director and Vice Chancellor Pramod Kumar Pal MD Contributors Dayanand Medical College and Hospital National Institute of Mental Health and Professor, Department of Neurology Unit Hero DMC Heart Institute Neurosciences, Bengaluru, Karnataka, India National Institute of Mental Health and Ludhiana, Punjab, India Neurosciences, Bengaluru, Karnataka, India Dukhabandhu Naik MD DM (Endocrinology) E Mohandas MD (Psych) Assistant Professor Aparna Palit MD Head and Chief Consultant, Department of Christian Medical College Professor, Department of Dermatology Psychiatry, Sun Hospital and Research Centre Vellore, Tamil Nadu, India Sri BM Patil Medical College Thrissur, Kerala, India BLDE University, Bijapur, Karnataka, India Sita Naik MD KM Mohandas MD DNB Ex-Professor and Head, Department of Ashok Panagariya MD DM (Neurology) FRCP (UK) Senior Consultant, Department of Digestive Immunology, Sanjay Gandhi Post-graduate Member (State Planning Board), Health, Diseases, Tata Medical Centre Institute of Medical Sciences Medical Education, Research and Allied Areas Kolkata, West Bengal, India Lucknow, Uttar Pradesh, India Professor Emeritus (Neurology) Sawai Man Singh Medical College, Jaipur Prasanta Raghab Mohapatra MD MAMS FICP Maj Gen Velu Nair AVSM VSM Honorary Neurologist, Armed Forces of India Professor and Head, Department of Pulmonary Senior Consultant in Clinical Haematology and Jaipur, Rajasthan, India Medicine, Certiﬁ ed Medical Oncologist Bone Marrow Transplant All India Institute of Medical Sciences Dean and Dy- Commandant, Armed Forces Anjana Pandey MD (Gen Medicine) Bhubaneswar, Odisha, India Medical College, Pune, Maharashtra, Inidia Assistant Professor, Post-graduate Department of Medicine, Sarojini Naidu Medical College V Pratap Mouli MD DM Ranjith Nair MD DM and Hospital, Agra, Uttar Pradesh, India Consultant Gastroenterology, Anjani SS Army Hospital (Research and Referral) Hospital (VGS Hospitals) Delhi Cantt, New Delhi, India Ramesh Balwant Pandit MD Guntur, Andhra Pradesh, India Honorary Physician and Cardiologist, MGM Praveen Namboodiri MD DM (Nephrology) Hospital and Fortis Hiranandani Hospital Sukumar Mukherjee MD FRCP FRCPE FICP FSMF Consultant Vashi, Navi Mumbai, Maharashtra, India FICN FISE FIMSA FIAMS Department of Nephrology Ex-Professor and Head of Medicine Sankar’s Institute of Medical Sciences Sanjay Pandit MD (Medicine) Medical College, Kolkata Kollam, Kerala, India Assistant Professor, Department of Medicine Consultant Physician Maulana Azad Medical College and Associated R Narasimhan MD FRCP (UK) FCCP (USA) Calcutta Medical Research Institute Hospitals, New Delhi, India Pulmonologist, Apollo Hospitals GD Hospital and Diabetes Institute Chennai, Tamil Nadu, India Ghan Shyam Pangtey MD Kothari Medical Centre Brothers Associate Professor, Department of Medicine Kolkata, West Bengal, India G Narsimulu MD FICP FIACM Lady Hardinge Medical College and Associated Senior Consultant Rheumatologist Rita Mulherkar PhD FNASc Hospitals, New Delhi, India Yashoda Hospital Professor Ex-Professor and Head Department of Gopi Krishna Panicker MD Advanced Centre for Treatment, Research and Rheumatology, Nizam’s Institute of Medical Quintiles Cardiac Safety Services Education in Cancer, Tata Memorial Centre Sciences, Hyderabad, Telangana, India Mumbai, Maharashtra, India Kharghar, Navi Mumbai, Maharashtra, India AS Narula MD DM FACP Manotosh Panja MD DM FICP FACC Akshay Munjal MDS Additional Director General Ex-Professor and Director (Cardiology) Reader in Periodontics, SGT Dental College Armed Forces Medical Services Head of the Department, Institute of Post- Gurgaon, Haryana, India Professor, Department of Medicine graduate Medical Education and Research Yash Pal Munjal MD FICP MAMS FIAMS FACP Army College of Medical Sciences Director, Interventional Cardiology, Belle Vue FIACMS FRCP (Edin) New Delhi, India Clinic Kolkata, West Bengal, India Medical Director and Hon Senior Consultant Prashant Nasa MD FNB (Critical Care) Neeraj Parakh MD DM Diabetes and Life Style Disease Centre Specialist, Critical Care Medicine Assistant Professor, Department of Cardiology Banarsidas Chandiwala Institute of Medical NMC Speciality Hospital Dubai, UAE All India Institute of Medical Sciences Sciences, Kalkaji, New Delhi New Delhi, India Past President of Association of Physicians of Aruna Nigam MS (Obs & Gynae) India, Past Dean of Indian College of Physicians, Associate Professor Rajiv Parakh MS (Surgery) FRCS Hon Professor of IndianJaypee College of Family Department of Obstetrics and Gynaecology Division of Peripheral Vascular and Physician, New Delhi, India Hamdard Institute of Medical Sciences and Endovascular Sciences, Medanta—The Research, Jamia Hamdard University Medicity, Gurgaon, Haryana, India BS Rama Murthy MD DMRD DNB New Delhi, India Consultant Radiologist Satish Kumar Parashar MD FACC FCSI Srinivasa Ultrasound Scanning Centre Swapan Kumar Niyogi Senior Consultant Cardiologist and Director Bengaluru, Karnataka, India Deputy Director Non-invasive Cardiac Laboratory National Institute of Cholera and Enteric Diseases Metro Hospitals and Heart Institute A Muruganathan MD FRCP (Glasg) FRCP (London) Kolkata, West Bengal, India New Delhi, India FACP (USA) FPCP (Philippines) FICP Adjunct Professor, The Tamilnadu Dr MGR Nagaraja Rao Padaki MD DM Vibhor Pardasani DM (Neurology) Medical University, Vice President, Indian Red Chief of Hepatology Consultant Neurologist and Epileptologist Cross Society, Tamil Nadu State Branch Asian Institute of Gastroenterology Bombay Hospital Institute of Medical Sciences xix Chairman, AG Hospital, Tirupur, Tamil Nadu, India Hyderabad, Telangana, India Mumbai, Maharashtra, India

API _ Prelims _ Vol-1 for (TRADE).indd xix 29-01-2015 14:22:08 API _Prelims _Vol-1for(TRADE).indd xx

xx API Textbook of Medicine FRCS FCCP (USA)FICPFICC FICEFACP (USA) Jodhpur, Rajasthan, India CollegeDr SampurnanandMedical ofMicrobiology Department Associate Professor Prabhu Prakash Ghaziabad, UttarPradesh, India Indian Pharmacopoeia Commission Principal Scientiﬁ Jai Prakash Associated Hospitals, NewDelhi, India Lady HardingeCollege Medical and Professor, ofMedicine Department Anupam Prakash Sciences, NewDelhi, India Cancer Hospital, AllIndiaInstitute ofMedical Institute, Ambedkar Dr BhimRao Rotary Oncology ofMedical Department PrabhuMP Ram and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical ofNeurology Department Professor andHead S Prabhakar Lucknow, UttarPradesh, India SciencesMedical Sanjay Post-graduate Gandhi Institute of Professor, Genetics ofMedical Department Shubha RPhadke Research Centre, Cochin, Kerala, India Amrita InstituteSciences ofMedical and Professor, Oncology ofMedical Department K Pavithran Indore, Madhya Pradesh, India and Maharaja Yeshwantrao Hospital College Medical Memorial Gandhi Mahatma Professor, ofNeurology Department Apoorva Pauranik Kozhikode, Kerala, India Charitable Trust College Medical Rheumatology, Kunhitharuvai Memorial Professor andChiefof ofMedicine Binoy JPaul Mumbai, Maharashtra, India CardiologyInterventional Executive President, IndianCollege of Lekha Adik Pathak Hospital, Mumbai, Maharashtra, India Bharatiya Arogya NidhiHospital, andBSES Physician Honorary CPatelKirti Mumbai, Maharashtra, India Haematology, BSESHospital Oncology ofMedical and Department PM Parikh Hospital, Mumbai, Maharashtra, India College andBYLNairCharitable Ex-Associate Professor, TN Medical Dhirubhai Ambani, Hospital, Mumbai Consultant Internal Medicine, Kokilaben Falguni SParikh PDCDM (DialysisMedicine) FICP MNAMSPDCC (HospitalManagement) DM (Medical genetics) DM (Medical MDDNBFICPPhDECMOCPIMB MPharmPhD MD DM MD(Mumbai)FRCP(UK) MD PhD DNB MD DMFAMS FIAN c Ofﬁ cer

MD MDDNBMNAMSFICP MD (Gen Medicine) Medicine) MD(Gen MD (Paediatrics) MD DM Jaypee DM(Cardiology) MD(Med) College, Gaya, Bihar, India Principal, Anugrah Narayan Medical Magadh ofMedicine Department Ex-Professor andHead Abhay Narain Rai Hyderabad, Telangana,India Scientist F, NationalInstitute ofNutrition M Raghunath Hyderabad, Telangana,India Nizam’s InstituteSciences ofMedical Professor, Oncology ofMedical Department Chennai, Tamil Nadu, India India Diabetes Research Foundation Hospitals, andPresident Chairman, DrARamachandran’s Diabetes A Ramachandran Hyderabad, Telangana,India Nizam’s InstituteSciences ofMedical ofNephrology Department Additional Professor andHead Sree BRaju Rohtak, Haryana, India Post-graduate InstituteSciences ofMedical ofEndocrinology Department ProfessorSenior andHead Rajput Rajesh Sciences, Kochi, Kerala, India Gastroenterology, AmritaInstitute ofMedical Associate Professor, of Department Rajesh Gopalakrishna Hyderabad, Telangana,India Hospital andResearch Institute Basavatarakam Indo-AmericanCancer Consultant,Senior Oncology Medical Rajappa Senthil Sciences, NewDelhi, India Metabolism, AllIndiaInstitute ofMedical ofEndocrinologyand Department Nishant Raizada University, Varanasi, UttarPradesh, India Institute Sciences, ofMedical Banaras Hindu Professor, ofMedicine Department Madhukar Rai D Raghunadharao Hospital, Ram Sir Ganga NewDelhi, India Consultant,Senior Centre Genetics ofMedical graduate Education Medical andResearch Professor, Institute ofPost- Ram SirGanga DuaPuriRatna New Delhi, India Army HospitalResearch andReferral Unit Gastroenterology andHepatobiliary Professor andHead, of Department Pankaj Puri Vellore, Tamil Nadu, India Leprosy, College ChristianMedical ofDermatology,Department Venereology and Susanne APulimood Thiruvananthapuram, Kerala, India Oncology,Medical RegionalCancer Centre Consultant Haematology, of Department Shruti Prem FICP FIACM FIMSA MD (Medicine) DM(Gastroenterology) MD(Medicine) MD DM(AIIMS)DNBFISNFICPFIACM MD DM MSc PhD MDDM(Endocrinology) MD MD DM MD MD DNBDM MD DSc MDFRCPFICP MD DM MD MDDNB(Gastro) Brothers and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical ofGastroenterology Department Assistant Professor Surinder SRana Safdarjung Hospital, New Delhi, India Vardhman Mahavir College Medical and Dermatology andApexRegionalSTDCentre Professor andHead, of Department V Ramesh Hospitals, Chennai, Tamil Nadu, India Diseases, HIVand Tropical Medicine, Apollo Consultant,Senior ofInfectious Department DTM &H(Lon) V Ramasubramanian Chennai, Tamil Nadu, India SRM Institutes for Sciences Medical Consultant,Senior Gastroenterology BS Ramakrishna Vellore, Tamil Nadu, India CollegeChristian Medical andHospital Professor, ofHaematology Department Ramachandran Shaji V Chandigarh, India EducationMedical andResearch Nephrology, Post-graduate Institute of Assistant Professor, of Department Ramachandran Raja New Delhi, India Director, NutritionFoundation ofIndia Prema Ramachandran V Ravi Sciences,Medical NewDelhi, India Cancer Hospital,Rotary AllIndiaInstitute of Chief, Institute of Ambedkar DrBhimRao Professor, ofRadiotherapy Department GK Rath Centre, Hyderabad, Telangana, India Rheumatologist, Rheumatology SriDeepti URK Rao Mysuru, Karnataka, India Shivarathreeswara University CollegeMedical Hospital, JagadguruSri Psychiatry, JagadguruSriShivarathreeswara Professor andHead, of Department TS Sathyanarayana Rao Gulbarga, Karnataka, India Ex-Professor College andHeadofMedical Former President, API, RSSDIandHIS Murlidhar SRao Sciences,Medical Tirupati, Andhra Pradesh, India Medicine, Sri Venkateswara Institute of Anaesthesiology andCriticalCare andPain ProfessorSenior andHead, of Department M Hanumantha Rao Centre, Bengaluru, Karnataka, India Oncology, Shaw Mazumdar Cancer Kiran Oncologist,Medical ofMedical Department Bharath Rangarajan Bengaluru, Karnataka, India Health andNeurosciences Neurovirology, NationalInstitute ofMental Professor andHead, of Department DM (Gastroenterology) MAMSFASGE MDFAMS FASc MD MD (Medicine) MD MD(Internal Medicine) MDFACP FCCP FICPFICC FCSI MDDMPhDFAMS FNA

MDDMECMO MDFRCP(Glas) MD DM(Nephrology) MD MNAMS MSc PhD MD 29-01-2015 14:22:08 K Ravishankar MD Banshi Saboo MD FICP FICN Vivek Anand Saraswat MD DM Consultant In-charge, The Headache and MNAMS (Diabetology) FACE Professor Migraine Clinic, Jaslok Hospital and Research Consultant Diabetologist, DIACARE Department of Gastroenterology Centre, Lilavati Hospital and Research Centre Ahmedabad, Gujarat, India Sanjay Gandhi Post-graduate Institute of Mumbai, Maharashtra, India Medical Sciences, Lucknow, Uttar Pradesh, India S Sacchidanand MD (Dermatology) DVD DHA D Raja Reddy FRCS (Edin) FRACS Dermatologist/Cosmetologist Kavitha Saravu MD DNB (Med) Senior Consultant, Neurosurgeon Sujala Poly Clinic and Lab Additional Professor, Department of Medicine

Apollo Hospitals, Hyderabad Bengaluru, Karnataka, India Kasturba Medical College, Manipal University Contributors Emeritus Professor Neurosurgery Manipal, Karnataka, India Nizam’s Institute of Medical Sciences Bibhuti Saha DTM&H (Cal) Rajiv Sarin Hyderabad, Telangana, India MD (Tropical Medicine) (Cal) Professor and Head In-Charge, Cancer Genetics Unit YC Janardhan Reddy DPM MD Department of Tropical Medicine Director, ACTREC Tata Memorial Centre Professor Calcutta School of Tropical Medicine Kharghar, Navi Mumbai, Maharashtra, India Department of Psychiatry Obsessive- Kolkata, West Bengal, India AS Savitha MD (Dermatology) DVD DHA Compulsive Disorder (OCD) Clinic National Institute of Mental Health and BK Sahay MD Dermatologist/Cosmetologist Neurosciences, Bengaluru, Karnataka, India Consultant Physician and Diabetologist Sujala Poly Clinic and Lab Hyderabad, Telangana, India Bengaluru, Karnataka, India BB Rewari MD Anurag Saxena MD (Medicine) Associate Professor, Dr Ram Manohar Lohia Manisha Sahay MD DNB MAMS Hospital and Post-graduate Institute of Professor and Head Senior Consultant, Physician, Primus Super- Medical Education and Research Department of Neurology Osmania General speciality Hospital, New Delhi, India Hospital and Medical College New Delhi, India P Saxena MD EDIC (Europe) FCCP Hyderabad, Telangana, India Head and Senior Consultant SNA Rizvi MD FICP FAIID FIMSA FIAMS FISM Senior Honorary Consultant Rakesh K Sahay MD DNB DM (Endo) FICP FACE (Pulmonology, Critical Care and Sleep Sanjeevan Medical Research Centre, Delhi Professor Medicine) Ex-Director Professor and Head of Medicine Department of Endocrinology Saket City Hospital, New Delhi, India Osmania Medical College and Osmania Maulana Azad Medical College and Associated Pikee Saxena MD FICOG PGCC (Hospital General Hospital, Hyderabad, Telangana, India Hospitals, New Delhi, India Management) PGDCR (Clinical Research) Professor Yasir S Rizvi MD DM Tapan Kumar Saikia MD Assistant Professor, Department of Head of Medical Oncology and Director of Department of Obstetrics and Gynaecology Nephrology, Vardhman Mahavir Medical Research, Prince Aly Khan Hospital, Mazagaon Lady Hardinge Medical College and Smt College and Safdarjung Hospital Mumbai, Maharashtra, India Sucheta Kriplani Hospital New Delhi, India New Delhi, India GS Sainani MD FRCP (Lond) Hon FRACP PhD DSc Renu Saxena MD Camilla Rodrigues MD FICP (Ind) Consultant Microbiologist, PD Hinduja Director, General Medicine Department Professor and Head National Hospital and Medical Research Jaslok Hospital and ResearchBrothers Centre Department of Haematology Centre, Mumbai, Maharashtra, India Emeritus Professor of Medicine All India Institute of Medical Sciences Grant Medical College and JJ Hospital New Delhi, India Cecil Ross MD (General Medicine) Mumbai, Maharashtra, India MS Seshadri MD PhD FRCP (Edin) Professor and Head, Division of Haematology St John’s Medical College Rajesh Sainani MD DNB Consultant Physician and Endocrinologist Bengaluru, Karnataka, India Consultant Gastroenterologist, Jaslok Hospital Honorary Medical Director, Thirumalai Mission Bhatia Hospital, Raheja Fortis Hospital and Hospital Ambuj Roy MD DM Jagjeevan Ram Railway Hospital Ex-Professor and Head Additional Professor Mumbai, Maharashtra, India Department of Endocrinology Department of Cardiology Diabetes and Metabolism All India Institute of Medical Sciences R Sajithkumar MD PhD Christian Medical College and Hospital New Delhi, India Chief, Infectious Diseases Vellore, Tamil Nadu, India Government Medical College Hospital Mrinal Kanti Roy MD DM FICP Kottayam, Kerala, India V Seshiah MD FRCP DSc (Hony) Professor, Department of Medicine Chairman Calcutta National Medical College Vinay Sakhuja MD DM Dr V Seshiah Diabetes Research Institute and Kolkata, West Bengal, India Director Dr Balaji Diabetes Care Centre Nephrology and Transplant Medicine Chennai, Tamil Nadu, India Rakesh Roy MD (Pharmacology) Max Super-speciality Hospital In-Charge of Palliative Care Mohali, Punjab, India KK Sethi MD DM FACC FHRS FCSI Saroj Gupta Cancer Centre and Research Director of Cardiology, Delhi Heart and Lung Institute, Kolkata, West Bengal,Jaypee India AM Samuel MD (Paed) DCH FAMS Institute, New Delhi, India Ex-Director, Bio-Medical Group, Bhabha Priscilla Rupali MD DTM & H Atomic Research Centre Ashok Shah MD Professor, Department of Medicine, Christian Mumbai, Maharashtra, India Professor, Department of Respiratory Medicine Medical College, Vellore, Tamil Nadu, India Fellow, National Academy of Medical Sciences Jaspal S Sandhu MS DSM (India), Immediate Past President M Sabir MD Professor and Dean, Faculty of Sports The Indian College of Allergy, Asthma and Professor and Head Medicine and Physiotherapy, Guru Nanak Dev Applied Immunology Department of Medicine University, Amritsar, Punjab, India Maharaja Agrasen Medical College, Agroha Bela Shah MD (Dermatology) Ex-Professor and Head, Respiratory Division Carani B Sanjeevi MD MSc PhD Professor and Head, Department of Department of Medicine, Sarder Patel Medical Professor, Department of Medicine Dermatology, BJ Medical College and Civil xxi College, Bikaner, Rajasthan, India Karolinska Institute, Stockholm, Sweden Hospital, Ahmedabad, Gujarat, India

API _ Prelims _ Vol-1 for (TRADE).indd xxi 29-01-2015 14:22:08 API _Prelims _Vol-1for(TRADE).indd xxii

xxii API Textbook of Medicine (hcNTR) DSc(hcRGUHS) Psychology, NationalInstitute ofMental Associate Professor, ofClinical Department Manoj KSharma New Delhi, India Hospital, AllIndiaInstituteSciences ofMedical Cancer Institute ofRotary Ambedkar Rao Oncology, ofMedical Department DrBhim Additional Professor Atul Sharma and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical Wing, ofInternal Medicine Department Assistant Professor, andHIV Rheumatology Aman Sharma Chennai, Tamil Nadu, India Endocrinologist, Hospital KMSpeciality G Shanmugasundar Neurosciences, Bengaluru, Karnataka, India Centre, NationalInstituteHealthand ofMental (Human Brain Bank), Neurobiology Research Co-ordinator, HumanBrain Tissue Repository Neuropathology andPrincipal Emeritus Professor, of Department SK Shankar Gulbarga, Karnataka, India University ofHealthSciences Gandhi Rajiv ofMedicine Department Emeritus Professor PS Shankar New Delhi, India All IndiaInstituteSciences ofMedical ofGastroenterology Department Assistant Professor Shalimar and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical ofEndocrinology Department Professor andHead Viral NShah Mumbai, Maharashtra, India Western Hospitals Railway Consultant,Visiting Central and Railway Nurrotumdas Hospital Sir Hurkisondas Diabetes, Saifee Hospital, BhatiaHospital HospitalandAllIndiaInstitute of SL Raheja Consulting Physician andDiabetologist of Mumbai Post-graduate Teacher inDiabetes, University NShah Siddharth Sadvichar Parivar, Ahmedabad, Gujarat, India Professor Emeritus, Oncology Medical Trustee- Special Advisor to Chairman, GCRI President,Vice Gujarat Cancer Society Pankaj ManubhaiShah KEM Hospital, Mumbai, Maharashtra, India Endocrinology, College GSMedical Seth and Professor andHead, of Department Nalini SShah Mumbai, Maharashtra, India Institute Sciences ofMedical ofNephrology,Department Bombay Hospital Assistant ProfessorHonorary Hardik Shah FRCP (Edin) DM MDFRCP(Lond) FAMS DSc(hcGul)

MD DM MD FAMS FNAScFICP DM MD (Med) DNB(Nephro)MD (Med) MD MAMSFRCP(London) PhD MDFICPFACP (Hon)

Jaypee MD DM MD MRCP (UK) (Health Care Administration) Apollo Hospital, NewDelhi, India Diabetes andEndocrinology, Indraprastha Consultant,Senior ApolloCentre for Obesity Mohammad AsimSiddiqui Kolkata, West Bengal, India Faculty Member, Clinic Geriatric Hospital Memorial Karnani and ResearchSukhlal andSeth Institute of Post-graduate Education Medical Medicine General Assistant Professor SiddhantaSattik Sciences,Medical NewDelhi, India Neurosciences Centre, AllIndiaInstitute of Associate Professor, ofNeurology Department Shukla Garima West Bengal, India Secretary, Foundation Stroke ofBengal Institute ofNeurosciences, Kolkata Consultant, CriticalCare andStroke Amritsar, Punjab, India and Physiotherapy, University GuruNanakDev Associate Professor, Faculty Medicine ofSports Sciences, NewDelhi, India Radiology, AllIndiaInstitute ofMedical Professor andHead, ofCardiac Department Sharma Sanjiv Sciences, NewDelhi, India Institute ofHumanBehaviour andAllied Neuropsychopharmacology Professor andHead, of Department Sharma Sangeeta Sciences, NewDelhi, India Professor, AllIndiaInstitute ofMedical Sharma Raju Lucknow, UttarPradesh, India Institute Sciences ofMedical Nephrology, Sanjay Post-graduate Gandhi Professor andHead, of Department KumarRaj Sharma Lucknow, UttarPradesh, India George’sKing University Medical ofNeurology Department Praveen Kumar Sharma Hospital,Rockland NewDelhi, India Board Advisory and Member Head, ofGastroenterology Department MP Sharma Shweta Shenoy New Delhi, India All IndiaInstituteSciences ofMedical Professor andHead, ofMedicine Department Surendra KSharma Research, Chandigarh, India graduate Institute Education ofMedical and Medicine, UnitofRheumatology, Post- Assistant Professor, ofInternal Department Shefali KhannaSharma Bengaluru, Karnataka, India Health andNeurosciences A Shobhana MDDMFAMS FACG MD MD MNAMS MD (Radiology) PhD MD MD(Pharmacology) MBA FISNFASN FAMS MD PhD

MD MAMS Brothers MD DM MD (Gen Med) Med) MD(Gen (Lon) FAMS FISN FICP Sciences, NewDelhi, India Cardiology, AllIndiaInstitute ofMedical Additional Professor, of Department Singh Sandeep and Research, Chandigarh, India Post-graduate InstituteEducation ofMedical Medicine ofPulmonary Department Assistant Professor Navneet Singh Ghaziabad, UttarPradesh, India Medicine, Pushpanjali Crosslay Hospital, ConsultantSenior inNephrology and Chairman, andAlliedSpecialities Medicine Narinder Pal Singh Hospital, NewDelhi, India College Medical andGBPant Azad Maulana Professor, ofNeurosurgery Department Daljit Singh New Delhi, India Fortis HospitalNoidaand Vasant Kunj ofNeurosciences Department Executive Director AK Singh New Delhi, India Hospital Memorial Dr BLKapur Chairman, ofMedicine Department RK Singal Mumbai, Maharashtra, India Institute Sciences ofMedical ofNeurology,Director Bombay Hospital BS Singhal Hospital,General Pune, Maharashtra, India NavaleSmt Kashibai College Medical and Professor, ofInternal Medicine Department Yudh Dev Singh New Delhi, India Hospital Memorial Dr BLKapur Associate Consultant, ofMedicine Department Vivek Pal Singh Jaipur, Rajasthan, India CollegeSawai SinghMedical Man Medicine Head, DivisionofAllergy andPulmonary Professor ofMedicine Virendra Singh Chandigarh, India Institute Education ofMedical andResearch Advanced Paediatrics Centre, Post-graduate In-Charge, Paediatric Allergy ImmunologyUnit Professor, ofPaediatrics and Department Surjit Singh Gurgaon, Haryana, India Medanta—The Medicity Disorders, Institute ofNeurosciences Head, ofNeuromuscular Department Sumit Singh Varanasi, UttarPradesh, India Sciences,Medical Banaras HinduUniversity Endocrinology andMetabolism, Institute of Professor andHead, of Department SK Singh FAMS MDDM(Endocrinology) MDFRCPFICPFACP MS MCh(Neurosurgery) MDDCH(Lon) FRCP(Lon) FRCPCH MD FRCP(London andEdinburgh) MD DM(Neurology) MD MD DM MD (Medicine) FIACM MD(Medicine) DIT MD DM MDMBAFRCP(Edin) FAMS 29-01-2015 14:22:08 Rajiv Singla MD DNB MNAMS DKS Subrahmanyam MD Nikhil Tandon MD PhD (Cantab) Department of Medicine, Maulana Azad Professor, Department of Medicine Professor and Head, Department of Medical College, New Delhi, India Jawaharlal Institute of Post-graduate Medical Endocrinology and Metabolism Education and Research, Puducherry, India All India Institute of Medical Sciences Sumeet Singla MD DNB MNAMS MIRA New Delhi, India Assistant Professor, Department of Medicine AP Sugunan Maulana Azad Medical College and Associated Scientist ‘E’, Regional Medical Research Centre PN Tandon MD FRCS DSc (hc) FAMS FNASc FASC Lok Nayak Hospital, New Delhi, India Port Blair, Andaman and Nicobar Islands, India FTWAS

Emeritus Professor, Department of Contributors Sanjeev Sinha MD S Sukumaran MD (Med) MSc (International Health Neurosurgery, All India Institute of Medical Additional Professor Management) Sciences, New Delhi, India Department of Medicine Assistant Professor, KJ Somaiya Medical All India Institute of Medical Sciences College and Hospital Rakesh Tandon MD PhD FRCP (Edin) FAMS FICP New Delhi, India Mumbai, Maharashtra, India FAGA Head, Department of Gastroenterology Sanjib Sinha MD DM TK Suma MD DNB Medical Director and Head, Pushpawati Additional Professor, Department of Professor, Department of Medicine Singhania Research Institute for Liver Neurology, National Institute of Mental Medical Superintendent, Government Renal and Digestive Diseases Health and Neurosciences Tirumala Devaswom Medical College New Delhi, India Bengaluru, Karnataka, India Kerala, India Kamlesh Tewary MD FICP FIAMS Pradyot Sinhamahapatra Vivek Suman MD Professor and Head Associate Professor (Rheumatology) Assistant Professor Department of Medicine Department of Medicine, North Bengal Department of Medicine Sri Krishna Medical College Medical College, Darjeeling, West Bengal, India Lady Hardinge Medical College and Muzaffarpur, Bihar, India C Snehalatha MSc DSc Associated Hospitals, New Delhi, India Ashish K Thakur MD DM FRCP FESC FICP FRSM Director Jamshed D Sunavala MD FCCP (USA) FICP FISE Consultant Cardiologist and Honorary Senior Research, India Diabetes Research Foundation Director, Department of Critical Care Medicine Lecturer, The Mid Yorkshire NHS Trust and Egmore, Chennai, Tamil Nadu, India Jaslok Hospital and Research Centre University of Leeds Medical School, UK Rumneek Sodhi Mumbai, Maharashtra, India BB Thakur MD FICP FIAMS FIACM FISPD Division of Peripheral Vascular and A Shyam Sundar MD DNB Consultant Physician and Cardio-diabetologist Endovascular Sciences Assistant Professor, Department of Psychiatry Muzaffarpur, Bihar, India Medanta—The Medicity National Institute of Mental Health and Gurgaon, Haryana, India Neurosciences, Bengaluru, Karnataka, India Smita Thakur MRCGP (UK) General Practitioner, United Kingdom Rajeev Soman MD Shyam Sundar MD FRCP FAMS FNA FSc FNASc Consultant Physician, PD Hinduja Hospital Professor of Medicine DM Thappa MD DHA FAMS FIMSA Mumbai, Maharashtra, India Institute of Medical Sciences Professor, Dermatology and STD Department Banaras Hindu University, Varanasi Jawaharlal Institute of Post-graduate Medical Ajit Sood MD (Medicine) DM (Gastro) Education and Research, Puducherry, India Professor and Head Uttar Pradesh, India Brothers R Thara MD Department of Gastroenterology Vikas Suri MD Dayanand Medical College and Hospital Assistant Professor, Department of Internal Director, Schizophrenia Research Foundation Ludhiana, Punjab, India Medicine, Post-graduate Institute of Medical (SCARF), Chennai, Tamil Nadu, India Rita Sood MD MMEd Education and Research, Chandigarh, India Nihal Thomas MD MNAMS DNB (Endo) FRACP (Endo) FRCP (Edin) FRCP (Glas) Professor, Department of Medicine Rupjyoti Talukdar MD Professor and Head, Department of All India Institute of Medical Sciences Clinical Pancreatologist and Endocrinology, Christian Medical College New Delhi, India Gastroenterologist, Asian Institute of Vellore, Tamil Nadu, India D Sreeramulu PhD Gastroenterology, Clinician Scientist Endocrinology and Metabolism Division (Wellcome-DBT Fellow), Asian Healthcare Sanjeev V Thomas MD DM FANA National Institute of Nutrition Foundation, Hyderabad, Telangana, India Professor, Department of Neurology Hyderabad, Telangana, India Sree Chitra Tirunal Institute for Medical KK Talwar MD DM (Cardiology) Sciences and Technology GR Sridhar MD DM FRCP (Glasgow) FAMS Chairman, Department of Cardiology Max Thiruvananthapuram, Kerala, India Director, Endocrine and Diabetes Centre Healthcare Institute Ltd, New Delhi Vishakhapatnam Ex-Chairman, Board of Governors Medical Anil Kumar Tripathi Editor in Chief, International Journal of Council of India, New Delhi, India Vice Chairman and Head Diabetes in Developing Countries Department of Clinical Haematology and AB Taly MD DM Oncology Chhatrapati Sahu Ji Maharaj Shiva Prakash Srinivasan MD ABPN Professor Medical University Consultant Psychiatrist JaypeeDepartment of Neurology, National Institute Lucknow, Uttar Pradesh, India Schizophrenia Research Foundation (SCARF) of Mental Health and Neurosciences Chennai, Tamil Nadu, India Bengaluru, Karnataka, India CD Tripathi MD (Pharmacology) Director, Professor and Head MV Padma Srivastava MD DM FAMS Shruti M Tandan MD FNB (Critical Care) Department of Pharmacology Professor, Department of Neurology Senior Intensivist, Department of Critical Care Vice Principal, Vardhaman Mahavir Medical All India Institute of Medical Sciences Medicine, Jaslok Hospital College and Safdarjung Hospital New Delhi, India Mumbai, Maharashtra, India New Delhi, India

Sushma Srivastava PhD PDCR Abhinav Tandon MD Pankaj Tyagi MD DM (Gastroenterology) Research Scientist, Delhi Institute of Lecturer, Department of Psychiatry Consultant Gastroenterologist, Department Pharmaceutical Sciences and Research Maharani Laxmi Bai Medical College of Gastroenterology, Sir Ganga Ram Hospital xxiii New Delhi, India Jhansi, Uttar Pradesh, India New Delhi, India

API _ Prelims _ Vol-1 for (TRADE).indd xxiii 29-01-2015 14:22:08 API _Prelims _Vol-1for(TRADE).indd xxiv

xxiv API Textbook of Medicine Chennai, Tamil Nadu, India Gujarati Hospital Sahayakari Executive Director, Parvatiben Trikamji Bhatt Sciences Founder Chair, IndianInstitute ofNutritional Certiﬁ Consultant, ClinicalNutritionist Varsha Education andResearch, Chandigarh, India Medicine, Post-graduate Institute ofMedical Professor andHead, ofInternal Department Subhash Varma Zone),(North NewDelhi, India Secretary, ofNephrology IndianSociety President Elect, ofNephrology IndianSociety ChiefIntegrated DefenceDy Staff(Medical) PP Varma Sciences,Medical NewDelhi, India JPN Apex Trauma Centre, AllIndiaInstitute of Medicine ofEmergency Department VankarSameer Kerala, India College Medical Muslim Educational Society ofPsychiatry Department Associate Professor V Rajmohan Research, Puducherry, India of Post-graduate Education Medical and ofMedicine,Department Jawaharlal Institute Assistant Professor Muktha V Shalimar Bagh, NewDelhi, India Hepatology, Hospital Super-speciality Max ofGastroenterology and Department ConsultantSenior andHead UpadhyayRajesh Mumbai, Maharashtra, India ResearchMedical Centre PD HindujaNationalHospitaland Consultant, ChildNeurology andEpilepsy Vrajesh Udani New Delhi, India All IndiaInstituteSciences ofMedical Professor, ofHaematology Department TyagiSeema New Delhi, India Cardiology, College Medical Azad Maulana Director, Professor andHead, of Department EducationMedical andResearch Director, GBPant Institute ofPost-graduate Sanjay Tyagi (Glasgow) FICP (Nephro) FACP FICPFISN ed Nutrition Injury Specialist ed NutritionInjury MScPhDRDCNIS MD (General Medicine) MD(General SM DMMNAMS MDDNB(Med) VSM MD MDDMFACC FCSIFAPI FAMS

MD MD FICP Jaypee MDMRCP(UK)FRCP FRCP (Edin) Chennai, Tamil Nadu, India University Sri Ramachandra College Medical Sri Ramachandra Gastroenterology ofMedical Department Professor andHead Shanthi Vijayaragavan University ofDelhi, NewDelhi, India Ex-Director Vallabhbhai Patel ChestInstitute Research inEnvironmental Health, Bhopal and Research Centre, NationalInstitute for Research,Medical Hospital BhopalMemorial Advisor to General, Director IndianCouncil of VK Vijayan Saket, NewDelhi, India Hospital Super-speciality Max Hospital BLK Super-speciality Centre for Digestive andLiver Diseases Head andDirector JC Vij Dehradun, Uttarakhand, India Division, Cancer Research Institute University andIn-Charge, Oncology Medical Professor, ofMedicine, Department HIHT SK Verma Hospital, ChananDevi Mata NewDelhi, India Consultant Physician andNeurologist Sundaram Venkatraman Tirupati, Andhra Pradesh, India Sri Venkateswara InstituteSciences ofMedical ofNeurology Department Director, Professor andHead B Vengamma Mumbai, Maharashtra, India Glenmark Cardiac Centre Amit Vora Kerala, India Pushpagiri InstituteSciences ofMedical Professor, ofNephrology Department R Kasi Visweswaran Chennai, Tamil Nadu, India MV Hospitalfor Diabetes Head andChiefDiabetologist Vijay Viswanathan CollegeMedical Vellore, Tamil Nadu, India ofClinicalHaematology,Department Christian (Toronto, Canada) Stem Cell Transplantation Fellowship Haematology inMalignant and Professor Auro Viswabandya FICA FICPFIAN MDDM(Gastroenterology) MDFICPFIACM MDDMDNB MD PhD DScFAMS DM (Neuro) MDPhDFRCP(London) FICP MD DM MD DM(Nephrology) MD DM

Brothers MD DM(Neurology) DM (Cardiology) Naveet Wig Ludhiana, Punjab, India Institute Unit Hero DMCHeart Dayanand College Medical andHospital ofCardiology Department Professor andHead Gurpreet Singh Wander University, Lucknow, UttarPradesh, India Rheumatology, George’s King Medical Associate Professor, of Department Anupam Wakhlu Pune, Maharashtra, India Consultant Histopathologist UL Wagholikar Ruby HallClinicPune, Maharashtra, India Professor,Director ofNeurology Department RS Wadia Puducherry, India EducationMedical andResearch Jawaharlal Institute ofPost-graduate Associate Professor, ofMedicine Department Jyoti Wadhwa New Delhi, India All IndiaInstituteSciences ofMedical Metabolism ofEndocrinologyand Department Associate Professor Jyotsna VP Srinagar, JammuandKashmir, India Institute Sciences of Medical ofEndocrinology,Department Sher-i-Kashmir Ex-Professor andHead Member, Council Medical ofIndia Abdul HamidZargar Thiruvananthapuram, Kerala, India SciencesMedical Sree Uthradom Thirunal Academy of ofMedicine Department Assistant Professor Sanjay Zachariah Mumbai, Maharashtra, India CollegeKJ Somaiya Medical andHospital ofInternal Medicine Department Professor ME Yeolekar Hospital,Max Pitampura, NewDelhi, India Consultant,Senior Internal Medicine Pushpa Yadav Sciences,Medical NewDelhi, India ofMedicine,Department AllIndiaInstitute of Professor MD FIANFICP DM (Endocrinology) MD MD MNAMS (Med) FICP MDMNAMS(Med) MD

MD (Medicine) MD DM DM MD (Medicine) 29-01-2015 14:22:08 CONTENTS

Volume 1

Part 1 Introduction

1. The Practice of Medicine 2 Yash Pal Munjal 2. Disease Profi le and Epidemiology of Communicable and Non-communicable Diseases in India 11 Jugal Kishore

Part 2 Clinical Approach to Key Manifestations

1. Pain: Mechanism and Management 22 PN Kakar 2. Headache 24 K Ravishankar 3. Chest Pain 34 Sanjay Tyagi and Amit Mittal 4. Acute Abdomen: Non-surgical Causes 40 Sumeet Singla and AK Agarwal 5. Cough 47 Suman Kirti 6. Haemoptysis 52 Randeep Guleria and Jaya Kumar Brothers 7. Jaundice 56 Aparna Agrawal 8. Clinical Approach to Upper Gastrointestinal Bleeding 62 JC Vij 9. Approach to Patient with Lower Gastrointestinal Bleeding 65 Surinder S Rana 10. Fever of Unknown Origin 69 Priscilla Rupali 11. Generalised Lymphadenopathy 76 SK Verma 12. Dizziness and Vertigo 79 M Maiya 13. Syncope 83 Pushpa Yadav 14. Coma 87 B Vengamma Jaypee15. Appropriate Ordering of Radiological Investigations 94 Chandan J Das 16. A Clinical Approach to Patients with Ascites 107 Richa Dewan 17. Anasarca: A Clinical Approach 111 Yash Pal Munjal 18. Approach to a Patient with Dyspnoea 115 Praloy Chakraborty 19. Clinical Approach to Exanthematous Fever 120 Bibhuti Saha and Manab Kumar Ghosh

API _ Prelims _ Vol-1 for (TRADE).indd xxv 29-01-2015 14:22:08 API _Prelims _Vol-1for(TRADE).indd xxvi

xxvi API Textbook of Medicine 5. 3. 1.

Part 6 Part 5 Part 4 Part 3 Part

Jaypee Diagnostic Imaging Medical Genetics Immunology Clinical Pharmacology 3. Immunology of Infectious Diseases ImmunologyofInfectious 3. 186 Positron EmissionComputed Tomography andPositron EmissionMagneticResonance Imaging 6. MagneticResonance Imaging 4. . MendelandBeyond 2. toMedicalGenetics Introduction 1. Laboratory Investigations Diseases inImmune-mediated 5. Approach toaPatient Immunodefi Primary withSuspected 4. General Concepts ofImmuno-infl 2. oftheImmuneSystem An Overview 1. Pharmacovigilance: Safety MonitoringofMedicines 5. Pharmacokinetic andPharmacodynamic BasisofPharmacotherapy 4. Use Rational ofMedicines 3. toPharmacology Introduction 2. DrugDiscovery andClinicalEvaluation ofNew Drugs 1. Ultrasound inMedicine 2. . Clinical, Conventional andMolecularCytogenetics 3. . ImmunologyofOrgan andHaematopoietic StemCell Transplantation 7. Pharmacological Manipulation oftheImmuneSystem 6. RoleofNational Formulary ofIndiainNational HealthCare System 6. RajuSharmaandDevasenathipathy Kandasamy andNishigandhaBurute BhavinJankharia Ratna Dua Puri RatnaDua LateShyam Swarup Agarwal CDTripathi Manocha andSachin SKGuptaandSushmaSrivastava BSRamaMurthy BhallaandManishaJana AshuSeith NarinderKMehra andNeeraj Kumar ChatterjeeandAlakendu Mitali Ghosh JaiPrakash andYK Gupta Rakesh KumarKarunanithi andSellam BR Nuclear Ashutosh Surjit Sita Ramnath Sita Rajani Sangeeta Computed Conventional Amita Amita V Kalaiselvan Mittal Naik Naik Singh Aggarwal Mathur Imaging Halder Misra Sharma Tomography Radiology Radiology

ammatory ammatory Disorders Brothers ciency ciency Disorder 29-01-2015 14:22:08 196 246 156 249 290 261 221 173 242 147 282 278 232 213 210 141 126 227 204 256 270 4. Genetic Tests 301 Ashwin Dalal 5. Inborn Errors of Metabolism 306 Madhulika Kabra 6. Molecular Genetics, Human Genome Project and Genomic Medicine 316 Girisha KM

7. Gene Therapy 322 Contents Rita Mulherkar 8. Genetic Counselling and Prenatal Diagnosis 325 Shubha R Phadke 9. Pharmacogenomics and Personalised Medicine 332 C Adithan 10. Cancer Genetics 335 Rajiv Sarin

Part 7 Critical Care Medicine

1. Basic Considerations in Critical Care 342 RK Mani and P Saxena 2. Monitoring of Critically Ill Patients 346 M Hanumantha Rao 3. Fluid and Electrolyte Balance in Health and Disease 352 Sanjay Jain 4. Acid-Base Disorders 360 Alladi Mohan and Surendra K Sharma 5. Enteral and Parenteral Nutrition in Critically Ill Patients 368 Shilpa S Joshi 6. Acute Respiratory Failure 374 Ashit M Bhagwati 7. Sepsis and Acute Respiratory Distress Syndrome 381 Alladi Mohan and Surendra K Sharma Brothers 8. Mechanical Ventilation 388 Tamilarasu Kadhiravan 9. Non-invasive Positive Pressure Ventilation 395 Dhruva Chaudhry and Rajesh Chawla 10. Hypotension and Shock 404 Piyush Jain and Rene P Eapen 11. Advanced Cardiac Life Support 407 Sanjeev Bhoi and Sameer Vankar 12. Brain Death and Support of Brain Dead Organ Donor 417 Rajesh Chawla and Prashant Nasa

Part 8 Bone Disorders

1. Bone and Mineral Metabolism in Health and Disease 424 Deepak Khandelwal and Ravinder Goswami Jaypee2. Investigation and Diagnosis of Bone Disorders 430 Sukumar Mukherjee and Somnath Bhar 3. Rickets and Osteomalacia 437 Bindu Kulshreshtha and Sachin K Jain 4. Osteoporosis 442 SNA Rizvi 5. Developmental Disorders of Bone 448 Rakesh K Sahay 6. Miscellaneous Bone Disorders 451 xxvii CV Harinarayan

API _ Prelims _ Vol-1 for (TRADE).indd xxvii 29-01-2015 14:22:09 API _Prelims _Vol-1for(TRADE).indd xxviii xxviii API Textbook of Medicine

17.

16. 10. 7. 5.

Part 10 Part 9 Part

18. Sexual Dysfunction inDiabetes Sexual Dysfunction 18. 2 Prevention ofDiabetesMellitus 22. DiabetesintheElderly 21. DiabetesandPregnancy 20. Management ofDiabeticFoot 19. 5 DiabetesandKidney Disease 15. Microvascular Diseases:Pathogenesis ofChronic Complications 14. Macrovascular Complications ofDiabetes 13. inDiabetesMellitus Infections 12. Jaypee DiabeticKetoacidosis, Hyperosmolar Hyperglycaemic Acidosis State andLactic 11. Endocrinology Diabetes Mellitus . Disorders ofHypothalamusandPineal Gland 3. EndocrineDisorders: AClinicalApproach 2. BasicConsiderations ofEndocrinology 1. In-HospitalManagement ofDiabetesMellitus 9. Newer Modalitiesof Treatment in Type 2DiabetesMellitus 8. Oral Antidiabetic Drugs 6. ClinicalFeatures andDiagnosisofDiabetesMellitus 4. Pathogenesis of Type 2DiabetesMellitus 3. Pathogenesis of Type 1DiabetesMellitus 2. EpidemiologyandBasicConsiderations ofDiabetes 1. . Disorders ofAnterior Pituitary 4. Manish Modi and Anu Gupta ManishModiandAnu Yash Pal Munjal JamalAhmad andMohammadAsimSiddiqui andVBalaji VSeshiah andRajivParakh RumneekSodhi ShashankRJoshi GuptaandReemaBansal Amod MurlidharSRao RajKumar Sharma Ashok Kumar Das AshokKumar Das NShah Siddharth NaikandNihalThomas Dukhabandhu BhansaliandGShanmugasundar Anil Yash Pal Munjal BhansaliandViral Anil NShah Hemraj BChandalia Carani andVijay Viswanathan BSanjeevi ARamachandran andCSnehalatha AbdulHamidZargar andShariqRashidMasoodi Diabetic Suman Samar MS Anupam Rajesh Diabetic RV Insulins Banshi Hypoglycaemia Life-style Jayakumar Seshadri Rajput Banerjee Saboo Kirti Prakash Neuropathy Retinopathy Modifi cation intheManagement ofDiabetes Brothers 29-01-2015 14:22:09 492 545 508 557 457 524 519 514 576 566 539 554 550 534 528 571 470 465 461 542 580 497 486 480 502 477 5. Disorders of Posterior Pituitary 589 GR Sridhar 6. Disorders of Thyroid Glands 592 Nikhil Tandon and Nishant Raizada 7. Disorders of Parathyroid Glands 606 Ambrish Mithal and Beena Bansal

8. Disorders of Adrenal Glands 610 Contents Eesh Bhatia and Vijayalakshmi Bhatia 9. Disorders of Puberty 621 AC Ammini and Jyotsna VP 10. Disorders of Growth and Development 626 Nalini S Shah 11. Disorders of Gonads 634 Shashank R Joshi 12. Endocrine Disorders of Female Gonads 645 Pikee Saxena and Aruna Nigam

Part 11 Dermatology

1. Introduction and Principles of Diagnosis in Dermatology 656 Vibhu Mendiratta 2. Infections and Infestations 665 Surabhi Dayal 3. Allergic and Infl ammatory Disorders 674 Sanjeev Handa 4. Psoriasis and Papulosquamous Disorders 678 Bela Shah 5. Acne and Acneiform Eruptions 685 V Ramesh 6. Bullous Diseases 691 Vibhu Mendiratta Brothers 7. Pigmentary Disorders 695 Sandipan Dhar 8. Cutaneous Responses to Environmental Factors 702 DM Thappa and M Malathi 9. Skin Manifestations of Systemic Diseases 708 Sunil Dogra and Rahul Mahajan 10. Pre-malignant Conditions and Malignant Tumours of the Skin 720 Arun C Inamadar and Aparna Palit 11. Sexually Transmitted Infections 724 Yogesh S Marfatia 12. Hair and Nail Disorders 733 S Sacchidanand and AS Savitha 13. Leprosy 741 Hemanta Kumar Kar 14. Dermatology Therapy 747 Jaypee Asit Mittal Part 12 Cardiology

1. Basic Considerations in Cardiology 757 Upendra Kaul and Aijaz H Mansoor 2. Cardiovascular Diseases: A Clinical Approach 763 GS Sainani 3. Electrocardiology 774 xxix MJ Gandhi

API _ Prelims _ Vol-1 for (TRADE).indd xxix 29-01-2015 14:22:09 API _Prelims _Vol-1for(TRADE).indd xxx

xxx API Textbook of Medicine

22. 21. 15. 20.

9. 7. 5.

7 Acute Coronary Syndrome—NSTEMI 17. Disease IschaemicHeart 16. 25. Heart inSystemic Heart Diseases 25. Disease Congenital Heart 24. SuddenCardiac Arrest 23. 19. Hypertension and Its Management andIts Hypertension 19. Acute Myocardial Infarction— 18. Infective Endocarditis 14. Valvular Disease(II) Heart 13. Valvular Disease(I) Heart 12. Acute RheumaticFever 11. Treatment Failure ofHeart 10. 6 Disorders oftheMyocardium 26. 28. Surgical Management of Heart Disease Surgical Management ofHeart 28. DiseasesofthePericardium 27. 0 Vascular Disorders oftheExtremities 30. DiseasesoftheAorta 29. 2 Prevention ofCardiovascular Diseases 32. Disease Pregnancy andHeart 31. Jaypee . Cardiac Catheterisation andAngiocardiography 8. Cardiac Imaging 6. Inder S Anand andShibbaTakkar InderSAnand Chhabra andSLahiri KKSethi AshishKThakur Yash YLokhandwala Panicker andGopiKrishna BBThakurandSmita Naved AslamandAbhishekGoyal Shyam SKothari VKBahlandNeeraj Parakh Kumar RKrishna Veronica Franco Breathett andKhadijah andVeronica Kikta Donald Franco Sandhya AKamath AspiRBillimoria Lekha Adik Pathak andNOBansal Vikram RLele andParag Aland Priya Sharma JagiaandSanjiv Kumar Satish Parashar Yash Pal Munjal Sanjay Tyagi Sanjay Mittal andAmit KKTalwar Bahl andAjay ManotoshPanja andSoumitra Kumar Muhammad AbidGeelani Amal Kumar Amal Banerjee Gurpreet SinghWander andBishavMohan Sunita Amit Tachyarrhythmias Bradyarrhythmias Ambuj Ambuj Atherosclerosis CN Resistant Heart Heart Nuclear Echocardiography Exercise SKD Manjunath Bhardwaj Vora Failure Maheshwari Roy Cardiology Testing Hypertension Hypertension

BrothersSTEMI 904 29-01-2015 14:22:09 1029 1023 1015 1005 973 985 890 884 916 943 935 930 959 950 827 898 873 862 854 845 834 996 821 809 794 838 785 968 Part 13 Gastroenterology

1. Basic Considerations in Gastroenterology 1034 Vineet Ahuja and V Pratap Mouli 2. Clinical Approach to a Patient with Gastrointestinal Disease 1038 AC Anand and Pankaj Puri 3. Investigations: Gastrointestinal Disorders 1042 Contents Ashok Chacko 4. Diagnostic and Therapeutic Utility of Endoscopy 1045 Gourdas Choudhuri 5. Oesophageal Disorders 1051 Shobna Bhatia and Deepak Kumar Gupta 6. Diseases of the Stomach and Duodenum 1061 Pankaj Dhawan and Rajesh Sainani 7. Gastrointestinal Bleeding 1069 Rakesh Kochhar and Jahangeer Basha 8. Acute Pancreatitis 1079 Pramod Kumar Garg 9. Chronic Pancreatitis 1092 V Balakrishnan and Gopalakrishna Rajesh 10. Neoplasms of the Pancreas 1098 V Balakrishnan and Gopalakrishna Rajesh 11. Functional Gastrointestinal Disorders 1103 Philip Abraham 12. Constipation: Diagnosis and Management 1108 Uday Chand Ghoshal 13. Diarrhoea and Malabsorption 1112 BS Ramakrishna 14. Abdominal Tuberculosis 1120 Govind K Makharia 15. Infl ammatory Bowel Disease 1128 Ajit Sood and Vandana Midha Brothers 16. Ischaemic Bowel Disorders 1134 Deepak Kumar Bhasin 17. Gastrointestinal Symptoms in Extra-abdominal and Systemic Diseases 1137 Sudeep Khanna and Rakesh Tandon

Part 14 Hepatology

1. Basic Considerations of Hepatobiliary Disorders 1144 Vivek Anand Saraswat 2. Hepatobiliary Disorders: Clinical Approach and Investigations 1148 Nagaraja Rao Padaki 3. Hepatobiliary Disorders: Imaging 1158 Shrinivas B Desai 4. Acute Viral Hepatitis 1167 Jaypee DN Amarapurkar 5. Chronic Viral Hepatitis 1174 Radha K Dhiman 6. Chronic Non-viral Hepatitis 1181 CE Eapen 7. Alcoholic Liver Disease 1184 Rajesh Upadhyay and Nitin Gupta 8. Cirrhosis of the Liver 1190 Philip Abraham 9. Extrahepatic Portal Venous Obstruction 1196 xxxi Yogesh K Chawla

API _ Prelims _ Vol-1 for (TRADE).indd xxxi 29-01-2015 14:22:09 API _Prelims _Vol-1for(TRADE).indd xxxii xxxii API Textbook of Medicine

17. 16. 14. 13. 11. 8. 5. 4. 1. 15. Part 15 Part Haematology 5 PlasmaCell Dyscrasias 15. 2 Chronic Lymphocytic Leukaemia 12. Chronic Myeloid Myeloproliferative Leukaemia andOther Neoplasms 10. 6 Pregnancy andLiver Diseases 16. Jaypee BladderandBiliary DiseasesoftheGall Tract 19. Tumours oftheLiver 18. Liver inSystemic Diseases 17. Toxic andDrug-induced Liver Injury 14. Parasitic DiseasesoftheLiver 13. InheritedMetabolicDisorders oftheLiver 12. Acute Liver Failure 11. Non-alcoholic Fatty Liver Disease 10. . Acute Leukaemia 9. . Acquired HaemolyticAnaemia 7. HaemolyticAnaemia Hereditary 6. . Splenomegaly:AClinicalApproach 3. Anaemia: AClinicalApproach 2. Pankaj ManubhaiShah Bharath Rangarajan andPMParikh MMahapatra andRenuSaxena Rajat KumarTyagi andSeema Tapan Kumar Saikia andTuphan RChoudhary Dharma KantiDolai Tarun Kumar Dutta Kumar SubashGuptaandAjay RenuSaxena andMMahapatra ShajiVRamachandran andVikram Mathews andRakesh UshaDutta Tandon KaushalMadanandPankaj Tyagi Premashis KarandRajivSingla MPSharmaandVaibhav Gupta PAdvaitham andShanthiVijayaragavan SKAcharya andShalimar Prantar Platelet Kanjaksha Bleeding Auro Non-Hodgkin’s Hodgkin’s SH Myelodysplastic Aplastic Farah MB Subhash Megaloblastic Pankaj Haematopoiesis Ashish Liver Abraham Ajay Iron Advani Agarwal Duseja Defi Viswabandya Transplantation Jijina Goel Malhotra Chakrabarti ciency ciency Anaemia Disorders Varma Anaemia Koshy Disorders Ghosh Lymphoma Anaemia Lymphoma

Syndromes Brothers 29-01-2015 14:22:09 1341 1337 1331 1316 1321 1310 1297 1327 1225 1291 1285 1274 1268 1262 1253 1306 1222 1220 1216 1258 1238 1234 1210 1204 1199 1245 1230 18. Idiopathic Thrombocytopenic Purpura 1346 Cecil Ross 19. Disorders of Coagulation 1351 Jina Bhattacharyya and Sangit Dutta 20. Hypercoagulable Disorders 1355 Mammen Chandy 21. Transfusion Medicine 1360 Contents Neelam Marwaha 22. Haematopoietic Stem Cell Transplantation 1365 Velu Nair

Part 16 HIV and AIDS

1. Epidemiology of Human Immunodefi ciency Virus Infection 1374 OC Abraham and Susanne A Pulimood 2. HIV Virology and Immunology Including Diagnosis 1376 V Ravi and Anita Desai 3. Pathophysiology and Clinical Features 1380 UL Wagholikar and Alaka Deshpande 4. Antiretroviral Therapy 1386 BB Rewari 5. Drug Resistance 1390 Alaka Deshpande 6. Non-opportunistic Infections 1394 Anil Kumar Tripathi and D Himanshu 7. Opportunistic Infections 1398 Jyoti Wadhwa 8. Non-pharmacologic Interventions and Prevention 1403 R Sajithkumar Brothers Volume 2

Part 17 Infectious Diseases

A. General Considerations 1. Basic Considerations of Infections 1411 Subhasish Kamal Guha 2. Laboratory Diagnosis of Infections 1414 Camilla Rodrigues and Niyati Desai 3. Syndromic Approach to Infectious Diseases 1422 Rajeev Soman and Neha Gupta 4. Antimicrobial Therapy 1429 Jagriti Bhatia and Dharamvir Singh Arya 5. Infection in the Immunocompromised Host 1437 Jaypee Ghan Shyam Pangtey and Anupam Prakash 6. Hospital-acquired Infections/Nosocomial Infections 1440 A Shobhana 7. Prevention of Healthcare Associated Infections 1446 BB Rewari and Usha K Baveja 8. Hospital Infection Control 1452 Rohini Kelkar B. Bacterial Infections 9. Staphylococcal Infections 1455 xxxiii Rita Sood

API _ Prelims _ Vol-1 for (TRADE).indd xxxiii 29-01-2015 14:22:09 API _Prelims _Vol-1for(TRADE).indd xxxiv xxxiv API Textbook of Medicine 34. 31. 30. 28. 23. 22. 19. 18.

16. 15. 13. 12. AbhayNarain Rai 11. 36. 26. 25. 33. Bartonella Infections Infections Bartonella 33. Actinomycosis andNocardiosis 32. 9 Atypical Mycobacterial Infection 29. Spirochaetal Lyme Infections: Other BiteFever DiseaseandRat 27. 21. Clostridial Infections ClostridialInfections 21. PlagueandOther Yersinia Infections 20. DiseasesCaused by Gram-negative Enteric Bacilli 17. 4 Typhoid Fever (Enteric Fever) 14. 10. Streptococcal Infections 35. Rickettsial Infections Rickettsial Infections 35. Syphilis 24.

. Rickettsial, Chlamydial andMycoplasma Infections D. Jaypee C. Miscellaneous Bacterial Infections Miscellaneous Bacterial C. Dwijendra NathGangopadhyay Dwijendra Sandeep BBavdekar Sandeep Kumar andArvind MKDaga andMansoorAhmed MSabir Ganguly andSandipan SujitKBhattacharya Swapan Kumar Niyogi RKSingalandVivek Pal Singh DP Bhadoria and Sanjay Pandit DPBhadoriaandSanjay MalaChhabra andVeena Mittal Kavitha Pallavi A Melioidosis Donovanosis BG Brucellosis Surendra R Kamlesh Veena PS Richa Cholera Anaerobic TK AP Leptospirosis YK Pertussis: Diphtheria Legionnaires’ Haemophilus Pankaj Bacillary Chander Chlamydial Taru Non-syphilitic Debabrata Gonococcal Meningococcal Pneumococcal Sajithkumar Muruganathan Shankar Suma Amdekar Sugunan Mantur Garg Dewan Mittal Bhargava Tyagi Saravu Tewary Grover Daga Dysentery Dysentery Whooping Bandyopadhyay Infections Infections

Infections Infections Infections Infections Infl Disease Treponematoses Infections Infections Infections Infections uenzae Infections Cough Brothers 29-01-2015 14:22:09 1539 1467 1463 1544 1542 1537 1491 1486 1534 1529 1526 1511 1508 1495 1483 1502 1498 1522 1553 1531 1480 1472 1460 1547 1514 1476 1519 37. Mycoplasma Infections 1556 Dilip Mathai E. Viral Infections 38. Basic Considerations of Viral Diseases 1558 Usha K Baveja 39. Herpes Simplex Virus Infections 1565 Contents Aditya Prakash Misra 40. Human Papillomavirus and Parvovirus Infections 1569 Neerja Bhatla and Biswa B Dash 41. Swine Flu/Avian Flu 1575 Arvind Mathur and Prabhu Prakash 42. Dengue 1580 ME Yeolekar and S Sukumaran 43. Ebola and Marburg Infections 1584 Partha Pratim Chakraborty 44. Japanese Encephalitis 1586 Deepshikha 45. Rabies 1590 Tarun Kumar Dutta 46. Viral Gastroenteritis 1595 Prabhash Chandra Bhattacharyya and Rupjyoti Talukdar 47. Mumps 1597 Falguni S Parikh 48. Measles (Rubeola) 1599 RK Goyal 49. Smallpox 1602 Ramesh Balwant Pandit 50. Lymphocytic Choriomeningitis 1604 Praveen Gupta 51. Prion Disease 1607 PK Maheshwari and Anjana Pandey Brothers 52. Human Babesiosis 1609 Yash Pal Munjal and Kusumita Chaudhuri F. Protozoal Diseases 53. Malaria 1611 AK Agarwal and Sarit Chatterjee 54. Amoebiasis and Giardiasis 1620 MP Sharma and Vaibhav Gupta 55. Leishmaniasis 1624 Shyam Sundar 56. Toxoplasmosis 1629 Madhukar Rai 57. Trypanosomiasis 1632 Prashant P Joshi 58. Cryptosporidiosis, Trichomoniasis, Balantidiasis and Isosporiasis 1636 Jaypee Atul Bhasin G. Helminthic Diseases 59. Ankylostomiasis, Ascariasis and Other Nematodal Infections 1639 Narender Pal Jain 60. Tapeworm and Hydatid Diseases 1650 Anurag Saxena 61. Filariasis and Other Related Infestations 1658 Sanjay Zachariah 62. Schistosomiasis/Bilharziasis 1664 Kirti C Patel xxxv

API _ Prelims _ Vol-1 for (TRADE).indd xxxv 29-01-2015 14:22:09 API _Prelims _Vol-1for(TRADE).indd xxxvi xxxvi API Textbook of Medicine

7. 7. 10. 6. Part 19 Part 18 Part Nephrology 4 Pneumocystis Jirovecii Pneumonia 64. Systemic Fungal Infections 63. 0 Polycystic Kidney DiseaseandInherited Tubular Disorders 10. Disorders ofAdipose Tissue andObesity 11. 2 The MetabolicSyndrome 12.

Jaypee H. Fungal Infections Disorders ofMetabolism 1. Structure andFunction Structure oftheKidney 1. LipidsandLipoprotein Metabolism 3. InbornErrors ofCarbohydrate Metabolism 2. BasicConsiderations ofMetabolism 1. . Vascular toKidney Injury 9. Nephrolithiasis andUrinary Tract Obstruction 8. Glomerular Diseases Secondary 6. GlomerularDiseases Primary 5. Chronic Kidney Disease 4. Acute Kidney Injury 3. Kidney Disease:AClinicalApproach 2. Lysosomal Storage Disorders 8. Iron MetabolismandIron Overload Syndrome 5. Disorders ofPurine Metabolism andPyrimidine 4. . InheritedDisorders ofMembrane Transport 9. Siddharth NShah Siddharth ShrutiPrem andRajatKumar PPVarma andRanjithNair AKHoodaandASNarula RKasi Visweswaran andPraveen Namboodiri OPKalra Mahajan andSandeep andRajaRamachandran Vinay Sakhuja andHardik Shah Ashok LKirpalani Langote Alan FAlmeidaandAmit andPranaw Vijay Kher Kumar Jha MahajanandYasir Sandeep SRizvi SinhaandABTaly Sanjib Kumar Dhanpat Kochar Anoop Misra Anoop andSwati Bhardwaj ShashankRJoshi Prasanta Kumar Bhattacharya BK V PD Manisha RV Soneil Urinary Urinary Wilson’s Amyloidosis SK Porphyrias Mukesh Ramasubramanian Singh Sahay Jayakumar Gulati Guptha Desai Tract Sahay Disease Infections Infections

Brothers 29-01-2015 14:22:09 1735 1682 1750 1698 1684 1797 1783 1772 1687 1807 1740 1678 1667 1802 1762 1757 1726 1716 1791 1730 1711 1722 1744 1700 11. Dialysis and Other Extracorporeal Therapies 1814 NK Hase 12. Renal Transplantation 1827 George T John 13. Tubulointerstitial Diseases of the Kidney 1833 Sree B Raju

14. Drug Nephrotoxicity and Renal Dosage Adjustment 1839 Contents Ankur Gupta and Pritam Gupta

Part 20 Neurology

1. Neurological Disorders: Basic Consideration and Clinical Approach 1847 MV Padma Srivastava and RS Wadia 2. Clinical Neurophysiology 1859 J Kalita and UK Misra 3. Neuroimaging 1867 Rakesh K Gupta and Krishan K Jain 4. Epilepsy 1874 Sanjeev V Thomas 5. Disorders of Speech 1890 Apoorva Pauranik 6. Disorders of Cranial Nerves 1900 Sankar Prasad Gorthi and Sundaram Venkatraman 7. Ischaemic Cerebrovascular Diseases 1912 PM Dalal and M Bhattacharjee 8. Haemorrhagic Cerebrovascular Diseases 1926 MV Padma Srivastava and Ajay Garg 9. Cerebrovenous Thrombotic Disorders 1933 D Nagaraja and N Karthik 10. Bacterial Meningitis and Brain Abscess Brothers 1937 Ravindra Kumar Garg and Praveen Kumar Sharma 11. Neurotuberculosis 1944 Shyamal Kumar Das and Debal Laha 12. Neurosyphilis 1954 S Prabhakar and Manish Modi 13. Viral Infections of Central Nervous System 1958 Nadir E Bharucha 14. Slow Virus Infections and Prion Diseases 1966 SK Shankar 15. Fungal and Parasitic Diseases of the Nervous System 1971 Ashok Panagariya and Parul Dubey 16. Raised Intracranial Pressure and Hydrocephalus 1977 Daljit Singh 17. Dementia 1981 PS Mathuranath 18. Extrapyramidal Disorders 1987 Jaypee BS Singhal 19. Cerebellar Disorders 1993 Netravathi M and Pramod Kumar Pal 20. Hyperkinetic Movement Disorders 2013 Mohit Bhatt 21. Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases 2018 BK Bajaj 22. Demyelinating Diseases of Nervous System 2026 Man Mohan Mehndiratta and Prachi Mehndiratta xxxvii

API _ Prelims _ Vol-1 for (TRADE).indd xxxvii 29-01-2015 14:22:09 API _Prelims _Vol-1for(TRADE).indd xxxviii xxxviii API Textbook of Medicine 16. 11. 10. 14. 9. 32. 31. 29. 27. 7. 26. Part 21 Part

17. Supportive Care Supportive inCancer 17. Cancers inthePredisposed Host 15. Cancer Site Primary ofUnknown 13. andSoft Bone Tissue Sarcoma 12. 0 DiseasesofMuscles 30. Disorders ofAutonomic System Nervous 28. Jaypee Intracranial Lesions Space-occupying 25. MetabolicDisorders System ofNervous 24. Nutritionaland Toxic Disorders System oftheNervous 23. Oncology . Tumours oftheGastrointestinal Tract (StomachandOesophagus) 8. . HeadandNeckCancers 6. Principles ofRadiotherapy 5. Principles ofDrug Treatment ofCancer 4. Cancer Screening andPrevention 3. Principles ofCancer BiologyandPathology 2. Developments inOncology 1. MadhuchandaKarandRakesh Roy RajappaandDRaghunadharao Senthil KGovind Babu HemantMalhotra andAshwin Mathur Vinay HDeshmane KantiRoy Mrinal SumitSinghandAtmaRamBansal AKMeenaandSAJabeen LalitKumar andPrabhat SinghMalik AtulSharmaandMPRamPrabhu MBorges Anita LalitKumar andPrabhat SinghMalik PSarat Chandra andPNTandon Vrajesh UdaniandNeeluDesai Avinash K Avinash PP Sudeep Genitourinary Vibhor Gynaecological Paraneoplastic Colorectal KM Compressive Myelopathies Non-compressive SV Garima Peripheral AK Oncological Myasthenia Breast VP GK Head UK Pavithran Khadilkar Bapsy Gangadharan Singh Misra Rath Mohandas Injury Injury Pardasani Cancer Gupta Shukla Deo Deo Cancer Neuropathy Gravis Emergencies Cancers Syndromes Malignancies Myelopathies Brothers 29-01-2015 14:22:09 2173 2202 2206 2120 2125 2197 2191 2180 2167 2164 2113 2041 2134 2107 2150 2094 2090 2073 2065 2147 2143 2131 2034 2184 2086 2055 2157 Part 22 Psychiatric Medicine

1. Introduction and Basic Considerations in Psychiatry 2212 Yatan Pal Singh Balhara and Koushik Sinha Deb 2. Organic Mental Disorders 2222 SK Khandelwal 3. Substance Use Disorders 2229 Contents Debasish Basu 4. Psychosis and Schizophrenia 2236 R Thara and Shiva Prakash Srinivasan 5. Mood Disorders 2241 Yatan Pal Singh Balhara 6. Anxiety Disorders 2247 A Shyam Sundar and YC Janardhan Reddy 7. Somatoform Disorders 2254 Rakesh K Chadda 8. Emergency Psychiatry 2260 Dipesh Bhagabati 9. Sexual Disorders 2266 TS Sathyanarayana Rao and Abhinav Tandon 10. Biological and Somatic Treatment of Psychiatric Disorders 2276 E Mohandas and Rajmohan V 11. Psychotherapies in Mental Health 2284 Manoj K Sharma

Part 23 Pulmonary Medicine

1. Respiratory System: Basic Anatomy and Physiology 2290 SK Chhabra 2. Pulmonary Disorders: A Clinical Approach 2300 Jyotsna M Joshi Brothers 3. Diagnostic Procedures in Pulmonary Disorders 2306 Gautam Ahluwalia and Surendra K Sharma 4. Upper Respiratory Tract Infections 2313 DG Jain 5. Bronchial Asthma 2317 Virendra Singh 6. Chronic Obstructive Pulmonary Disease 2328 Surendra K Sharma 7. Pneumonia 2339 Digambar Behera 8. Suppurative Pleuro-pulmonary Diseases 2352 Sahajal Dhooria and Navneet Singh 9. Pulmonary Tuberculosis 2363 MS Jawahar 10. Fungal Infections of the Lungs 2371 Jaypee Ashok Shah 11. Diff use Interstitial Lung Diseases 2378 Surinder K Jindal 12. Eosinophilic Lung Diseases and Tropical Pulmonary Eosinophilia 2388 VK Vijayan 13. Sarcoidosis 2395 VK Vijayan 14. Sleep-related Breathing Disorders 2403 R Narasimhan and AR Gayathri 15. Deep Venous Thrombosis and Pulmonary Embolism 2408 xxxix Jamshed D Sunavala and Shruti M Tandan

API _ Prelims _ Vol-1 for (TRADE).indd xxxix 29-01-2015 14:22:10 API _Prelims _Vol-1for(TRADE).indd xl API Textbook of Medicine xl

13. 12. 11. 10. 8. 7. 20. 6. 4. 19. Part 25 Part 24 Part

8 Tropical RheumaticDiseases 18. Emergencies inRheumatology 17. Miscellaneous RheumaticDisorders 16. RheumaticManifestations ofSystemic Diseases 15. 4 Mixed Connective Tissue DiseaseandOverlap Syndromes 14. Jaypee Atelectasis Fibrosis andPulmonary 18. andMalignant Benign Tracheobronchial Tumours 17. DiseasesofPleura, Mediastinum,Diaphragm andChest Wall 16. Nutrition Rheumatology . Systemic Lupus Erythematosus 9. . Assessment ofNutritionalStatus 2. Nutrition: BasicConsiderations 1. Arthritides Crystal andOther Gout 5. Low BackPain 3. Soft Tissue RheumatismandRegionalRheumaticPain Syndromes 2. BasicConsiderations ofRheumatology 1. Madhumita PDas Binoy JPaul Shefali Khanna Sharma Shefali Khanna Alakendu GhoshandPradyot Sinhamahapatra Vikas Agarwal Wakhlu andAnupam UmaKumar YNadkar Milind andManishWItolikar SinhaandFaraz Sanjeev AhmedFarooqui URKRaoandSripurnaDeepti Kumar Das Siddharth GhanShyam Pangtey andHemantGopal Prasanta RaghabMohapatra LalitKumar andMPRamPrabhu Aman Aman Debashish G Pradeep The Systemic Antiphospholipid VR AN Pulmonary Sandeep Infl Sjögren’s Spondarthritides Prema SV Rheumatoid Osteoarthritis Ved Rohini Cor Alladi Narsimulu ammatory MuscleDiseases ammatory Madhu Joshi Malaviya Chaturvedi Pulmonale Vasculitides Mohan Sharma Handa Ramachandran Bambery Bambery Singh Sclerosis Syndrome Danda Danda Rehabilitation Arthritis Arthritis Syndrome Brothers 29-01-2015 14:22:10 2579 2564 2574 2568 2560 2549 2545 2534 2522 2513 2483 2458 2539 2492 2447 2454 2584 2478 2469 2463 2438 2428 2589 2525 2417 3. Protein Energy Malnutrition 2593 Piyush Gupta 4. Water-soluble Vitamins 2598 Milind Y Nadkar 5. Fat-soluble Vitamins 2603 Ghan Shyam Pangtey and Moti Lal 6. Minerals, Trace Elements and Antioxidants 2608 Contents M Raghunath and D Sreeramulu 7. Food Allergy and Food Intolerance 2615 UV Mani 8. Eating Disorders 2618 Anupam Prakash 9. Enteral and Parenteral Nutrition Support 2621 Varsha

Part 26 Poisoning and Toxicology

1. Poisoning: Basic Considerations and Epidemiology 2628 Narinder Pal Singh and Gurleen Kaur 2. Aluminium Phosphide Poisoning 2632 Surjit Singh 3. Organophosphorous Poisoning 2634 Surjit Singh 4. Corrosive Poisoning 2637 Rakesh Kochhar 5. Alcohol Poisoning 2640 Pritam Gupta and Ankur Gupta 6. Plant Poisoning 2644 DKS Subrahmanyam and Muktha V 7. Drug Overdose 2649 Narinder Pal Singh Brothers 8. Snake Bite Poisoning 2656 HS Bawaskar 9. Scorpion Sting 2662 HS Bawaskar 10. Fluorosis 2670 D Raja Reddy 11. Lathyrism 2677 UK Misra and J Kalita 12. Epidemic Dropsy 2679 Vivek Suman and Shubha Laxmi Margekar 13. Heavy Metal Poisoning 2681 Praveen Aggarwal 14. Miscellaneous Poisonings 2693 Subhash Varma and Vikas Suri

Part 27 JaypeeEnvironmental Medicine

1. Basic Considerations of Environmental and Occupational Diseases 2704 Randeep Guleria 2. Climate Change: Health and Disease 2707 Anil Gurtoo 3. Air Pollution and Public Health 2713 Anumita R Chowdhury 4. Air-borne Pollutants and Smoke-related Hazards 2719 Rajeev Gupta xli

API _ Prelims _ Vol-1 for (TRADE).indd xli 29-01-2015 14:22:10 API _Prelims _Vol-1for(TRADE).indd xlii

xlii API Textbook of Medicine

11. 10. 9. 7. Index 5.

2. 1. 12. 7. 6. 5. 3. 11. 10. Part 29 Part 28 Part

Jaypee Care of Terminally Ill 14. Law andMedicine 13. Future ofMedicine Miscellaneous . HighAltitude Medicine 8. . Drowning, NearDrowning andSubmersionInjury 5. 6. Electric Shock and Lightning Injury ShockandLightning Injury Electric 6. . NanotechnologyandNanomedicine 4. toSpace Introduction Medicine 3. . Polypharmacy inElderly 4. Geriatric Medicine:An Overview 2. Oral HealthandSystemic Diseases 1. . Tobacco Smoking-related Diseasesand Tobacco Cessation 9. DietinMedicalDiseases 8. Naveet Wig andSourabh Malviya Yudh Singh Dev RomanDutta RDLele Yash Pal Prakash MunjalandAnupam AMuruganathanandYash Pal Munjal Yash Pal MunjalandAditya Prakash Misra andShweta JaspalSSandhu Shenoy Prakash Kothari Jyotirmoy Pal Siddhanta andSattik MEYeolekar andSSukumaran AkshayMunjalandShilpaKhullar AKAgarwal andSumeetSingla RajKumar NShah Siddharth andRameshAggarwal ShridharDwivedi Eff G Environmental AM Radiation Radiation JS Anuj Anuj Aerospace Rajvir R Velu Anil Anil Prabha Robotic Regenerative Futuristic Perioperative Sports Sexual Frailty Vinod Travel Adult Life-style Gerzer Immanuel ects of Extremes of ofExtremes ects Temperature Kulkarni Samuel Chaturvedi Nair Chawla Bhalwar Kumar Immunisation Medicine Syndrome Adhikari Medicine Medicine Surgery Surgery Modifi Medicine Hazards Medicine Medicine Management Disasters cations toPrevent andControl Diseases Brothers 29-01-2015 14:22:10 2757 2728 2752 2825 2746 2738 2731 2861 2868 2846 2840 2783 2778 2774 2766 2834 2829 2818 2771 2854 2805 2790 2800 2787 2725 2762 I–1 Part 16

HIV and AIDS Editors of the Part: Alaka Deshpande and BB Rewari

1. Epidemiology of Human Immunodeficiency Virus Infection 1374 OC Abraham and Susanne A Pulimood 2. HIV Virology and Immunology Including Diagnosis 1376 V Ravi and Anita Desai 3. Pathophysiology and Clinical Features 1380 UL Wagholikar and Alaka Deshpande 4. Antiretroviral Therapy 1386 BB Rewari 5. Drug Resistance 1390 Alaka Deshpande 6. Non-opportunistic Infections 1394 Anil Kumar Tripathi and D Himanshu 7. Opportunistic Infections 1398 Jyoti Wadhwa 8. Non-pharmacologic Interventions and PreventionBrothers 1403 R Sajithkumar

Jaypee 1374 HIV and AIDS PART 16 Nearly 60millionpeople aresuspectedtobeinfected become oneofthegreatest pandemicinhumanhistory. Human immunodeficiency virusinfectionhasevolvedto 3. 2. 1. The majorroutesforHIVtransmissionare: clades (Table 1). are furthersubdivided into groupsandsubtypesor viruses arebroadlyclassifiedintoHIV-1 andHIV-2 and and hasveryclosegeneticsimilaritytoHIV. TheHIV which naturallyinfectsnon-humanprimatesin Africa to manofthesimianimmunodeficiencyvirus(SIV), HIV originatedfromthecross-speciestransmission Molecular studieshaverevealedthepossibilitythat in Medicineforthisdiscovery. and Barre-Sinoussiwereawardedthe2008NobelPrize Health, Bethesda, Maryland, USA). Drs. Montagnier (National Institutesof France) andRobertGallo Francoise Barre-Sinoussi(PasteurInstitute,Paris, AIDS wasdiscovered in 1983by Luc Montagnier, immunodeficiency virus(HIV),theagentthatcaused who weresexually involved with men (MSM).Human first recognisedintheUnitedStates1981amongmen The acquiredimmunodeficiencysyndrome(AIDS)was GLOBAL AIDSSCENARIO INTRODUCTION Type Table 1:Classification of HIV HIV-1 HIV-2

infected mothertoherchild. Peri-partum (vertical) needles, needle-stickinjuries,etc.) HIV (e.g.,bloodtransfusion,sharingofinfected Exposure to already infectedwithHIV. Unprotected sexualintercoursewithapartner Group M (major) non-outlier) N (non-major and O (outlier) 1

Jaypeeblood and blood products infected with (clades) Subtype G, H,J,andK B, C,D, F1, F2, A1, A2,A3, transmission from an HIV-

A4, Epidemiology ofHumanImmunodeficiency Distribution Limited to Africa west Africa west Limited to equatorial Africa west Limited to equatorial in India C mostSubtype prevalent Global (UNAIDS) isgiveninTable 2. epidemic aspertheirProgrammeonHIV/AIDS The UnitedNation’s globalsummaryofthe AIDS programmes. deaths. duetosuccessofpreventionandtreatment the numberofnewHIVinfectionsand AIDS-related the last decade, therehas been asignificant decline in accounts for roughly 50% of Asia’s HIV prevalence. In are theregionsofsub-Saharan Africa and Asia. India 1981. The regions most affected by the HIV epidemic since thetimefirstcasewasreportedfromUSA in and 25millionpeoplehavediedofHIV-related causes, and 7%childrenlessthan 15years. Young adults HIV infectedpeople. Among these,39%arewomen (NACO), inIndiathere arenearly2.09million According totheNational AIDS ControlOrganization the generalpopulation. sexual partnersofdrugusers,andultimatelyentering to ‘bridge’ populations,i.e.,clientsofsexworkersand FSWs andinjectingdrugusers(IDU first amongthemostsusceptiblepopulations,such as where thenewinfectionsarefoundtohaveoccurred HIV epidemicinIndiahasfollowedthe‘type4pattern’, reports oncasesofHIVinfectionfromeverystate. The in Chennai, Tamil Nadu. Subsequently, there have been documented in1986amongfemalesexworkers(FSW) In India,thefirstcasesofHIVinfectionwere BURDEN OFHIVEPIDEMICININDIA 2012 living withHIVin Number ofpeople Table 2: Source: UNAIDS. in 2012 deaths AIDS-related in 2012 Brothers withHIV infected People newly Global S ummary of Epidemic,2012 theAIDS ummary years Children <15 Women Adults Total years Children <15 Adults Total years Children <15 Adults Total OC Abraham andSusanne A Pulimood Virus Infection 3.3 million(3.0–3.7 million) 17.7 million(16.4–19.3 million) 32.1 million(29.1–35.3 million) 35.3 million(32.2–38.8 million) 210,000 (190,000–250,000) 1.4 million(1.2–1.7 million) 1.6 million(1.4–1.9 million) 260,000 (230,000–320,000) 2.0 million(1.7–2.4 million) 2.3 million(1.9–2.7 million) ]), thenspreading

CHAPTER 1 Epidemiology of Human Immunodeficiency Virus Infection 1375 Control

EPIDEMIC

December, 2013. December, rd

Joint United Nations Programme on HIV/AIDS (UNAIDS) Joint United Nations Programme on at http:// Available 2013. AIDS epidemic report on the global www.unaids.org/en/media/unaids/contentassets/documents/ epidemiology/2013/gr2013/UNAIDS_Global_Report_2013_ Accessed on 3 en.pdf. Brothers

SUGGESTED READING NATIONAL RESPONSE TO THE HIV RESPONSE NATIONAL Programme (NACP) was launched in 1992 and the was launched in 1992 and Programme (NACP) of in 2007. The overall goal third phase (NACP-III) and turn round the HIV epidemic NACP-III is to stop 99% next 5 years. Since more than in India over the is free from HIV infection, population of the country’s is on the efforts to prevent highest priority NACP-III’s it seeks to of the disease. Further, further occurrence with care, support and treatment. integrate prevention risk populations with the highest In the third phase, and IDUs) will be of exposure to HIV (FSWs, MSMs and comprehensive given the priority in the prevention to All infected persons will have access management. aims accelerate the treatment. NACP-IV (2012–2017) strengthen the process of epidemic reversal and further epidemic response. 1. The pre-dominant mode of transmission of the disease disease the of transmission of mode pre-dominant The is it while exposure, heterosexual is country the in states. drug use in the north-eastern injecting AIDS of the National The first phase Jaypee Jaypee (15 years to 49 years) account for 86% of the burden the 86% of for account years) 49 to years (15 among HIV prevalence The overall of HIV infection. epidemic past decade, HIV 0.27%. Over the adults is National the national level. a decline at has shown adults living the number of prevalence, or adult HIV has of the total population, with HIV as a proportion an reach to 2000 from points 0.10% over by declined in 2009. estimated 0.31% concentrated among vulnerable HIV epidemic is India’s for HIV infection, the prevalence groups at high risk higher among various high-risk being significantly FSWs and sexually transmitted groups (IDUs, MSMs, than among antenatal clinic disease clinic attendees) attendees. in in India is also heterogeneous The HIV epidemic distribution geographic distribution and the statewise The four ‘high is available on www.racoonline.org. than (HIV prevalence higher prevalence states’ Pradesh, 1% among antenatal women)—Andhra Nadu—account Karnataka, Maharashtra and Tamil population in the for 53% of the total HIV infected Nagaland and Manipur are also considered country. 87 district level, But, at the prevalence states. as high than 1% among districts have HIV prevalence more more than 5% among ANC clinic attendees, and 47 have are in moderate and FSWs. Several of these districts West Chattisgarh, low prevalence states like Bihar, Bengal, Gujarat, etc. 1376 HIV and AIDS PART 16 Retroviridae andsubfamily Human immunodeficiencyvirusesbelongtothefamily in somecountriesincludingIndia. HIV-2 remainsasignificantminorityofHIVinfections HIV-1 isresponsibleformajorityoftheinfections, people werelivingwithHIVattheendof2012.While the globe,35.3million(32.2to38.8million) have diedsincethebeginningofepidemic. Across infected withtheHIVandabout36millionpeople syndrome (AIDS). Almost 75millionpeople havebeen the causativeagentofacquiredimmunedeficiency discovery ofhumanimmunodeficiencyvirus(HIV)— More thanthreedecadeshaveelapsedsincethe HIV-2 and simianimmunodeficiencyvirus(SIV)strains there existsaremarkablycloserelationshipbetween HIV-2. StudiesofHIV-2 genomeshaveshown that to allotherHIV-1 subtypesbutlesssocomparedto subtypes O and N are more distantly related genetically of transmission. Human immunodeficiency virus-1 distribution, biologicalcharacteristicsandmajormodes between subtypes. The subtypes vary in geographical gene sequences that vary by 20% to 50% or more clades designated A toK;thesesubtypeshaveenvelope virus-1 Mcanbefurthercategorisedintosubtypesor and outlier(HIV-1 O)group.Humanimmunodeficiency are, HIV-1 majorgroup(HIV-1 M),HIV-1 new(HIV-1 N) transmissibility. Therearethree groups ofHIV-1, they and molecularcharacteristicsaswelltheextentof of virusdifferingeographicaldistribution,biological recognised inthissubfamilyHIV-1 andHIV-2. Bothtypes shows thesubgroups.Two types ofhumanvirusesare CLASSIFICATION OFHIV INTRODUCTION Table 1:Sub-groups of HIV HIV

2 HIV-2 HIV-1

Jaypee clades Su O N M

b-groups outlier new major A

Lentivirinae.

H clades A

Table 1 K

bilayer, calledtheenvelope. a matrixlayer(p17)thatinturnisenclosedlipid proteins (p9,p7)).Thecapsid(p24)issurroundedby reverse transcriptaseorRT(p66,p51)andnucleocapsid RNA-dependent DNA polymerase[pol],alsocalledthe capsid (p24)together with certainviralenzymes (viral stranded RNA moleculesareembeddedinaprotein the bindingsiteforcellularreceptor(s).Thetwoplus The virion gp120 located on the virus surface contains glycoprotein—gp120 andgp41(HIV-1) orgp36(HIV-2). bilayer withuniformlyarranged72spikesorknobsof measures 120nmindiameterandconsistsofalipid positive strandedribonucleicacid(RNA)virusthat As depictedin India andhasbeensubclassifiedintoclades A toH. from countriesotherthanwestern Africa specially immunodeficiency virusHIV-2 hasalsobeenreported that infectsootymangabeymonkeys(SIVsm).Human the US federal government, the imageisinthepublicdomain) a work of As ofHealthandHumanServices. United States Department ofthe Institutes ofHealth,part imageisawork ofthe National (This virus deficiency ofhuman immuno- thestructure Figure depicting 1:Acartoon repeats (LTRs) ofnucleotidesflankthestructural and of HIV-2 measure10.3kb( The genomeofHIV-1 measuresabout9.8kbwhilethat Genome Organisation HIV STRUCTURE Brothers HIV Virology andImmunology Figure 1,HIVisanenveloped Including Diagnosis Including Figure 2).Longterminal V Ravi and V Ravi Anita Desai

CHAPTER 2 HIV Virology and Immunology Including Diagnosis

Figure 2: The genome of HIV and the genes encoded in a single positive-stranded RNA. Note that both HIV-1 and HIV-2 have similar genetic organisations except the accessory gene vpu is unique for HIV-1 and is replaced by vpx in HIV-2 (This figure is generated by Department of Neurovirology, NIMHANS, is not copyrighted and is in public domain. Hence, no permission is required to use this figure) regulatory genes. Both HIV-1 and HIV-2 have similar making use of CD4 and CCR5 (receptor for RANTES). genetic organisations encoded in a single positive- After attachment to CD4, gp120 is displaced leading stranded RNA. The accessory gene, viral protein to uncovering of domains on the envelope gp41 needed unique (vpu), is unique for HIV-1 and is replaced by for virus cell fusion. Glycoprotein 41 is involved in viral protein x (vpx) in HIV-2. The primary transcript infectivity as well as syncytium formation. of HIV is a full length viral mRNA, which is translated Shortly after the viral capsid enters the cell, the into the gag and pol proteins. The gag gene codes for the enzyme RT releases the single-stranded RNA genome proteins p24, p17, p9 and p7. The pol gene codes for RT, from the attached viral proteins and copies it into a the protease (PR) and the integrase (IN) proteins. The complementary deoxyribonucleic acid (cDNA). The envelope gene codes for the gp120 and gp41 proteins cDNA and its complement form a double-stranded viral which are made from a precursor gp160. One of the DNA that is then transported into the cell nucleus regulatory proteins is tat, a trans activating protein, where it is integrated into the host cell’s genome by the which along with certain cellular proteins, interacts enzyme IN (Figure 3). The integrated DNA provirus with an RNA loop structure formed in the 3’ portion is transcribedBrothers into mRNA, which is then spliced into of the viral LTR and up-regulates HIV replication. smaller pieces during viral replication. These small The other viral regulatory proteins include, regulation of viral protein expression (rev), which is needed for pieces are sent out from the nucleus into the cytoplasm the synthesis of viral proteins, negative factor (nef), where translation into the proteins takes place. The whose actual function remains unclear is believed to final step of the viral cycle, the assembly of new HIV-1 down regulate viral expression the accessory HIV virion, starts at the plasma membrane of the host cell viral gene products and vif, vpr, vpu or vpx appear to where the various structural components assemble to influence events such as assembly and budding, as well produce a mature HIV virion. This cleavage step can be as infectivity involved in the production of infectious inhibited by protease inhibitors. The mature virus has, viruses. thereafter, the ability to infect another cell.

REPLICATION OF HIV IMMUNOLOGY OF HIV INFECTION Human immunodeficiency virus enters the body when The principal impact of HIV infection on the immune an individual comes in contact with infected blood, system is destruction of the CD4 T lymphocytes. semen and/or vaginal secretions. The principal target During primary infection, HIV and HIV infected cells Jaypeereach the lymph nodes and other lymphoid tissues. The site for HIV attachment is the CD4 receptor; however specific chemokine receptors appear to serve as virus rapidly disseminates during this early phase of important secondary cellular receptors for HIV. Human HIV infection. As a result, there is a significant fall immunodeficiency virus-1 strains have been divided in CD4 cells and viral levels may be as high as 106 to into T-tropic (preferring to replicate in T lymphocytes) 107 viral copies/mL. The next stage is down-regulation and M-tropic (macrophages) viruses. The chemokine of viraemia. This occurs along with a robust, intense receptor usage differs for each of these viruses, with immune response by the host (Figure 4). Effective T-tropic viruses making use of CD4 and CXCR4 (or cellular immune response mediated by HIV specific fusin, the receptor for SDF-1) and M-tropic viruses cytotoxic T lymphocytes (CTL) and humoural response 1377 1378 HIV and AIDS PART 16 This periodonanaverage lastsfor8yearsto10years. are unabletointerferewith celltotransmission. viral proteins,buttheantibodies arenotprotective and and specificantibodiesare producedagainstdifferent the asymptomaticstage humoural immunityisintact viral loadduringthelongasymptomaticstage.During in thenumberofCD4cellswithasteadyincrease in continuous virusreplication. A gradualreductionisseen nodes andlymphoidorgansarethesitesforactive and values slightlylowerthanthenormallevels.Thelymph is adropinviraemiaandCD4levelsbounceback to specific antibodiescomesintoplay. As aresult,there mediated bycomplementfixingandneutralising HIV Invariant noFront-Cover Sections, Texts, andnoBack-Cover Texts) any later version publishedby theFree Foundation; Software withno under theterms ofthe GNUFree License, Documentation Version 1.2or (Permission isgranted to copy, distribute thisdocument and/ormodify replication ofHIV Figure 3:Aschematic representation ofthevarioussteps inthe Jaypee even forcommercial purposes,permission) allwithoutasking lowed by law. You can copy, modify, thework, distribute andperform law, includingallrelated rights, andneighbouring al to theextent waiving allofhisorherrightsto thework worldwide undercopyright work withthisdeedhasdedicated thework to thepublicdomainby Universal Public Dedication. Thewhoassociated a person Domain imageismadeavailable undertheCreative Commons CC0(This 1.0 infection Figure events 4:Immune inrelation to natural course ofHIV sample isconsideredpositive forantibodiestoHIV. testing. Only, ifall the threetestsarereactive, or rapid assay using different antigen or principle of found reactive, it is subjected to second and third ELISA immunosorbent assay(ELISA) orrapidtest.Ifitis Initially asampleistestedbyanenzyme-linked immunodeficiency virusinfectioninclinicalsettings. three-tiered strategyisadoptedfordiagnosisofhuman (DAC), GovernmentofIndiaTesting Guidelines,a sample. According totheDepartmentof AIDS Control detection ofantibodiestoHIVinthepatient’s serum over diagnosisofHIVinfectionislargelybasedon the isolation frombloodandtissues.However, theworld acid bypolymerasechainreaction(PCR);and(4)virus (2) antigeninbloodandbodyfluids;(3)viralnucleic detection of:(1)antibodiesinbloodandbodyfluids; Diagnosis ofHIVinfectioncanbeachievedbythe declines further. at thisstageisusually<200cells/µL andprogressively infections set in,which may provefatal. The CD4count immune suppressionandavarietyofopportunistic by fibroustissue.Consequently, thereisprofound Lymphoid tissue,whichistotallydestroyedreplaced p24 antigen,etc.)inperipheralbloodandlymphnodes. increase inallthevirologicalparameters(virusload, The advancedstageofHIVinfectionisdistinguishedby OF HIVINFECTION LABORATORY DIAGNOSIS Brothers -

Samples that are negative in the first and second levels infection. However, its detection has limited of testing are considered negative while samples that diagnostic potential because antigenaemia is CHAPTER 2 are positive in the two tests and negative in the third restricted to two stages of HIV infection early in the are considered equivocal and subjected to Western Blot illness during the latter half of the window period and for confirmation. late in the illness (end stages) when immune collapse has set in.

Detection of HIV-specific Antibodies HIV Virology and Immunology Including Diagnosis Immunoassays for the detection antibodies to HIV-1 Detection of Viral Nucleic Acid were developed in a series of stages, called generations. Detection of HIV nucleic acid in plasma or serum is The first generation assays were very sensitive but used for diagnosis of HIV infection in children aged not specific and the technology was improved by using <18 months (early infant diagnosis-EID) and for recombinant and synthetic peptides as antigens (second estimation of viral loads. It is not recommended by and third generation kits). More recently, fourth DAC as a routine diagnostic procedure to detect generation immunoassays have been developed that HIV infection in other clinical situations. Human detect both antibody and p24 antigen simultaneously. immunodeficiency virus nucleic acid is usually detected The different HIV-1 antibody detection tests available by polymerase chain reaction (PCR). For EID, the DAC currently are ELISA, rapid immunoassays such as HIV recommends the use of a HIV DNA PCR using dried spot tests and other rapid immunochromatography- blood spot specimens. based assays. Antibodies to HIV-2 in clinical samples are detected by ELISA with synthetic gp36 (TM portion SUGGESTED READING of the HIV-2 envelope) antigens. 1. NACO (2007). Guidelines on HIV testing http://www.nacoonline. org/Quick_Links/Publication/Blood_Safety_Lab_Services/ Detection of Viral Antigen in Blood Operational_Technical_guidelines_and_policies/Guidelines_for_ and Body Fluids HIV_test/. Accessed on 15th May, 2014. 2. Zuckerman AJ, Banatvala JE, Griffiths PD,et al. Principles and The p24 antigen of HIV can be detected in the Practice of Clinical Virology. 6th ed. London: Wiley-Blackwell; blood of infected individuals early during acute 2008:Brothers pp. 897-939.

Jaypee

1379 1380 HIV and AIDS PART 16 Figure virusgenes 1:Humanimmunodeficiency thymosin, gp120andneuroleukin,etc.).Anti-HIV antigens resemble human components (e.g., p17 and person-to-person andtime-to-time(inaperson).Some responses tothemdifferfromantigen-to-antigen, Viral componentsareantigenictoman.Antibody the CD4cellandbeginsitslifecycle(Figure3). membranes, the virus is uncoated and released inside or CXCR4. After the fusion of the viral and CD4 cell this stage gp120 binds to the co-receptors like CCR5 and anchors the virus to theCD4cell membrane. At change ingp41,whichunfoldsaspringlikemanner Once gp 120 bindswith CD4, thereis a transformational (Figure 2). determinants (CD)receptors,playapivotalrole (T-cell). TheTlymphocytes,identifiedbycluster both humoral(Bcell)andthecellmediatedimmunity Invasion bypathogenincitesimmuneattackinvolving genes inatypicalvirus. daltons, e.g.,p24,p17,gp120. are allottednumbersaspermolecularweightinmicro- indicated byletters‘p’and‘gp’,respectively,these acid (RNA).Theproteinandtheglycoproteinsare like viralproteins,enzymesandribonucleic viral genes encode for various components of the virus and HIV-2 areidentifiedbytheirunsharedantigens.The specific retrovirus. Two typesofviruses,namely, HIV-1 Human immunodeficiencyvirus(HIV)isahuman- INTRODUCTION Jaypee 3 Figure 1depictsviral Pathophysiology andClinicalFeatures Figure ofCD4inimmunesystem 2:Role autoimmune lesionsinthecourseofHIVdisease. antibodies maycrossreactwithhosttissuestocause Figure 3:Beginning oflife ofHIV cycle Brothers UL Wagholikar and Alaka Deshpande and Alaka UL Wagholikar INVASION OF TARGET CELLS with greater ease and success. Later, it mutates to T tropism and switches on to the most susceptible target. CHAPTER 3 The ‘CD4’ molecules on cells and ‘gp120’ molecules on T tropic strains, with syncytium inducing (SI) capacity HIV have affinity for each other (Figure 3). A chance on targets, are more devastating. contact leads to firm bondage and lays the foundation Other retroviruses can replicate only in cells capable for cell invasion. T-helper lymphocytes (including of multiplication. But HIV has the capacity, albeit immature, mature and derived cells), monocytes, Pathophysiology and Clinical Features limited, of replication, even in terminally differentiated macrophages, dendritic cells (DCs), in epidermis non-dividing macrophages. Viral protein R (p15) makes (Langerhans cells), mucosal surfaces of alimentary and this possible. genital tracts, lymphoid depots and tissues, epithelial cells lining mucosae of the said tracts and microglial Activation status, co-receptor profile and nature are cells of the central nervous system (CNS) carry CD4 significant cell-related factors. In an individual, co- molecules. HIV targets them all. receptor production (quality and quantity) is genetically controlled. Co-receptor produced in excess, may be FACTORS INFLUENCING REPLICATION shed by the cell. Co-receptors floating in the micro- environment around a cell can hinder meeting of gp120 Interplay, between regulatory factors of the virus and and cell-bound co-receptor, thus protect it partially. of the host cell, determines when, in which cell and how Delta-32 chromosomal mutation causes a homozygous much the virus replicates. Virulence, mutations and defect in the gene responsible for expression of CCR5 in tropism of HIV are significant viral factors. HIV-1 is about 1% of population in western European Caucasians more virulent than HIV-2. Group M is most virulent. and their American descendents. M tropic HIV-1 cannot Infections by more virulent strains are more prevalent replicate in them. In individuals with a heterozygous and progress at a faster pace. Arguably, differences in defect, the virus cannot replicate rampantly; in them virulence are related to efficiency of replication. Human the disease progresses slowly. immunodeficiency virus-1 (M) is the most common isolate all over the world. Clade B is the most common EFFECTS OF VIRUS ON CELLS in USA and Europe and Clade E in Thailand. Clade C is emerging as the fastest spreading subtype in India, The effects of HIV virus on host cells can be following Ethiopia and South Africa. Isolates from different cases (Figure 4): of HIV infection (even when of same type, group or 1. The virus is known to kill cells by replicating, clade), are seldom identical, on account of mutations. Brothersbudding from them and harming the cell memory. Mutations are clustered in POL, ENV and regulatory 2. The T4 cells may also get killed indirectly by HIV, genes. Some mutations favour viral replication. by means of a viral protein gp120, which is present Some act the other way. Recently some circulating on the surface of the infected cells. The CD4 recombinant forms (CRF) have also been identified. receptor present on the healthy T4 cell has a strong Cells have an inherent mechanism of protecting them affinity for gp120 and can bind to it and merge with selves against any viral invasion. They produce ‘APOBEC the infected cell. The end result is called syncytium 3G’, a factor which inhibits viral replication. Its effect which cannot survive and all the healthy cells along is counteracted by p23, encoded by the gene VIF. By with the infected cell are eliminated. corollary, ‘VIF negative’ mutants will be impotent. 3. Human immunodeficiency virus can also evoke Strains which bind only with CXCR4 are called X4 normal cellular immune defences opposing the strains. The CXCR4 is present only on T-lymphocytes. infected cells. Thus, X4 strain is ‘T tropic’. Strains with affinity for 4. The free protein may attach itself to the CD4 CCR5 are R5 strains. Since, CCR5 co-receptors are receptor of uninfected cells thus making it seem that predominant on macrophages and monocytes (MM they are infected. This evokes an immune response. series); R5 strain isJaypee ‘M tropic’. Strains with affinity for Interactions between HIV and the host cell are both receptors are ‘dual tropic’. summarised in Table 1. Besides MM series, CCR5 is present on DCs and T-lymphocytes also. So, M tropic strain has a large CD4+ T Lymphocytes extent of target cells. Normally, in the early phase of Infected cells suffer most and by various mechanisms. infection, M tropic strains predominate in viral isolates Even non-infected cells suffer accelerated apoptotic from patients. In the later phases, T tropic strains death (AAD), induced by excess, prolonged activation. predominate. It is likely that M tropic virus, with many Molecular basis of AAD is not clear. Non-infected cells, targets at the portal of entry, establishes infection carrying viral antigens on the surface, are sequestered 1381 1382 HIV and AIDS PART 16 due tocompensatoryproliferation ofprecursorcells. an immediate,proportionate dropintheirbloodcount, phases ofinfection,enormous lossdoesnotreflectas cells canbemorethanthat ofinfectedcells.Intheinitial two millioncellsperday. Sometime lossofnon-infected In activephaseofinfection,CD4+losscanbeup to immune (CMI)responsearethemajordefects. antigen-induced proliferationandcell-mediated may notdie;thesegetfunctionallyimpaired.Deficient lymphocyte (CTL) T-cells. Cellswithlesserviral loads by antiviralIgM/IgGantibodiesandkilledcytotoxic (Adapted from 1988). Oct ScientificAmerican Figure 4:EffectsofHIVvirusonhost cells Jaypee

establish viralreservoirs ingonads,kidneys,genital to manyorgans,including CNS.Tissue macrophages less significant.Migratory monocytestransportHIV Viral replication in thesecellsislessprofoundbutnot Cells ofMMSeriesandDCs explanation ofdropincount. workers accept this asasatisfactory and complete cells becomes increasingly inadequate. Not all research lymphoid precursorcellsandreplenishmentof lost The CD4+countsstartdropping,whenthevirus kills Brothers Table 1: Interactions Between HIV and Host Cells Adaptive Immune Response of the Host CHAPTER 3 Peaceful co-existence of cell and virus In an immunologically normal adult, immune response, When virus is non-replicating, the infected cell is unharmed as in other infections, would be expected in HIV Latent virus retains viability, can start replicating at opportune time infection too. Immune control of any viral replication is Pathogenetic virus-cell relationship (Figure 4) achieved through virus specific CD4+ T-cells, antibody When virus replicates, host cell is always damaged

dependent cellular toxicity and by CTLs. But, in HIV Pathophysiology and Clinical Features Cell may be killed by direct or indirect effects of the virus infection CD4+ T-cells, themselves, are the viral targets. Direct cell death of infected cells: due to enormous replication of virus: Due to the vagaries of HIV antigens, the magnitude By ‘fragmentation’ of cell due to excess ‘budding’ and pattern of antibody response can be unreliable. By ‘lysis’ of cell due to cytotoxic protein components of virus By ‘causing fusion’ of cells (only by ‘X4’ strains of HIV) Antibody levels may be high, but viral neutralisation, (It is also called syncytium inducing (SI) effect of virus) not proportionately so. Moreover, mutant strains can Indirect cell death of infected as well as non-infected cells: escape immune surveillance. Cytotoxic lymphougtes Due to apoptosis are the body’s major effective measure of inhibiting Due to IgM and IgG antibodies and cytotoxic lymphocytes HIV replication. Efficiency of their action determines When viral replication is not sufficient to kill the cell, it causes dysfunction: the future course of events. Initially, in HIV infection, Functional damage these are variably successful but later on these fail. Reduced normal function As infection continues, CTL counts fall, due to AAD. Abnormal function On exhaustion of CD8+ cells, CTL response gets suppressed (immunosuppression). Other reasons for lack of effective immune control of viral replications are mucosa, etc. In transmucosal (rectal/vaginal/oral) magnitude of HIV reservoirs in body, functional defects infections, DCs get infected first. These carry the virus in immunocompetent cells, life-style (intravenous drug on the surfaces of their processes, migrate and present abuse) of patient and his genetic make-up. it to susceptible cells in the regional lymph nodes. Cell- Balance of forces ‘producing and killing HIV’ sets a level to-cell transfer is a more efficient mechanism of cellular of viral load in body. Higher the ‘set point’, worse is the infection than random contact between the free virus prognosis. When CTL response declines, the ‘set point’ and receptors on cell. gets raised. Disease progresses faster. Antiretrovirus When CD4+ counts drop, MM series and DCs act as therapy, aiming at lowering the load, has to be life-long. virus supplying factories. These infected cells show significant functional defects. Their microbicidal Brothers PROGRESS AND CLINICAL STAGES activity is reduced, response to chemotactic agents is OF DISEASE decreased and capacity to present antigens to T-cells is poor. Secretion of useful IL-1 is reduced. These produce The CD4 count in peripheral blood is used as an harmful IL-6. indicator of immune function. It is, however, not a perfect guide. Two percent of the total pool of CD4 cells B-cells is in blood; rest is in tissues. Even a bit of change in the These are not infected, but are functionally affected distribution can bring about a vast change in the count. by viral replication in other cells. The IL-6 and In some studies, CD4 percentage was a more reliable gp41 molecules instigate proliferation of B-cells and indicator than CD4 count. As of today, absolute CD4 synthesis of abnormal immunoglobulins in excess count is used and has served as a useful practical guide. quantity (hypergammaglobulinaemia). The abnormal The CD4 cells are gradually destroyed. As the immunoglobulins form immune-complexes with other immunodeficiency advances, the patient becomes microbial antigens. Circulating immune-complexes can vulnerable to various minor and major opportunistic initiate type III allergicJaypee lesions. infections (OIs) (Table 2). CD8+ Lymphocytes Pathogenesis of CNS Lesions These also are ‘indirectly’ damaged. In the initial phases When HIV cannot cross the blood-brain barrier (BBB), of infection, these produce CTLs, which minimise infected monocytes carry HIV across the BBB. A pre- viral replication by killing infected CD4 lymphocytes existing inflammatory focus in brain attracts HIV and also by producing cytokines, which inhibit viral infected macrophages and facilitates CNS infection. The replication. As infection prolongs, the number of CTLs M tropic strain is the main invader. CNS macrophages tends to fall, due to AAD. In terminal phases, CD8+ and microglial cells pick-up HIV and suffer. Virus and cells get exhausted. antibodies are present in cerebrospinal fluid (CSF). 1383 1384 HIV and AIDS PART 16 survival ofmanyHIV-related malignanciesarerising. has markedlydecreased.However, withprolongationof With antiretroviraltreatment, the incidence of theOIs 4. 3. 2. 1. immune depletion(Figure5). Clinical manifestationsdependontheseverityof Tumours Viral infections mycobacteriosisAtypical Bacterial infections Fungal infections Protozoal andhelminthicinfections Type of lesion Table Defining 2:AIDS Lesions inHIV Infection

cytomegalovirus retinitis, etc. canmanifest. cryptosporidial diarrhoea, disseminated tuberculosis, like neurotoxoplasmosis,fungalmeningitis, advanced immunodeficiency AIDSdefiningOIs Advanced immune depletion CD4<200:With India, re-activationofTBiscommonlyseen. minor opportunisticinfections(OIs)candevelop.In During this stage, many skin manifestations and Intermediate immune depletion: polymyositis, etc.canbeseen. phenomenon like ITP, Guillain-Barre syndrome, stimulation of IgGs, hence a variety of autoimmune more than500.Inthisstage,thereispolyclonal extended periodofclinicallatencywhenCD4is Seroconversion syndrome: It is followed by an behaviour. Asepticmeningitismayalsobeseen. unnoticed unlesspatientgiveshistoryofrisk lymphadenopathy maybeseen.Usually,itgoes mononucleosis like features. Fever, myalgia, presents withflulike syndromeoracuteinfectious seroconversion. Thisseroconversionsyndrome viraemia leadingtohostimmuneresponse,i.e. Acute HIVinfection:Itischaracterisedbyhigh Jaypee The CD4 350–500 Invasive cancerofcervix Primary lymphoma ofbrain B-cell non-Hodgkin’s lymphoma Kaposi’s sarcoma JC polyomavirus disease Varicella-zoster disease simplexdisease Herpes Cytomegalovirus Histoplasmosis Coccidioidomycosis Cryptococcosis Pneumocystis jirovecii pneumonia Candidiasis Salmonellosis Nocardiosis Mycobacterium tuberculosis Toxoplasmosis Cryptosporidiosis/Isosporiasis Disease cells. Itisconceptually acceptable that thelevel escalates thelevelofactivation ofimmunocompetent CTL responseallowsongoingviralreplication,which production ofpro-inflammatory cytokines.Weak even non-infectedimmunocompetent cellsandelevated of CD4+,CD8+, CTL and natural killer cells, AAD of HIV infection,activationleadstoreducedfunction which isfavourabletothehost.Paradoxically, in immunocytes leads to heightening of their performance, of theimmunesystem.Inotherinfections,activation of coincides withtheactivationofallcellularelements Further, inHIVinfection,depletionoftheCD4 pool under shroud. replicate. MechanismofprogressiveT-celldepletion is despite theremarkablecapacityofCD4+cellsto self- destroyed cellsarenotreplenishedatthesamerate, well understood(andaccepted)isthereasonwhy HIV diseasearewellunderstood.Whatisnotequally HIV infection.Mechanismsoflosslymphocytesin Their progressivedepletionistheuniquethemein normal, oncetheantigenisclearedfrombody. but homeostatic control brings the counts back to infections thereareoutburstsofincreaseinnumber, of subsetsinblood/tissues are constant.Inother enormous dailyturnover,theirnumberandproportion control, inhealth/disease,isveryefficient.Despite T-lymphocytes areveryversatile.Theirhomeostatic BrothersWHAT WEDONOTKNOW Uterus Brain Anywhere Anywhere Progressive multi-focal leukoencephalopathy Localised/disseminated Localised/disseminated Pulmonary/intestinal/retinal/CNS Disseminated Disseminated CNS Pneumonia Oesophageal/tracheal/pulmonary Pneumonia/CNS/disseminated Pulmonary/meningeal/disseminated Pulmonary/extrapulmonary Disseminated/extrapulmonary Pneumonia/CNS Enteritis Distribution/Disease CHAPTER 3 Pathophysiology and Clinical Features

Brothers

Figure 5: Detailed correlation between the immune depletion, pathological changes and the clinical manifestations of immune activation (if it could be measured in and there is no immune activation. SIV infected SMM numerical figures) would be a more precise estimate of do not get immunodepleted. Obviously, up its sleeve, the advancement of the disease than the CD4 count. We HIV has secrets, we do not know yet. do not know the causeJaypee and mechanism of HIV-induced widespread, progressive immune activation. SUGGESTED READINGS ‘Sooty mangabeys’ monkeys (SMM) are natural hosts to 1. Lane HC. Pathogenesis of HIV infection: total CD4+ T-cell pool, rimian immunodeficiency virus (SIV). The magnitude immune activation and inflammation. Top HIV Med. 2010;18:2-6. and mechanisms of death of SMM CD4+ cells by SIV 2. Mosier DE. How HIV changes its tropism: evolution and are identical to those of human CD4+ cells by HIV. adaptation. Curr Opin HIV AIDS 2009;4:125-36. However, in infected SMM, CD4+ counts remain normal 3. Robertson M. What we still do not know about AIDS? J Biol; 2009;8:1.

1385 1386 HIV and AIDS PART 16 in India.Considering thelifelongmanagement, one States Food And Drug Administration areavailable Nineteen ofthe26 ARV agents approvedbyUnited is calledpost-exposureprophylaxis (PEP). stick injuryandincases of sexualassaultandrape.It exposure toHIVtoo,asincasesofaccidentalneedle to hernewbornchild.The ARVs canbeusedafter of verticaltransmissionfrominfectedpregnantwomen Antiretroviral drugscanalsobeusedtoreducethe risk reduced transmissibility. functions. The reduction in viral load also leads to plasma virallevelsandrestorationofimmunological goals of ART aremaximalanddurablereductionin of plasma viraemia to <50 copies/mL. The primary with alonghalf-life,evenprolongedsuppression the earlieststagesofacuteHIVinfectionandpersists pool oflatentlyinfectedCD4cellsisestablishedduring HIV infectionfromhumanbody. Thisissobecausea The currentlyavailable ARV drugscannoteradicatethe as Prevention’. has led to development of a new concept of ‘Treatment serodiscordant couplesbyearlyinitiationof ART. This reduction inchancesoftransmissionHIVamong Prevention Trials Network(HPTN)052hasshown96% to a‘chronicmanageableillness’. A recentstudyHIV HIV infectionfrombeinga‘virtualdeathsentence’ have nowtransformedthecommonperceptionabout Successes achievedbyantiretroviraltherapy(ART) the viruswithcurrentlyavailableantiretroviral(ARV). and increasesthelongevity, thoughitcannoteradicate the diseaseprogression, improves thequalityoflife viraemia toundetectablelevels.Treatment slowsdown drugs inhibitthereplicationofHIVandreduce evidence thateffectivecombinationsofantiretroviral (ART). Thereisenoughepidemiologicalandclinical antiretroviral therapy(cART)or therapy (HAART)orsimplyascombination commonly referredtoashighlyactiveantiretroviral from differentgroupsisthecurrentstandardofcare, combination of at least three antiretroviral drugs human immunodeficiencyvirus 1990s beganarevolutioninthemanagementof The adventofantiretroviraldrugsintheearly GOALS OFANTIRETROVIRALTHERAPY INTRODUCTION Jaypee 4 (HIV)infection.The drugs. the virus.The in viralreplicationandthepointswhere ARVs target Figures 1A andB (RT) inhibitorsandprotease(PIs).The mainly byinhibitingtheenzymesreversetranscriptase replication. Mostcommonlyuseddrugstargetthevirus these drugscanactatthefollowingstepsinviral interrupt theprocessofviralreplication.Theoretically, various stages ofreplication HIV inthe body and destroyed eachday. Theantiretroviraldrugsacton At leastonebillionviralparticlesareproducedand in thebodyright from theearly stages of infection. A continuoushighl considerations forHIVmanagement. estimation anddrugresistanceassayareimportant monitoring facilitiessuchasCD4counts,viralload drug-to-drug interactionanddrugresistance,besides repeated viralmutability. Therefore,long-termtoxicity, has tosequence drugs to initiate and sequence treatment. Since, the etc. Theydefinetheoptimum time,parametersand (IAS), Association (BHIVA), International AIDS Society of HealthandHumanServices (DHHS),British HIV such asWorld Health Organization(WHO),Department have beendevelopedbyvariousinternationalagencies Based onthescientificevidence,therapyguidelines Figure 1A:Therapy targets BrothersTHERAPY PRINCIPLES OFANTIRETROVIRAL

National AIDS ControlOrganisation(NACO), Table 1liststheclassesofvarious ARV Antiretroviral Therapy thedrugtherapyinviewofeasyand depictthevariousenzymesinvolved evel ofreplicationHIVtakesplace BB Rewari conditions such as hepatitis B virus (HBV), hepatitis

C virus (HCV) need to be evaluated for proper selection CHAPTER 4 of ARVs considering the efficacy and drug interactions. The guidelines on when to start ART are depicted in Tables 2 and 3.

As regards what ART regimen to start in a treatment Antiretroviral Therapy naïve patient, the principle is to start a combination of at least three agents from different classes of ARV drugs as this gives maximal achievable suppression of HIV replication over a prolonged period of time and reduces the chances of emergence of drug resistant strains. The current national guidelines on various ART Figure 1B: Antiretroviral drugs regimens are depicted in Table 4. drug therapy is lifelong the selection of patients for However, the WHO 2013 ARTguidelines, recommend therapy is based on clinical, immunological and viral use of fixed dose combination (FDC) of tenofovir parameters. Patients’ preparedness for such a prolonged (TDF) with emtricitabine (FTC) or lamivudine [3TC]) therapy and monitoring ensures their adherence. in a single pill as initial regimen for all patients Opportunistic infections (OIs), if any, should be treated unless there are specific indications for other drugs first. Patients should undergo therapy counselling. or contraindication to this regimen. The alternative Along with detailed clinical evaluation, co-morbid regimen includes combination of zidovudine (AZT)

Table 1: Classes of ARV Drugs Nucleoside reverse transcriptase inhibitors Non-nucleoside reverse Protease inhibitors (PIs) Integrase inhibitors (NRTIs) transcriptase inhibitors (NNRTIs) Zidovudine (AZT) Nevirapine (NVP) Atazanavir (ATV) Raltegravir (RAL) Lamivudine (3TC) Efavirenz (EFV) Ritonavir (RTV) Dolutegravir (DTG) Abacavir (ABC) Etravirine (ETR) Lopinavir (LPV) Fusion inhibitor (FI) Didanosine (ddI) Saquinavir (SQV) Emtricitabine (FTC) BrothersDarunavir (DRV) Enfuviritide (ENF) Stavudine (d4T) Indinavir (IDV) CCR 5 co-receptor Zalcitabine (ddC) Nelfinavir (NFV) antagonists Nucleotide reverse transcriptase inhibitors Amprenavir (APV) (NtRTI) Fosamprenavir (FPV) Maraviroc (MVC) Tenofovir (TDF) Tipranavir (TPV)

Table 2: Indications to Start Antiretroviral Therapy (WHO 2013 ART Guidelines) Clinical stage CD4 count value Stage I or II ART if CD4 <500 mm3 Stage III and IV ART regardless of CD4 These guidelines also recommend initiating ART for all patients with HIV TB co-infection, HIV-infected pregnant women and sero-discordant couples regardless of CD count (Guidelines by National AIDS Control Organisation still recommend the cut-off at CD<350. Table 3: Treatment in SpecificJaypee Situations HIV and tuberculosis (start efavirenz-based regimen) Pulmonary and extrapulmonary TB and HIV: Start ART for all patients irrespective of CD4 count (start TB treatment first and start ART as soon as possible after 2 weeks of ATT but definitely within 8 weeks) HIV and pregnancy (Efavirenz not to be prescribed in first trimester) WHO stages I and II: start ART at CD4 <350 cells/mm3 WHO stages III and IV: start ART irrespective of CD4 count All pregnant positive women should be initiated on ART from 14 weeks onwards for prevention of HIV transmission to their infant. Those not eli- gible for ART for their own health may stop ART 1 week after the breastfeeding period is over. 1387 1388 HIV and AIDS PART 16 a quarterlyreviewisrecommended. on amonthlybasis.Oncethepatientisstable ART, should bedoneinitially at 2weeksand then regularly therapy. Clinicalassessmentandadherencemonitoring occur inthefirst3monthsto6ofinitiation (IRIS). Generally, morbidityandmortalityon ART OIs andimmunereconstitutioninflammatorysyndrome issues andtodiagnoseanyclinicalmanifestationslike adverse events, to work with the patient on adherence order toensuretimely diagnosis andmanagement of initial monthsofthetreatmentisveryimportantin Frequent andregularfollow-upespeciallyduringthe nevirapine. (EFV) orcombinationoftenofovirandlamivudinewith with lamivudine,nevirapine(NVP)orefavirenz Long-term Medium-term Short-term Occurrence Table 5: Toxicity of Commonly Used Antiretroviral Drugs Regimen V(a) Regimen V Regimen IV(a) Regimen IV Regimen III(a) Regimen III Regimen II(a) Regimen II Regimen I(a) Regimen I Regimen Table 4:Initial Regimen for ART (NACO ART Guidelines 2012)(likely toberevised soon) MONITORING OFTHERAPY Lipodystrophy lactic acidosis hyperpigmentation,anaemia, Bone marrow suppression, Nausea, vomiting, diarrhoea Zidovudine JaypeeLopinavir/Ritonavir Stavudine +Lamivudine Atazanavir/Ritonavir Stavudine +Lamivudine Lopinavir/Ritonavir Tenofovir +Lamivudine Atazanavir/Ritonavir Tenofovir +Lamivudine + Lopinavir/Ritonavir Zidovudine +Lamivudine + Atazanavir/Ritonavir Zidovudine +Lamivudine Efavirenz Tenofovir +Lamivudine Efavirenz Zidovudine + Lamivudine + Nevirapine Tenofovir +Lamivudine + Nevirapine Zidovudine +Lamivudine ARV drug combinations For patients on regimenVwhodevelop severeatazanavir toxicity Second-line for those whoareonTDFcontaining regimeninthefirst-line ifHb First-line regimenfor all women exposed to sd-NVPinthepast First-line regimenfor patient withHIV/2 withHb<9g/dL infection For patients onregimenIVwhodevelop severeatazanavir toxicity Also for patients onTDFcontaining first-line regimenwhodevelop toxicity to both NVPandEFV Second-line regimenfor those whoareonAZT/d4T containing regimeninthefirstline First-line regimenfor patients withHIV-2 withHb≥9g/dL infection For patients ofregimenIIIwhodevelop severeatazanavir toxicity Also second-line regimenfor those whoareonTDFcontaining firstlineregimenifHb Regimen for patients onAZT containing firstlineregimen, whodevelop toxicity to both NVPandEFV First-line regimenfor pregnant women, withnoexposure to sd-NVPinthepast First-line regimenfor all patients withhepatitis Band/or hepatitis Cco-infection First-line regimenfor patients withHb<9g/dL andonconcomitant ATT First-line regimenfor patients withHb≥9g/dL andonconcomitant ATT First-line regimenfor patients withHb<9g/dL andnot onconcomitant ATT First-line regimenfor patients withHb≥9g/dL andnot onconcomitant ATT Indications dyslipidaemia Lipodystrophy, pancreatitis peripheral neuritis, Lactic acidosis, Nausea, vomiting Stavudine hepatotoxicity rash, Hypersensitivity Nevirapine managed withgoodclinicalmonitoringatalllevels most ofthetoxicity/effectscan be adequatelyco- hepatitis orrashinducedbyco-trimoxazole.However, medications otherthan ARVs, e.g.,isoniazid-induced illness (e.g.,hepatitis A, malaria,etc.) or reactionsto Conside of HIV disease and ART toxicity is very important. in limiting tolife-threateningsideeffectsandaredepicted ranging from low-grade intolerance which may be self- Antiretroviral drugshaveabroadrangeoftoxicities, monitoring forallpatientson ART atleast onceinayear. The 2013WHOguidelinesrecommendviralload requirement formonitoringofimmunologicalresponse. Regular CD4countevery6monthsisminimum Brothers ANTIRETROVIRAL DRUGTOXICITY Table 5. Differentiating between complications rations shouldalsoincludeintercurrent Dyslipidaemia confusion, vividdreams drowsiness, dizziness, Rash, hepatotoxicity, Efavirenz Lipodystrophy hyperuricaemia hypertriglyceridaemia, headache, hyperglycaemia, Weakness/tiredness, nausea or bowel movements, diarrhoea, Abdominal pain,abnormal stools Protease inhibitors <9 g/dL ≥9 g/dL of the healthcare system. As a general principle, mild in presence of rifampicin, but remain at therapeutic toxicity does not require discontinuation of ART or levels. It is recommended to use the standard dose of CHAPTER 4 substitution. Symptomatic treatment may be given. EFV (usually 600 mg/day) in patients receiving EFV Moderate or severe toxicities may require substitution and rifampicin or use rifabutin if patient is on LPV/r with a drug of the same ARV class but with a different based ART. Details on initiation guidelines have toxicity profile. Severe life-threatening toxicity requires already been discussed. discontinuation of all ARV drugs until the patient is Antiretroviral Therapy stabilised and the toxicity is resolved. Human Immunodeficiency Virus and Hepatitis B, Hepatitis C Co-infection Treatment Failure: When to Change and Liver-related morbidity and mortality is very common What to Change in patients on ART. The common cause for liver related deaths is co-infection with hepatitis viruses. All HIV- The adherence to ART is one of the most crucial deter- infected patients should be screened for HBsAg, anti- minants of success of ART on long-term basis. The HBcAb (if possible), HCV-RNA and HCV genotype adherence of 95% or more is crucial for patients to achieve at the baseline. It should be ensured that additional desirable suppression of viral replication. However, baseline investigations like liver function tests (LFTs), even with good adherence levels, resistance occurs to prothrombin time (PT), serum proteins, HBeAg and ARV drugs over a period of time due to viral mutation HBV-DNA are also done. and this requires change of ARV drugs. The virological failure appears first followed by immunological failure 1. Human Immunodeficiency Virus + Hepatitis B which finally leads to clinical failure. It is desirable to virus: switch the entire regimen from first- to second-line as (a) If treatment is not indicated for either infection, soon as virological failure is detected. monitor the patient. (b) If treatment is indicated for HIV, then initiate Table 6 depicts the criteria for suspecting and with TDF+3TC/FTC-based regimen along with confirming treatment failure. EFV. Table 6: Defining Antiretroviral Failure (c) If treatment is indicated only for HBV, pegylated Clinical failure New or recurrent WHO Stage-IV condition, after interferon is recommended. at least 6 months of ART 2. Hepatitis C virus treatment: Hepatitis C virus Immunological Fall of CD4 count to pre-therapy baseline (or infection increases the risk of developing hepatic- failure below); or Brotherstoxicity with ART. With regards to treatment, chronic 50% fall from the on-treatment peak value (if known); or HCV should be treated first if the patient does not Persistent CD4 levels below 100 cells/mm3 qualify for anti-HIV treatment. Patients who qualify for anti-HIV treatment should be first initiated on Virological failure Plasma viral load >1,000 copies/mL ART and when the CD4 rises to more than 350 cells/ The second-line regimen for patients failing on first-line mm3, anti-HCV treatment may be considered. The ART is AZT + 3TC + ATV/r (atazanavir/ritonavir) for treatment of choice for HCV is pegylated interferon those on TDF in first line regimen and TDF+3TC+ATV/r and ribavirin. If the patient is also on anti-HCV for those on AZT or d4T-(stavudine) based regimen in treatment, care should be taken not to administer first-line. a regimen that has AZT or Didanosine (ddI) as they are contraindicated with ribavirin. Human Immunodeficiency Virus/Tuberculosis Co-infection SUGGESTED READING

Initiation of treatment for active tuberculosis (TB) 1. Guidelines for Management of HIV-infected Adults and should always be on priority followed by initiation of Adolescents Including Post-exposure Prophylaxis, NACO. ARV therapy as per the guidelines and should be started Ministry of Health and Family Welfare, May, 2007 (updated Jaypee 2012). Available at http://naco.gov.in/NACO/Quick_Links/ as soon as the patient is stabilised on antituberculosis Publication/Treatment_Care__Support/. treatment (ATT). In HIV-infected patients with TB 2. Panel on Antiretroviral Guidelines for Adults and Adolescents. who are not currently on ART and who are provided Guidelines for the use of antiretroviral agents in HIV-1-infected rifampicin-based anti-TB treatment, initiate ART adults and adolescents. Department of Health and Human th directly with EFV. No lead in dose is required for Services, USA. 27 January, 2012. Available at http://www. th EFV. Nevirapine or PIs should not be administered aidsinfo.nih.gov/guidelines. Accessed on 10 July, 2013. along with rifampicin because of the enzyme-inducing 3. WHO consolidated Guidelines on Antiretroviral Therapy for HIV Infection: Recommendations for a public health approach. effect of rifampicin which renders NVP levels sub- July, 2013. Available at http://www.who.int/hiv/pub/guidelines/ 1389 therapeutical. Efavirenz blood levels are also decreased arv2013/download/en/. 1390 HIV and AIDS PART 16 immunodeficiency virus-1 isolatesareculturedinthe Phenotypic resistanceofHIV isan Phenotypic Assay International AIDS Society(IAS). Nationale deRecherchessurleSIDA with algorithmsoflargedatabaseStanford,Agence are sequenced.Theobservedmutationscompared The variousgenessuchasRTgene,andProtgene Genotypic Assay 2. 1. These mutationsinclude: Secondary/Minor Mutations protease inhibitors(PIs),thetermsareinterchanged. resistance. Theyinhibitthedrugaction.Incaseof These aredirectlyresponsibleforconferringdrug Primary/Major ResistanceMutations ing onanaverageonemutationforeachtranscription. scription ofviralRNA intoDNA iserrorproneintroduc mechanism; thereforewhile replicating, the reversetran Human immunodeficiencyviruslackstheproofreading from achangeinviralgenotype. drug susceptibility’. It isanaltered phenotype resulting inhibitors. Itcanappropriatelybetermedas‘altered viral replicationandsurvivalinthepresenceof can bebroadlydefinedasanychangethatimproves Human immunodeficiencyvirus(HIV)drugresistance which cansurviveinthepresenceofdrugs. survival, themicrobesmutateandselectthosemutants including drugpressureswhichposeathreattotheir selection ofthe‘fittest’.Underadversecircumstances, all organisms follow Darwinian model of continuous main goalsofeverylivingorganism.To achievethem, Self-survival and replicationforpropagation are thetwo DETECTION OFRESISTANCE INTRODUCTION

presence ofprimarymutations. Mutations thatcontributetoresistanceinthe resistant mutations. the rateofviralreplicationdespitepresence Compensatory mutations,whichaidinrestoring Jaypee 5 in vitro (ANRS)and test. Human - - into thegrowingviralDNA chain. prevent theincorporationofnucleosideanalogue viral DNA chain.Mutationsindrug-resistantviruses sensitive viruses resulting in the termination of the incorporation of a nucleoside analogue into drug- Figure 1showthedevelopmentofresistanceby Analogue intoDNA Impairment oftheIncorporation drugs: to nucleosidereversetranscriptaseinhibitors(NRTI) Two distinctmechanismsareinvolvedinHIVresistance cumbersome andtimeconsuming. most commonlyusedmethods.Theprocess is expensive, replication by 50%, i.e., Ic 50 or 90%, i.e., Ic 90, are the concentrations which are required to inhibit virus presence ofserialdilutionsinhibitordrugs.The not have access to a reverse transcriptase that has Adenosine triphosphatein drug-sensitivevirusesdoes the nucleosideanalogue. of adenosinetriphosphate (ATP)-mediated excisionof terminated DNA chain.Figure2 showsthemechanism It isremovaloftheanaloguefromprematurely Pyrophosphorolysis nucleoside analogue Figure 1:Resistance by interference with theincorporation of BrothersMECHANISMS OFDRUGRESISTANCE Drug Resistance Alaka Deshpande

CHAPTER 5 Drug Resistance

Figure 3: Mechanism of resistance to action of non-nucleoside reverse transcriptase inhibitors (NNRTIs) Figure 2: Resistance by ATP-mediated excision of the nucleoside analogue the polymerisation of DNA by reverse transcriptase. In drug-resistant viruses, mutations prevent the binding formed a complex with a nucleoside analogue. Mutations of NNRTIs, allowing DNA polymerisation to proceed that cause resistance to nucleoside analogues, referred normally.Brothers to as thymidine analogue mutations (TAMs), allow ATP to bind reverse transcriptase near the 3’ end Protease Inhibitors (PIs) of viral DNA terminated by the incorporation of a The three-dimensional structure of wild type HIV-1 is nucleoside analogue. Adenosine triphosphatase then shown in Figures 4A and B. The PIs bind to certain excises the analogue from viral DNA, allowing reverse sites and block the protease activity. transcription to proceed normally. Fusion Inhibitors Thymidine Analogue Mutations The fusion inhibitors destabilise the process of binding Mutations at positions 41, 67, 70, 210, 215 and 219 to hydrophobic region HR1, thus blocking the infectivity are referred to as TAMs because they are most often of HIV-1. Viral resistance to fusion inhibitors results selected by zidovudine (ZDV) and stavudine (Stav) from mutations located in a stretch of ten amino acids containing regimens. These mutations occur gradually in HR1. and their order of emergence can vary. Thymidine analogue mutations promote ATP or pyrophosphate Convention for Describing Drug-Resistant mediated removal ofJaypee nucleoside analogue from 3’ end of Mutation terminated DNA strand. Based on the amino acid sequences of RT and Protease, NON-NUCLEOSIDE REVERSE a standard numbering system has been developed in TRANSCRIPTASE INHIBITORS reference to wild type virus (mainly subtype B). For example, a change in genotype from ATG to GTG Figure 3 shows non-nucleoside reverse transcriptase at codon 184 would be reported as a change from inhibitors (NNRTIs) have a strong affinity for a pocket methionine to valine at residue 184 or as M184V. The next to the active site of reverse transcriptase. In drug- resistant mutations to different drugs are listed in sensitive viruses, NNRTIs bind this pocket and block Tables 1 and 2. 1391 1392 HIV and AIDS PART 16 Source: www.iasusa.org/http://hivdb.stanford.edu. ENF Fusion gp41 inhibitors: mutations andATV/rATV DRV/r TPV/r LPV/r FPV andFPV/r SQV andSQV/r NFV IDV andIDV/r Protease inhibitors Drug Table 2:Resistant Mutants toProtease Inhibitors andFusion Inhibitors NVP =Nevirapine; EFV=Efavirenz. ddl =Didanosine; TDF = Tenofovir disoproxil fumarate; NFV=Nelfinavir; 2′,3-dideoxy-3′-thiacytidine; ABC=Abacavir; FTC =Emtricitabine; Azidothymidine; d4T=2′,3-didehydro-2′,3-dideoxythymidine; 3TC = NNRTI =Non-nucleoside inhibitors; AZT reversetranscriptase inhibitors; NtRTI =Nucleotide analogue inhibitors; reversetranscriptase ARV =Antiretroviral; NsRTIs =Nucleoside analogue reversetranscriptase TDF ABC ddI FTC 3TC d4T AZT ARV Table 1:Resistant Mutants toVarious Drugs Figure ofprotease ofaction inhibitors 4AandB:Mechanism andresistance A 65R, 70E 65R, 74V, 115F, 184V 65R, 74V 65R, 184V/I 65R, 184V/I 67N, 70R,41L, 210W, 67N, 70R,41L, 210W, NsRTI/NtRTI Jaypee 215Y/F, 219Q/E 215Y/F, 219Q/E 50L, 84V,50L, 88S 50V, 76V, 54M/L, 84V 33F, 82L/T, 84V 32I, 47V/A, 84A/F/T/S 50V, 84V 48V, 90M 30N, 90M 82A/F/T,46I/L, 84V mutation Major EFV NVP NFV ARV 225H 181I/C, 190S/A, 188L, 100I, 103N,106M,108I, 181C/I, 188C/L/H,190A 100I, 103N, 106A/M, 108I, NNRTI 36D/S, 37V, 38A/M/E, 39R, 40H, 42T, 43D 64I/M/V, 71V/I/T/L, 73C/S/T/A, 82A/T/F/I, 85V, 90M,93L/M 10I/F/V/C, 16E,20R/M/I/T/V, 24I, 32I, 33I/F/V, 36I/L/V, 48V, 46I/L, 53L/Y, 54L/V/M/ T/A, 60E,62V, 11I,32I, 33F, 47V, 50V, 54L/M, 74P, 76V, 84V, 89V 10V, 13V, 20M/R/V, 35G,36I,43T, 47V, 46L, 54A/M/V, 58E,69K, 74P, 83D 10F/I/R/V, 20M/R/V, 24I, 33F, 50V, 46I/L, 54V/L/A/M/T/S, 53L, 63P, 71V/T, 73S,76V, 84V, 90M 10F/I/R/V, 32I,47V, 46I/L, 54L/V/M, 73S,76V, 82A/F/T/S, 90M 10I/R/V, 24I, 54L/V, 62V, 71V/T, 73S,77I,82A/F/T/S, 84V 10F/I, 71V/T, 36I,46I/L, 77I,82A/F/T/S, 84V, 88D/S 101/F/I/R/V, 20M/R, 24I, 32I, 36I,54V, 71V/T, 73S/A, 76V, 77I,90M Minor mutation

B 4. 3. 2. 1. resistant mutationsare: The various factors which are responsible for drug- The HIVmutatesanddevelopsdrugresistance. a continuous selection of the ‘fittest’ virus for survival. genomic sequences.Under the drugpressurethereis mechanism, replicatedvirusesshowchangesinthe copies areproducedperday. Inabsenceofproofreading The HIVreplicationratesareveryhigh. About 20billion Clinical Implications Brothers9. 8. 7. 6. 5.

Drug toxicity Poor adherence Episodic compliancefailure Gastrointestinal intolerance Infection withresistantstrain. Inadequate durationoftherapy Irrational combinations Drug interactions High pillburden

With efficacious antiretroviral (ARV) therapy, the wild type or drug sensitive virus is destroyed. As a result, CHAPTER 5 the viral load in the blood is suppressed to undetectable levels. Suppression to <400 copies/mL is considered as successful therapy. To achieve the same, the therapeutic concentration of the drug has to be maintained in the blood. However, with the factors mentioned above, Drug Resistance the serum concentration fluctuates and may reach suboptimal levels (Figure 5) at which resistant virus flourishes.

Figure 6: Treatment failure and drug resistance: virologic, immunologic and clinical definitions

If therapy is not changed, the number of mutations increase, TAMs accumulate and may cause cross- resistance with reduced susceptibility to other drugs. Undetected virological failure is followed by immunological failure which later on leads to clinical failure (Figure 6). In resource-limited countries, the public health approach may not monitor the viral load as it is expensive. Immunological and clinical failure criteria has shown poor performance in identifying HIV drug resistance in a timely manner. The strategy using public health approach potentially allows for long periods of unrecognisable viral failures during which drug resistant virus can be transmitted. The Brotherstransmitted drug resistance (TDR) is rising. In certain groups it is reported to be 18% in young people.

Figure 5 : Drug levels and growth of resistant virus As the number of new infections with resistant virus (TDR) will increase, it will be a grave challenge to AIDS Emergence of drug resistance can be delayed by control programme. maintaining the therapeutic concentration in the blood Therefore, it is now being advocated to initiate the ART which can be achieved by: early so that suppression of viral load will decrease 1. Rational combination of ARVs the transmissibility. The present policy envisages 2. Adherence to therapy ‘treatment as prevention’. Therapeutic adherence plays 3. Regular monitoring of viral load. a crucial role. The viral load is expected to be suppressed at 6 months after initiation of antiretroviral treatment (ART). SUGGESTED READING Thereafter it may be checked every 6 months. As long 1. Cortex KJ, Maldarelli F. Clinical management of HIV drug as the viral load remains suppressed, the same ARVs resistance. Viruses 2011;3:347-78. are continued. Whenever the viral load increases to a 2. Hamkar R, Mohraz M, Lorestani S, et al. Assessing subtype level of 1,000 copies/mL it indicates virological failure and drug-resistance-associated mutations among antiretroviral- Jaypee treated HIV-infected patients. AIDS 2010;24:S85-91. probably due to emergence of drug resistance. At this 3. Imaz A, Falcó V, Ribera E. Antiretroviral salvage therapy for stage, genotypic assays help in detecting the resistance multiclass drug-resistant HIV-1-infected patients: from clinical patterns and guide the selection of second-line drugs. trials to daily clinical practice. AIDS Rev 2011;13:180-93.

1393 1394 HIV and AIDS PART 16 on extremities. Neurological manifestations are also on extremities.Neurological manifestationsarealso erythematous foundonthe trunk,faceandoccasionally feature andaremainly painless,non-pruriticand Maculopapular rashes are the most common presenting clinical featuresinclude rash andlymphadenopathy. features inthesepatients.Theothercommonly seen Flu-like symptomsarethemostcommonpresenting in Table 1. and theirincidenceinacuteHIVsyndromearegiven to avoid dissemination to other organs. Symptoms However, treatmentinacuteviraemiaisrecommended the useofantiretroviraltherapy(ART)areavailable. presentation. Nodefinitiverecommendations about repeated after 3 months and 6 months of clinical assay (ELISA)-basedtestisusedthenitshould be can beuseful.Iftheenzyme-linkedimmunosorbent namely HIV p24 and HIV ribonucleic acid (RNA) levels linked immunosorbentassay(ELISA)basedtests, period thediagnosiscanbearrivedatbyenzyme- period). Sincetheacutesyndromefallsinwindow patients areseronegativeduringthisphase(window a highdegreeofsuspiciontoreachdiagnosisasthe antibodies. Clinically, atthispointoneneedstohave of 2weeksto4duetheformationHIV self-remitting withresolutionoccurringoveraperiod from otheracuteviralinfections.Thesyndromeis infected personsandisclinicallydifficulttodifferentiate phase ofHIVinfection.Itisseenin50%to90% primary infectionandcorrespondstoseroconversion This syndrome presents after 3 weeks to 6 weeks of are duetothesideeffectsofHAART. recognised entitiesduetothevirus with HIV(PLHIV).Fewoftheseconditionsarewell- problems whichincreasethemorbidityinpeopleliving However, thisbroughttothelimelightmanynon-OI counts, andthus,pronetolessernumberofOIepisodes. to maintainsustainedhigherT-helper cell(orCD4) (HAART), more and more patients have been able availability of highly active antiretroviral therapy immunodeficiency syndrome(AIDS). With the been themainfocusintreatmentofacquired of opportunisticinfections(OIs).Therefore,OIshave virus (HIV)hasbeendefinedprimarilyonthebasis The advancedstageofhumanimmunodeficiency ACUTE HIVSYNDROME Jaypee 6 per sebutothers posterior oropharynxand oesophagus.Theulcersmay or HAART. Aphthous ulcersaregenerallyfoundinthe enteropathy. Aetiologically, thesecanbeduetothevirus may rangefromsimple aphthousulcersto AIDS Non-OI manifestations of gastrointestinal (GI) tract Gastrointestinal Manifestations non-bacterial thromboticendocarditis. hypertrophy, pulmonary arterial hypertension and dysfunction, pericardialeffusion,rightventricular Other findings on echocardiography include diastolic virus cardiomyopathyhaspoorprognosis. counts mostly>200/cumm.Humanimmunodeficiency pro-BNP). Generally, thesepatientshavelowCD4+ serum N-terminal-pro-brainnaturetricpeptide(NT- electrocardiograph, echocardiographyandelevated Diagnosis canbesupportedbychestradiograph, myocardial cellsandisknowntocausemyocarditis. Human immunodeficiencyvirushasbeenisolatedfrom be duetoHIV occurs in5%to7%only. Thecardiacinvolvementmay varies from5%to50%butsymptomaticinvolvement Prevalence ofcardiacinvolvementinHIVdisease Cardiovascular Manifestations following paragraphs: The othersystemicmanifestationsarediscussedinthe Guillain-Barré syndrome(GBS)orperipheralneuropathy. seen whichincludemeningitis,encephalitis,myelopathy,

BrothersNeurological manifestations Thrush Weight loss Hepatosplenomegaly Nausea/Vomiting Headache Diarrhoea Myalgias orarthralgias Rash Pharyngitis Lymphadenopathy Fever Symptoms Table Manifestations 1:Clinical of Acute HIVSyndrome Non-opportunistic Infections Non-opportunistic per seorduetodrugtoxicitiesandOIs. Anil Kumar Tripathi andDHimanshu Incidence (%) 70 70 96 54 32 32 27 74 14 12 12 13 CHAPTER 6 Non-opportunistic Infections 1395

nating nating

, IL-6 and a, IL-6 and

Brothers

Peripheral Neuropathy It can present like acute inflammatory demyeli polyneuropathy resembling Guillain-Barré syndrome. HIV Myelopathy AIDS. Myelopathy is present in 20% patients with is pathologically similar to myelopathy Vacuolar of cord. The histologicaldegeneration subacute combined hallmarks are vacuoles and lipid laden macrophages isspinal cord. It and thoracic prominent in cervical most characterised by insidious onset of leg weakness and gait leg discomfort and paraesthesiae abnormalities. Vague are main sensory symptoms. Bladder and bowel dysfunction is also common. Posterior columns of cord can also be separately involved producing pure sensory myelopathy and pure sensory ataxia. Magnetic resonance of normal. Treatment usually is cord of spinal imaging ART is not much rewarding. myelopathy with macrophages and glial cells in central nervous system. nervous system. cells in central and glial macrophages such as of various cytokines/neurotoxins, Release necrosis factor- (IL)-1β, tumour interleukin responsible for β may be factor (TGF)- tumour growth of neuronal cells. involvement encephalopathy is a slowlyHuman immunodeficiency arecomplaints Typical dementia. subcortical progressive concentration, slowing of reasoning,forgetfulness, poor mild depression and emotionallack of energy drive, and become look apathetic and slow, blunting. Patients Sexual dysfunction is common.socially withdrawn. gait, include impaired Signs of HIV encephalopathy brisk alternating movements, tremor, slowing of rapidly gaze positive Babinski sign, slowed deep tendon reflexes, impairment including incontinencesaccades, sphincter findings,and frontal release signs. Neuropsychological impaired short- such as slowing of psychomotor speed, with problem term memory and mental flexibility, to time, disorientation recalling events in correct order, can occur. place and person and finally mutism is a preferred Magnetic resonance imaging (MRI) It reveals patchy or diffuse, hyperin- imaging modality. of white matter tense and relatively symmetrical lesions fluid Cerebrospinal of leukoencephalopathy. suggestive alternative to exclude (CSF) examination should be done is examination status mental systematic A diagnosis. Quantitative an important part of the examination. to see progressive neuropsychological tests can be done functions. Metabolic disorders, decline in neurological ruled out. depression and anxiety should be optimised. Highly Antiretroviral therapy should be should best be penetrant drugs system central nervous nevirapine used from the list of lamivudine, zidovudine, life is Outlook for prolonged independent and indinavir. guarded. Jaypee Jaypee It is an AIDS defining illness and usually occurs at CD4+ AIDS defining It is an counts >200/cumm. If untreated, 15% to 20% of HIV AIDS-dementia The patients will develop this entity. complex (ADC) or HIV encephalopathy (HIVE) is the term used to describe the advanced neurological involvement. Human immunodeficiency virus infects AIDS-Dementia Complex (HIV Encephalopathy) Neurological diseases due to direct HIV infection occur throughout the course of infection and may be due to basic pathology like inflammation, demyelination or degeneration. Neurological Manifestations Hepatobiliary Manifestations Hepatobiliary Manifestations commonly most is infections HIV in involvement Liver and hepatitis C and due to co-infection with hepatitis B drug reactions to HAART. present in 2% to 9% In India, hepatitis B co-infection is cases. Intravenous cases and hepatitis C in 2% to 3% in co-infection virus C hepatitis have may users drug up to 50% to 90%. (atazanavir) Drugs like nevirapine, protease inhibitors hepatic failure and can cause severe acute hepatitis or acidosis Lactic monitored. properly be should use their mitochondrial DNA syndrome occurs due to impaired inhibitors transcriptase reverse nucleoside by synthesis didanosine (ddI) and (NRTIs) such as zidovudine (AZT), the only curative stavudine. It has high mortality and treatment is liver transplantation. Acquired immunodeficiency syndrome cholangiopathy is a syndrome resembling sclerosing cholangitis with papillary stenosis. Diagnosis is made by endoscopic retrograde cholangiopancreatography (ERCP) and papillotomy can relieve the obstruction. produce dysphagia and severe odynophagia. Several severe odynophagia. dysphagia and produce inflammatory HIV-infected demonstrated studies have aetiological suggesting base of these lesions cells in the the the lesions resemble role. Endoscopically, may be one or infections and (CMV) cytomegalovirus intervening areas. Short-term multiple with normal are effective but relapse rates steroids and thalidomide are high. syndrome enteropathy Acquired immunodeficiency of the virus intestinal involvement is due to direct and blunting, low mitotic figures leading to villous present usually Patients ratio. villous-crypt decreased and weight loss. Stool studies, with chronic diarrhoea be upper GI endoscopy should sigmoidoscopy and/or includes other aetiologies. Treatment done to rule out antimotility agents, dietary fibre supplementation, octreotide and oral rehydration solution. 1396 HIV and AIDS PART 16 deterioration ofrenalfunction, normalsizeofkidneys,no of heavy proteinuria (90% have nephritic range), rapid individuals. Clinicalpresentations ofHIV-AN consist infection occurring in 2% to 10% of HIV infected pathy (HIV-AN) isatruedirect complicationofHIV Human immunodeficiencyvirus-associatednephro- Renal Manifestations present. Histologically follicularhyperplasiaoflymphnodes is at leastmorethan3monthswithoutobviouscause. of twoormoreextrainguinalsitessize>1cm for The conditionisdefinedaslymphnodeenlargement clinical presentationofbodyresponsetoHIVinfection. Persistent generalisedlymphadenopathyisanearly refractory cases. cautiously. Splenectomymaybeneededinrelapsed/ are few. Prednisolone0.5mg/kgto1.0isused Rh(D) areequallyeffectivebutsustainedresponses cumm. Intravenousimmunoglobulin(IVIG)andanti- initiated inpatientshavingplateletcount<20,000/ of megakaryocytes with HIV. Treatment should be and decreasedplateletproductionduetoinfection survival probably by immunological mechanism Thrombocytopenia can be due to decreased platelet be removed. regardless ofthecause.Myelosuppressivedrugsshould can beofuseinincreasingcountsneutrophils indicates advanceddisease.TheG-CSForGM-CSF or therapy-induced. Presence of neutropenia generally severe. Thecauseofneutropaeniacanbeadirecteffect Neutropenia ismostlymildbutsometimesitcanbe anaemia. Zidovudineshouldbereplaced. if itslevelsarelessthanthatexpectedforseverityof well to ART therapy. Erythropoietin is also effective immunodeficiency virus-inducedanaemiamayrespond corpuscular volume of RBCs is increased. Human earlier than othercomponents of bonemarrow. Mean other mainculprit. It canblockerythroid maturation is inappropriatelylow. Drugslikezidovudinearethe associated bonemarrowsuppression.Reticulocytecount Normocyctic normochronicanaemiaisfoundinHIV- Anaemia isthemostcommonhaematologicalfinding. Haematological Manifestations and analgesicscanprovidesymptomaticimprovement. carbamazepine, gabapentin,tricyclicantidepressants multiplex canalsobepresent.Pregabalin, itself or nucleoside analogue drugs. Mononeuritis common type of neuropathywhich can bedueto HIV been documented.Distalsensoryneuropathyismost (CIDP) with relapsing and remitting course has also Chronic inflammatory demyelinating polyneuropathy Jaypee Rheumatological Manifestations once renaldysfunctiondevelops. adjustments orstoppageofdrugshouldbeconsidered necrosis. Patient should be closely monitored and dose and radiocontrastagentscancauseacutetubular non-steroidal anti-inflammatorydrugs(NSAIDs) pentamidine, amphotericin,adefovir, tenofovir, drugs, hypovolaemia,shockandsepsis.Drugslike Acute tubularnecrosiscanresultfromnephrotoxic occur inHIVpatients. disease. Immunoglobulin A (IgA)nephropathycanalso have beeneffectiveinpreventingtheprogressof (ACE) inhibitorsandprednisolonewithtaperingdoses counts <200/cumm. Angiotensin converting enzyme glomerulopathy. MajorityofpatientshaveCD4+T-cell glomerular tuft which is distinctly known as collapsing cases. TheHIV-AN alsoexhibitssclerosisofthewhole (80%) andmesangialproliferationin10%to15% that ofidiopathicfocalsegmentalglomerulosclerosis Kidney biopsyisdiagnostic.Histologysimilarto disease commonlyoccursin6monthsto12months. or minimalincreaseinbloodpressure.End-stagerenal pentamidine and didanosine are main culprits. in thetreatmentofHIV disease. Proteaseinhibitors, Hyperglycaemia canoccur duetovariousdrugsused Endocrine andMetabolic Disorders infilt Histopathological studyofsalivaryglandshows eyes andmassiveenlargementofparotids are common. presumably ofautoimmuneorigin.Drynessmouth, Diffuse infiltrative lymphocytosis syndrome is the presenceofmononeuritismultiplex. pathy orarthritis,unexplainedorganischaemiaand in unexplained multi-systemdisease,myo Vasculitis should beconsideredinthesetting of immunosuppressive drugs. Zidovudine shouldbereplacedfirstbeforestarting from idiopathicpolymyositiscanalsobeseen. toxicity. Inflammatorymyopathyindistinguishable is zidovudine,probablyduetomitochondrial inflammatory. Drugnotoriousforcausingmyopathy Myopathy canbedrug-induced,inflammatoryornon- patients andcanappearatanystageofthedisease. disease. Myopathyoccursin1%to2%ofallHIV polyarticular, mainlyseeninthelaterstagesof simple arthralgiaswhichareintermittent,mildand Brotherscan alsooccur. Butmostcommonlyseenarethe and diffuseinfiltrativelymphocytosissyndrome arthritis andsepticarthritis.Myopathy, vasculitis syndrome, non-specificreactivearthritis,psoriatic Rheumatological manifestationsincludeReiter’s rating lymphocyteswhichareCD8+cells.

CHAPTER 6 Non-opportunistic Infections 1397 ed. rd ; 3 Therapy AIDS et al. et

of HIV medicine. Fundamental of Global Global of Fundamental medicine. HIV of H, Saag HS, Saag H,

ed. IHL Press; 2009; [email protected]; www. ed. IHL st American Academy Academy American HIV Medicine; 1 Brothers D, Masur Raphael Philadelphia: Churchill Livingstone/Elsevier; 2008. Philadelphia: Churchill Livingstone/Elsevier; ihlpress.com.

SUGGESTED READING 1. 2. diarrhoea or fatigue lasting more than 30 days in the more than 30 or fatigue lasting diarrhoea HIV infection. other than of a defined cause absence should weight monitoring assessment and Dietary HIV of management and prevention to Key done. be of infection. is aggressive management wasting Pulmonary Manifestations and manifestations are due to OIs Most of the pulmonary before attributing it to HIV disease. should be ruled out (LIP), non-specific interstitial pneumonitis Lymphocytic (NIP) and increased incidence interstitial pneumonitis are seen as hypertension (PAH) of pulmonary arterial of HIV disease. Lymphocytic the non-OI manifestations and is common in children interstitial pneumonitis It with untreated HIV infection. around 1% of adults and no specific treatment is is generally self-limiting in are given required. In severe cases, glucocorticoids is pneumonia interstitial Non-specific course. short This is ART. with seen in half of all patients untreated Pulmonary therapy. also self-limiting and requires no infection. of HIV 0.5% seen in is hypertension arterial PAH with a median ART in There is no clear benefit of survival of 2 years.

3-hydroxy-3-methyl-glutaryl- Jaypee (FSH) and luteinising hormone

reductase or HMGCR) inhibitors (statins) with diet inhibitors (statins) with diet reductase or HMGCR)

HIV-associated Wasting Disease AIDS defining illness. Centers for It is an definition of HIV- Control and Prevention (CDC) of >10% associated associated wasting is a weight loss fever and chronic with intermittent or constant (LH) in response to GnRH. Magnetic resonance (LH) in response to GnRH. see pituitary gland. imaging of brain should be done to therapy. Management includes hormone replacement and adrenal Hypothyroidism, hyperthyroidism with patients 5% of than Less are rare. dysfunction AIDS have adrenal insufficiency. stimulating hormone severe hypertriglyceridaemia. Hydroxy-methyl-glutaryl Hydroxy-methyl-glutaryl severe hypertriglyceridaemia. CoA reductase (or CoA CoA these exercises should be used to treat modification and can occur and lipoatrophy conditions. Lipohypertrophy and stavudine on long-term with protease inhibitors toxicity is the probable mechanism. use. Mitochondrial Patients patients. HIV in common is Hypogonadism libido, impotence, gynaecomastia present with decreased Production of gonadotrophin-releasing or amenorrhoea. release is abnormal. hormone (GnRH) is decreased or its levels of follicle- Diagnosis is made by low or normal Hypercholesterolaemia is usually seen with protease usually seen with is Hypercholesterolaemia era, high In the HAART and efavirenz. inhibitors levels are cholesterol lipoprotein (HDL) density (LDL) density lipoprotein total and low reduced, concomitant with levels are increased cholesterol 1398 HIV and AIDS PART 16 of itsbiologicalfeatures withprotozoa.Theolder fungus Pneumocystis pneumonia (PCP)iscausedbya mediated immunity. considered to be indicative of a severe defect in cell- one who develops one of the HIV-associated diseases infection andaCD4+T-cell count<200cells/µL orthe syndrome (AIDS)ismadeinapatientwithHIV <200 cells/µL. A diagnosisofacquiredimmunodeficiency HIV infectionoccurinpatientswithCD4+Tcellcounts The moresevereandlife-threateningcomplicationsof replication. alter thenaturalhistoryofHIVvirusandaidinviral atmosphere fortheseinfections;pathogensalso It isnotonlytheHIVviruswhichcreatesafavourable reduced complianceordrugresistance. advanced stagesofHIVinfectionorinpatientswith these infectionscontinue to manifestinpatients with (HAART) hasreducedtheincidenceofOIsseentoday, Even thoughhighlyactiveantiretroviral therapy and mortalityinHIVpatientsthroughouttheworld. (HIV) infection.Theycausesubstantialmorbidity advanced stagesofhumanimmunodeficiency virus manifest in a host with impaired immunity in Opportunistic infections(OIs)aresocalledasthey listed in AIDS surveillancecasedefinition. PNEUMOCYSTIS PNEUMONIA INTRODUCTION Recurrent Salmonellasepticaemia Toxoplasmosis ofthebrain Invasive cervical cancer Kaposi’s sarcoma lymphomaBurkitt’s Mycobacterium avium complex Mycobacterium tuberculosis pneumonia, oroesophagitis simplex:chronicHerpes ulcer(s) (>1month’s duration); orbronchitis, Cytomegalovirus (other thanliver, spleenornodes) Cryptosporidiosis Extrapulmonary cryptococcosis Pneumocystis jirovecii Candidiasis ofbronchi, trachea, lungs oroesophagus Table 1:Conditions Listed Surveillance Definition inAIDS Case 7 Pneumocystis jiroveciiwhichalsosharessome

Jaypee pneumonia Table 1

is showingconditions respiratory failurewhichcarriesapoorerprognosis. analysis mayrevealseverehypoxaemiawithType 1 fine crepitationswithrhonchi. Arterialbloodgas(ABG) Pulmonary examinationmaybenormalorreveal Rarely haemoptysismaybepresent. (95%), fever(80%),weightlossandchestdiscomfort. exertional dyspnoea(95%),non-productivecough symptoms whichusuallyconsistofprogressive course withpresentationafterseveralweeksof Clinical featuresincludeusuallyasubacuteindolent Clinical Features recurrent bacterial pneumonia and high HIV RNA levels. include oralcandidiasis,previousepisodesofPCP, counts lessthan200cells/µL.Otherpredisposingfactors About 90%ofPCP cases occurinpatientswithCD4 all theHIVpositiveadmissions. HIV patientsafter tuberculosis accounting for 13%of PCP was the second commonest pulmonary disease in In astudyconductedbyUdwadia, the distinctspeciesthatinfectshumans. Pneumocystis thatinfectsratsandP. jiroveciirefersto name uptake. Its sensitivity is as high as 100%, but specificity shows anincreaseddiffuse symmetricalpulmonary normal, especiallyinearly stagesofthediseasewhich cells. Galliumscansmay beusedwhenchestX-rayis which typicallydonotform aggregatesofsporesor of 2to8incontrast crushed ping-pongballsandarepresentinaggregates direct immunofluorescent stain.Thecystsresemble silver stainandperiodic-acidSchiff(PAS) stainor usually stainwithtoluidineblue,Gonorimethenamine examination orbronchoalveolarlavage(BAL).Cysts the histologicalconfirmationofcystsinsputum attenuation. Definitive diagnosis is based upon tomography (HRCT) may show patchy ground glass an alternativediagnosis.Highresolutioncomputed very rareanditspresenceshouldraisethedoubtof present withpneumatocoeles.Pleuraleffusionis commonly patchy asymmetric infiltrates may be perihilar infiltratesextendinguptolungbases.Less features apartfromthechestX-raywhichshows Diagnosis maybebasedupontheclassicalclinical Diagnosis Brothers Pneumocystis cariniinowrefersonlytothe Opportunistic Infections Opportunistic Histoplasma orCryptococcus et alfromMumbai, Jyoti Wadhwa may be as low as 20%. Nevertheless, it may be used as Clinical Features an adjunctive test when chest X-ray is normal in initial CHAPTER 7 Symptoms of tuberculosis include fever, productive stages and sputum fails to reveal the organism. cough, shortness of breath, anorexia and weight loss. Treatment In patients with advanced HIV disease, lower lobe, middle lobe and miliary infiltrates Figure( 1) are more Trimethoprim-sulphamethoxazole (TMP-SMX) is common than cavitation. Severe immunodeficiency Opportunistic Infections the recommended treatment and prophylactic agent. (CD4 counts <200 cells/µL) favours extrapulmonary Trimethoprim 15 mg/kg/day to 20 mg/kg/day and SMX tuberculosis development (lymph nodes, meningitis, 75 mg/kg/day to 100 mg/kg/day, given per orally in three gastrointestinal [GI] involvement, etc.) with poor divided doses should be given for 21 days. Patients with formation of granulomas. moderate to severe disease defined by PaO2<70 mmHg or alveolar arterial O2 gradient ≥35 mmHg should receive Diagnosis adjunctive steroids. Prednisolone is given as 40 mg bid for Diagnosis is based on the history, chest radiographs 5 days, then 40 mg/day for 5 days and 20 mg/day for next and acid-fast bacteria (AFB) staining and tissue 11 days. histology of the involved site (lymph node). Nucleic acid amplification tests yield rapid diagnosis of tuberculosis MYCOBACTERIUM TUBERCULOSIS and more sensitive than AFB smear producing positive India is the highest TB-burden country globally results for 50% to 80% of smear negative culture (29.9 million patients), accounting for one-fifth of the positive specimens. global incidence and two-third of the cases in south-east Asia. Each year, 1.9 million new cases of TB occur in the Treatment country, of which about 0.8 million are infectious new Treatment of suspected TB in HIV-infected individuals smear positive pulmonary TB cases. The 2007 survey is the same as for those who are HIV uninfected and on tuberculosis demonstrated that the prevalence of should include an initial intensive phase of four-drug HIV among TB patients varied between 1% and 13.8% combination of isoniazid, rifampin, pyrazinamide among the 15 surveyed districts. and ethambutol followed by maintenance phase with Tuberculosis can occur at any CD4 T lymphocyte two drugs (INH + Rif) for 4 months. The success of (CD4 cell) count, although the risk increases with treatment is greatly enhanced when given as directly progressive immunodeficiency. The estimated annual observedBrothers treatment, short-course (DOTS) though risk of active TB among HIV-infected patients with several studies have shown increased risk of treatment latent tuberculosis infection (LTBI) is 3 to 12 times failure or acquired resistance to rifamycin class when higher than for the general population. Furthermore, given treatment is given less than daily therapy. development of TB increases viral load and the risk Adjunctive corticosteroid therapy increases survival of HIV disease progression and death in TB-HIV for patients with HIV-related TB involving the central co-infected patients. nervous system (CNS) and pericardium.

Jaypee

Figure 1: Chest radiograph and HRCT of chest in a HIV positive patient with miliary tuberculosis 1399 1400 HIV and AIDS PART 16 cells/µL for3monthsto6months. can bediscontinuedwithCD4countsimprovingto>100 of clarithromycin,rifabutinandethambutol.Therapy of MACinsputum,bloodormarrow. Treatment consists may alsooccur. Diagnosisisusuallybydemonstration mottling. Hilarand/ormediastinallymphadenopathy predominantly lowerlobeinvolvementandmiliary abnormalities inonly25%ofthecases.ChestX-rayshows as thatofmycobacterialtuberculosiswithchestX-ray the riskofMACinfection.Clinicalfeaturesaresame tuberculosis conferssomeimmunityanddecreases MAC infection.PriorinfectionwithMycobacterium is littleevidenceforperson-to-persontransmissionof in theenvironment,includingbothsoilandwater. There complex (MAC). Atypical mycobacteriaareubiquitous caused byCryptococcusneoformans . Nearly1million Most oftheHIVassociated cryptococcalinfectionsare M. intracellulare atypical mycobacterialinfectioniswithM.aviumor specially withCD4<50cells/µL.Themostcommon increasing frequencyinpatientswithHIVinfection Infection with atypical mycobacteria is also seen with and possibledrugresistance. prompt aphysiciantoevaluatefortreatmentfailure months oftreatment,failurethistohappenshould Sputum culturesshouldcoverttonegativebyfour patient stopstakingPIduringthecourse. serum levelsofrifabutinwillbeinadequateifthe of thepatient,takingthisregimeisimportantas recommended withPI-based ART. Closemonitoring hence alowerdoseof150mg/dayrifabutinis increase serum concentration of rifabutin, markedly with rifabutinbasedantituberculartherapy. All PIs boosted proteaseinhibitor(PI)needstobegiven HIV strainswithresistancetobothNNRTIs, ritonavir nucleoside reversetranscriptaseinhibitor(NNRTIs)or closely. Ifthepatientisunabletotolerateanyofnon- 2 weeksandplasmaHIVRNA levelsshould bemonitored patients whoareestablishedonrifampinforatleast but thelead-indoseofnevirapineshouldbeomittedfor or earlypregnancy, nevirapine-based ART canbeused, absolutely unable to takeefavirenz due tointolerance nucleoside (tide)analogues.Forpatientswhoare antiretroviral (ARV) regimenofefavirenzplustwo TB diseaseisrifampin-based TB therapywith an The preferredtreatmentregimenforHIV-related 8 weeksto12forallothers. 2 weekswhentheCD4countis<50cells/µL andby For ART-naive patients, ART shouldbestartedwithin HIV-infected personswithTB. Antiretroviral therapy(ART)isrecommendedinall CRYPTOCOCCOSIS Jaypee species—the Mycobacterium avium

agglutination. and byCSFcryptococcalantigendetectionlatex staining with India-ink preparation or CSF culture of lymphadenopathy. Diagnosisismadebydemonstration may showreticulonodularinfiltrates,cavitiesand molluscum contagiosum may be seen. Chest X-ray papulonodular lesions (cryptococcomas) mimicking Skin involvement in theformofraisedumbilicated in theformoflobarconsolidationornodularinfiltrates. Any organmaybeinvolved.Lunginvolvement deficits arelesscommonlyobserved. loss maybeseen.Neckstiffness,photophobiaandfocal and malaise.Personalitychanges,insomnia,memory It usuallypresentswithinsidiousonsetfever, headache Clinical Features <100 cells/µL. counts in patientswhohaveCD4Tlymphocyte(CD4)cell more than600,000deaths.Mostcasesareobserved worldwide everyyearandthediseaseaccountsfor cases ofcryptococcalmeningitisarediagnosed in greymatterandbasal gangliawithperilesional imaging typicallyshows contrastenhancinglesions toxoplasma immunoglobulin (Ig)Gantibody. Cerebral Diagnosis isusuallymade bydemonstrationofanti- Diagnosis sensorium andfever. are headache, focal seizures, focal deficits, altered Most commonclinicalfeaturesoftoxoplasmosis Clinical Features cysts orhandlingcatfaecescontainingoocysts. consumption ofundercookedmeatcontainingtissue of latenttissuecysts.Primaryinfectionoccurs by Cerebral toxoplasmosisusuallyrepresentsreactivation infection and occurs at a CD4 count <200 cells/µL. gondii. Toxoplasmosis is a late complication of HIV Toxoplasmosis is caused by protozoan to ART.response count hasincreasedto>200cells/µL for6monthsin and thenfluconazole200mg/dayuntiltheCD4+ T-cell This isfollowedbyfluconazole400mg/dPOfor8weeks least 2weeksoruntiltheCSFcultureturnsnegative. to 6mg/kg)daily, withflucytosine25mg/kgqidforat (0.7 mg/kg)dailyorliposomalamphotericin(4mg/kg Treatment consistsofintravenousamphotericinB Treatment TOXOPLASMOSIS Brothers Cryptococcus incerebrospinalfluid(CSF)after Toxoplasma oedema. If feasible, CSF polymerase chain reaction Hence indication to treat a patient for hepatitis B in a (PCR) for Toxoplasma gondii may be performed. It has HIV hepatitis B co-infected individual is an indication CHAPTER 7 a sensitivity of 50% and specificity of 96% to 100%. for ART initiation irrespective of the CD4 count. Though considered as gold standard for diagnosis of toxoplasmosis, stereotactic brain biopsy is rarely HEPATITIS C performed and may be considered as an option in

Hepatitis C virus (HCV) is a linear single-stranded Opportunistic Infections patients deteriorating with empirical treatment for RNA positive sense virus; the estimated worldwide toxoplasmosis. prevalence of HCV infection is 2% to 3%. Seven distinct Treatment HCV genotypes have been described though worldwide genotype 1 is the most common. Since HCV does not Treatment consists of sulphadiazine and pyrimethamine replicate via DNA intermediate, it does not integrate with leukovorin as needed for a minimum of 4 weeks to into the host genome. Most cases of hepatitis C are 6 weeks. Alternative therapeutic regimens include TMP acquired through percutaneous exposure while sexual + SMX (5 mg/kg/day to 25 mg/kg/day), clindamycin contact is relatively inefficient mode of transmission. with pyrimethamine; atovaquone plus pyrimethamine; Hepatitis C virus RNA represents the gold standard and azithromycin plus pyrimethamine plus rifabutin. test for HCV diagnosis especially in HIV patients as anti-HCV antibody may be false low or absent in HIV/ Hepatitis B HCV co-infected patients. Human immunodeficiency virus infection is associated with approximately a three-fold increase in the devel- Treatment opment of persistent hepatitis B surface antigenaemia. After acute HCV infection, the likelihood of developing chronic hepatitis is 85% to 90% and is even more Clinical Features progressive and severe in HIV co-infected patients; With acute infection, patient may be asymptomatic hence all HIV/HCV co-infected patients should be or may present with jaundice, fever, right upper considered for treatment for HCV in contrast to HCV quadrant pain, nausea and vomiting. Patients with mono-infected patients. chronic infection may be asymptomatic or may develop Hepatitis C virus genotype should be determined prior jaundice, ascites, coagulopathy or encephalopathy. to treatment initiation as it is an important determinant Rarely, they may present with glomerulonephritis with of responseBrothers to interferon treatment for hepatitis C nephrotic syndrome, arthritis and cutaneous vasculitis (genotype 2>3>1 and 4). Before initiating HCV therapy, (palpable purpura). a patient’s HIV disease should be clinically stable with or without ART. Human immunodeficiency virus/HCV Treatment co-infected patients with CD4 counts <350 cells/µL who are receiving ART, should receive at least 6 months of Treatment is indicated for patients with chronic ART before starting HCV treatment; HCV treatment hepatitis B with persistence of HBsAg for more than six is not routinely recommended in patients with CD4 months and presence of IgG anti-HBc antibody. Anti- counts <200 cells/µL. HBV therapy is indicated for chronic hepatitis B with elevated alanine transaminase (ALT) levels (>2 times The combination of peginterferon-alfa (PegIFN) plus normal) and elevated HBV DNA >2,000 international ribavirin is the recommended treatment for HIV/ units/mL or clinically manifesting as cirrhosis or HCV-co-infected patients (48 weeks for genotype 1 and significant fibrosis on histopathology. 24 weeks for genotype 2 and 3). Two ongoing phase 2 clinical trials of boceprevir or telaprevir plus PegIFN/ For HIV/HBV co-infected individuals, ART must include ribavirin for the treatment of HCV genotype 1 infection two drugs active against HBV, preferably tenofovir in HIV/HCV co-infected patients also demonstrate and emtricitabine,Jaypee regardless of the level of HBV greater efficacy than PegIFN/ribavirin alone. DNA. This reduces the likelihood of development of immune reconstitution inflammatory syndrome (IRIS) CYTOMEGALOVIRUS against hepatitis B. Tenofovir is active against wild type and lamivudine resistant strains of hepatitis B. Usually manifests as cytomegalovirus (CMV) retinitis In case of renal dysfunction, entecavir can replace and is a late complication of HIV infection. It usually tenofovir. Since these drugs are active against HIV manifests at a CD4 count of less than 100 cells/µL. It also, they should not be used alone for the treatment of usually presents as progressive painless loss of vision hepatitis B in a HIV-hepatitis B co-infected individual. though patient may complain of floaters or blurring 1401 1402 HIV and AIDS PART 16 for oesophagealcandidiasis(Table 2). 7 days which should be extended to 14 days to 21days consists oforalfluconazole100mg/dayto200 for with potassiumhydroxide(KOH)stain.Treatment scraped off anddirectly examined under microscope the tonguesurface(Figure2).Theexudatescanbe exudates onhardorsoftpalate,buccalmucosa on Diagnosis isclinicalwithvisualisationofwhitecheesy complain ofburningsensationwithodynophagia. <300 cells/µL.Patientsmaybeasymptomaticor Oral candidiasis usually occurs at a CD4 count valganciclovir. course isfollowedbymaintenancetherapywithoral with relapsedCMVretinitis. A three-weekinduction than either ganciclovir or foscarnet alone in the patient foscarnet hasbeenshowntobeslightlymoreeffective alternative. Combinationtherapywithganciclovirand IV ganciclovir, orIVfoscarnetwithcidofovir as an Therapy forCMVretinitisconsistsoforalvalganciclovir, Treatment showing perivascularhaemorrhageandexudates. of vision.Diagnosisismadeonfundusexamination CANDIDIASIS Syphilis Cryptococcus neoformans (MAC) Mycobacterium avium complex Toxoplasma gondiiencephalitis (PCP) Pneumocystis pneumonia Opportunistic infectionOpportunistic Table 2:CDCGuidelines for Infection Opportunistic Prophylaxis Jaypee days or earlylatent syphilis withinthepast 90 with adiagnosis ofprimary, secondary, For individuals exposed to asexpartner disease for ≥6months withnoevidenceofactive May stop prophylaxis whenCD4>200/µL Prior documented disease for ≥3months May stop prophylaxis whenCD4>100/µL Prior documented disseminated disease CD4 <50/µL for ≥3months May stop prophylaxis whenCD4>200/µL Toxoplasma IgG +vewithCD4<100/µL for ≥3months May stop prophylaxis whenCD4>200/µL Prior episodeofPCP Oropharyngeal candidiasis CD4 <200/µL Indication

3. 2. 1. Figure 2:Oral candidiasisinbuccal mucosa ofanHIVpositive patient SUGGESTED READING Brothers

1 dose 2.4 millionunits IMfor Benzathine penicillinG day PO Fluconazole 200mg/ PO weekly Azithromycin 1,200 mg TMP-SMX DS1tabOD TMP-SMX DS1tabOD Treatment (Iline) org). Government ofIndia,2008(availableathttp://www.nacoonline. and CentralTBDivision.MinistryofHealthFamilyWelfare, The HIV-TB Co-infection. National Su YS, LuJJ,PerngCL, Chang FY. India. TheOpenInfectiousDiseasesJournal2011;5: 51-9. Pradeep Seth.ThesituationofHIV/Mtuberculosisco-infectionin virus infection.JMicrobiolImmunolInfect2008;41:478-82. pneumonia inpatientswithandwithouthumanimmunodeficiency Ceftriaxone 1gIMorIVdaily for 8–10days Or Doxycycline 100mg POBIDfor 14days Itraconazole 200mg/day PO Rifabutin 300mg/day PO 50 mg +leukovorin 25mg) POweekly Dapsone 100mg daily +(pyremethamine Dapsone 100mg OD Alternative treatment AIDS ControlOrganisation Pneumocystis jirovecii 8 Non-pharmacologic Interventions and Prevention CHAPTER 8 R Sajithkumar Non-pharmacologic Interventions and Prevention

INTRODUCTION ABC OF HIV PREVENTION Human immunodeficiency virus (HIV) is one with a long A—Abstinence, B—Being faithful with an uninfected incubation period and florid disease takes a long time partner and C—Condom use, proper and consistent, before manifesting clinically. This, therefore, provides has been the cornerstone of prevention of sexual a unique window period to the healthcare providers transmission of HIV. Such a strategy has been found to and the infected persons to prevent its progression be useful and successful but the first practice is hard to and, in case of disease, to reduce its morbidity. This follow and, in the second, the HIV status of the partner chapter deals with interventions in asymptomatic and has to be known, which at times is difficult. But effective symptomatic persons living with HIV/AIDS (PLWHAs) use of condom is possible and quite useful even when during any stage of HIV disease. Counselling is a the HIV serostatus is not known. This again helps in useful tool right from the stage when the tests are the prevention of many other infections as well. being planned to crisis situations. Nutritional support is another well-recognised intervention. Periodic INTERVENTIONS FOR SPECIAL GROUPS screening and monitoring will assist in early detection and treatment of infections and malignancies. There are Interventions in this category can be divided into two effective preventive vaccines for many infections which main groups: (1) those practising high-risk sexual can be used in PLWHAs. Human immunodeficiency behaviour, and (2) those indulging in IV drug use. virus vaccine development is advancing. Many vaccines are being studied for their potential therapeutic efficacy Reducing Sexual Transmission (delaying progress) even when primary prevention is The high-risk sexual behaviour includes: (1) male not possible. Many alternative therapies (like yoga) homosexuality with multiple partners; (2) multi- have been occasionally reported as useful. partnerBrothers sex; and (3) sex with casual (non-regular) The interventions in HIV disease can be grossly sex partners. All forms of paid sex can be considered classified as follows: dangerous. In heterosexual practice (sex between 1. Interventions for general public opposite sexes), the risk is graded differently as 2. Interventions for vulnerable groups unprotected anal intercourse, unprotected vaginal 3. General interventions amongst PLWHAs intercourse, unprotected oral sex and as protected sex 4. Specific interventions at certain stages. using condoms. The strategies aim at shifting a person from practices of higher risk to safer practices. Condom INTERVENTIONS FOR GENERAL PUBLIC promotion plays a major role in all these modalities. These include information, education and communi- Syndromic Approach to Sexually Transmitted cation (IEC) strategies, e.g., general education, sex Infections (STIs) education, health awareness programmes, etc. They Management is dealt with in Chapter 11 of Part 11. aim at generating knowledge which leads to healthy attitudes, improved behaviour translating to better Reducing Transmission by IV Drug Use practices. The behaviour change must be regularly reinforced with repeatedJaypee attempts. Health issues and Intravenous drug users have been recognised as a safe sex education at various levels have been found to vulnerable group from the early days of the epidemic. be useful in prevention and care. The IEC also generates Sharing syringes used for IV injection particularly was healthy attitudes in infected persons, special categories, an efficient mode of transmission in many populations. i.e., intravenous drug users (IVDUs), men having sex Recreational drug use is illegal in many countries and with men (MSM) and commercial sex-workers (CSWs). unacceptable in many cultures. Even non-injectable Across cultures, this is the most commonly tried drug use makes people vulnerable by modifying their intervention and adjudged the most acceptable. These level of judgement and taking away inhibitions leading will also ensure protection from many other recognised to unsafe sex behaviours. Intravenous drug users 1403 or unrecognised infections as well. have been targeted in many activities across the globe. 1404 HIV and AIDS PART 16 transfusion, etc.,areimportant strategies. blood components,compo nent transfusion,autologous reduce thewindowperiod risk.Supplyofnon-human Use ofbettermethods like antigentests,PCRcan of bloodandproducts shouldbediscouraged. possibility. Curtailingtheunnecessaryandcasualuse during windowperiodremainsasararebutimportant risk oftransmissionthroughasero-negativeblood encouraged andallprofessionaldonorsexcluded. The the globe.Recruitmentofvoluntarylowriskdonors is all unauthorisedbloodcollectionsareneededacross ensured. Licensingofbloodbanksandavoidance of storage anddeliveryarevital.Qualityofscreening is blood is required. Proper screening, donor selection, All healthesta Blood Products Reducing TransmissionbyBloodand successful forthem. context-specific counselling,etc.arestrategiesfound packages, condompromotion,integratedSTIcare, issues arealsoimportant.Specialisedsexeducation partner violence,depressionandotherpsychosocial and havingsexwithfemalepartners.Polydruguse, intercourse, habituationtoinjecting/otherdruguse any pointintime,havingSTIs,propensityforanal sex withmanypartners(regularandnon-regular)at the epidemic.Manyofthemhaveproblemslikehaving been recognisedasvulnerablefromtheearlydaysof Men havingsex Reducing TransmissionamongMSM confiscation anddestructi Supply reductionaimstopreventillegaltrafficking, reduction arethreemajorstrategiesinthisgroup. Supply reduction,demandreductionandharm significantly reduceHIVtransmission. There isevidencefrommulticentricstudiesthatthese promotion ofsafersexpracticesareneededforIVDUs. Community-based rehabilitationpackagesincluding and preventing transmission of many infections. of reducingthesharingneedlesandsyringes which aimatprovidingcleanneedleshavetheobjective injections arebeneficial.Needleexchangeprogrammes in centreswithfacilitiesforsterilisationorsterile adherence to counselling and healthy lifestyles. Walk- will gradually reduce dependency and promote methadone orbuprenorphinesubstitution,etc.These use patternbyscientificmethodslikecounselling, all ages.Rehabilitation and detoxification clinics modify the risksofdruguseareacceptabletoallsocietiesand educational institutions.ProperIECprogrammeson supply lines.Demandreductionispractisedinmany

Jaypeeblishments handleemergencieswhere with men(malehomosexuals)have on ofd rug suppliesand Voluntary CounsellingandTesting(VCT) control societies. financial assistanceandscrutinisedbyth and caresupportactivities.Theyarerunwith activities, behaviourchangecommunicationmonitoring need assessment,counselling,education,peergroup other agenciesacrossthecountry. Theyperform run bynon-governmentalorganisations(NGOs)and children, prisoners,etc.Therearehundredsofprojects like CSWs,MSMs,IVDUs,migrantlabourers,street approach tomarginalised and vulnerablepopulations strategy. Itenvisagescomprehensiveandintegrated of India has adopted targeted intervention as a regular Ministry ofHealthandFamilyWelfare, Government National AIDS (India) Targeted InterventionApproachofNACO It isdealtwithinChapter9ofPart17. Reducing TransmissioninHealthcareSettings increase theviralload.Therefore, PLWHA must clearly herpes orcandidacanactivate immunologiccellsand common infections and self-limited infections) like pathogens. Itiswellknown thatanyinfection(including HIV andmoreimportantly othersexuallytransmitted first orsubsequent infectionwithvarious subtypesof sex. Protectedsexatanystagewillhelpinpreventing partners areinfected,thereisnoneedforprotected well-educated people, there is awrong belief that ifboth partner sex,unprotectedsex)dohelp.Evenamong needle-sharing anddangeroussexpractices(multi- and sterileneedlesmustbeinsisted. Avoidance ofboth issues forPLWHAs atallstages.Theusageofcondoms sex andsaferinjectionpracticesarethemostimportant Avoidance ofhigh-riskbehaviourandchangetosafer Life-style Changes ART careforPLWHAs indesignated ART centrestoo. voluntarily and confidentially. They will start the pre- with high-riskbehaviourtoenterthecareset-up (ICTCs). Thesewillactastheportalofentryforpeople become integratedcounsellingandtestingcentres for serologicaltestingareavailable.Thesecentreshave for pre-/post-testcounsellingandlaboratorytechnician all states.Theservicesofmaleandfemalecounsellors counselling andconfidentialtestingcentres(VCTs) in available tothepublicatlowcostincludesvoluntary One majoractivityaimedatmakingtheabovefacilities HIV-INFECTED PERSONS GENERAL INTERVENTIONSAMONGST Brothers Control Organisation (NACO), e stateAIDS avoid contact with other infectious disease patients, and infection control practices in children. All vaccines pets and other animals, untreated animal products, etc. must be given to the newborn as in any other child. CHAPTER 8 Use of habit forming drugs like alcohol, psychedelic drugs, etc., can lead to chronic systemic ailments, EMERGING AVENUES IN PREVENTIVE hampering the health status. The person should be INTERVENTION cautious when working or travelling to high-risk Human Immunodeficiency Virus Vaccines Non-pharmacologic Interventions and Prevention environments including endemic areas. They should take only boiled water and well-washed vegetables to Even though a vaccine is the most sought after avoid gastrointestinal infections. preventive intervention in any disease, HIV vaccine development must overcome many obstacles like Regular exercise must be promoted. All life-style risk variations in antigen configurations, rapidity of new factors like smoking, sedentary life-style, high intake of mutant evolution, sanctuaries of virus persistence in fatty foods, etc. should be curtailed. Interventions like the body and the difficulty in immunologically active counselling, yoga, etc. can create a good mental make- cells being part of the disease process. However under up for the affected individuals. The International AIDS Vaccine Initiative (IAVI), Nutrition plays a major role. Improvement in nutritional many countries (including India) are enthusiastic about status of all family members of PLWHA gets reflected vaccines. Many candidate materials have been tried in the survival. High-calorie, high-protein diet rich in as prophylactic and therapeutic vaccines. The DNA micronutrients must be encouraged. Early screening for vaccines (either alone or with adjuvants), live vector diabetes, metabolic syndrome and other such ailments based vaccines, subunit vaccines, peptide vaccines, are to be done systematically. virus like particle (VLP) vaccines, fusion competent vaccines, tat toxoid vaccines, inactivated vaccines are Specific Interventions at Certain Stages all being tried. Many of them act through cytotoxic Crisis situations can occur any time in human life. T-cell (CTL) production or by inducing neutralising Issues related to marriage, contraception, conception, antibodies. There are many ethical and psychological childbirth, breastfeeding, death, etc. might make the issues involved in any vaccine trial and, hence, an easy services of a well trained counsellor absolutely essential. solution is not likely to evolve soon. A prophylactic Many vaccinations covered under adult immunisations vaccine is not going to prevent HIV infections in are to be administered in the early years. This will everybody and the importance of all other preventive include vaccination against hepatitis B, Haemophilus strategiesBrothers should not be underestimated. According influenzae type b and pneumococcal vaccines. to a model developed by IAVI, a 30% effective vaccine given to 20% of the risk population could reduce PREVENTION OF MOTHER-TO-CHILD new infections by just 17%. There have been several TRANSMISSION advanced-phased HIV vaccine trials to date that have been conducted in developed and developing countries. Human immunodeficiency virus affects women of the Phase 3 trials involve thousands of high-risk volunteers childbearing age and, hence, pregnancies associated to test the effectiveness of an HIV vaccine on HIV with HIV infection are bound to happen. Proper sero-incidence. Phase 2B trials involve a smaller contraceptive counselling in PLWHAs can prevent a number of volunteers and can determine a preliminary large number of avoidable pregnancies and thus help assessment of efficacy. They can guide future vaccine reduce the number of infected children being born. efforts, but are not enough for licensing or release of In many instances antenatal screening is the first a vaccine. Currently, there is no licensed preventive time a woman is found to be infected. Apart from the (in HIV-negative participants) or therapeutic (in HIV- psychological support needed for the expectant mother, positive participants) HIV vaccine. Despite the recent proper use of antiretrovirals (ARVs) can ensure a encouraging progress from the Thai RV144 trial, we significant reductionJaypee in vertical transmission. The use remain a long way from an affordable, effective vaccine of ARV drugs before labour, reduction in the time spent against HIV. in labour (may be by elective caesarean section), and avoidance of breastfeeding have all been shown to be Microbicides effective. Exclusive formula or breastfeeding is superior Microbicides are chemicals that work in the vagina by to mixed feeding. Routine screening of antenatal women different mechanisms. They are materials that can be (with informed consent and counselling) has become used by a woman without depending on the partner to the standard practice. Infected persons are given full protect her. Some of them are foaming agents, acidifying care and further counselling regarding childrearing gels, entry inhibitors or vaginal defence enhancers. 1405 1406 HIV and AIDS PART 16 have shownapossiblereductionof10%to20%new reduces trauma during penetrative sex. Many models over thepenisisdifferentincircumcisedmanwhich of Langerhans’ cells with receptors for HIV. The skin The innerpartoftheforeskinhasahighernumber HIV transmission if themalepartneriscircumcised. Many reportshavehighlightedthedecreasedriskof Male Circumcision purview ofthisbook. detailed evaluationofmicrobicidesisnotwithinthe being discarded and newer ones are being studied. A statistically proveneffectiveness.Manyagentsare approach thatlooksatthesideeffectsandactual vaginal microbicides has givenway to a more realistic The initialeuphoriaassociatedwiththeintroductionof Jaypee 3. 2. 1. use asthemostimportantintervention. be consideredalongwithproperandconsistentcondom infection rate as well. However, male circumcision is to rate willleadinfuturetoasimilarfallfemale circumcised everyyear. Thereductioninmaleinfection infections incommunitieswhereatleast10%malesare Brothers SUGGESTED READING

2010;52:11-6. interventions ingeneralpractice:HIV/AIDS. Kathleen VFitch,EllenJ Anderson, JaneL Derman EW, WhitesmanS,DreyerM, Cade WT, ReedsDN,MondyKE, disease riskfactors.HIVMed2010;11:379-88. reduces blood pressure in HIV-infected adults with cardiovascular the metabolicsyndrome.AIDS2006;20:1843-50. of alifestylemodificationprograminHIV-infected patientswith et al. Yoga lifestyleintervention et al.Healthylifestyle Hubbard, SA FamPract et al.Effects