Tb clinical

1. Tuberculosis CliniCal Fifth Edition

2. Tuberculosis CliniCal Fifth Edition Edited by Peter D O Davies, MA DM FRCP Professor and Consultant Physician, Liverpool Heart and Chest Hospital Liverpool, UK Stephen B Gordon, MA MD FRCP DTM&H Head of Department, Department of Clinical Sciences, Liverpool School of Tropical Medicine Liverpool, UK Geraint Davies, BM FRCP PhD DTM&H Reader in Infection Pharmacology and Consultant in Infectious Diseases, University of Liverpool, UK

3. CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 2014 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Version Date: 20140117 International Standard Book Number-13: 978-1-4441-5435-1 (eBook - PDF) This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professionals own judgement, their knowledge of the patients medical history, relevant manufacturers instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the drug companies printed instructions, and their websites, before administering any of the drugs recommended in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com

4. To Eleanor Whoso findeth a wife findeth a good thing, Proverbs 18:22 King James Version.

5. vii Foreword.......................................................................................................................................................................................xi Preface.....................................................................................................................................................................................xiii Contributors................................................................................................................................................................................. xv SECTION IBackground Chapter 1 The History of Tuberculosis from Earliest Times to the Development of Drugs....................................................3 Charlotte A. Roberts and Jane E. Buikstra Chapter 2 Epidemiology......................................................................................................................................................... 19 Ted Cohen and Christopher Dye SECTION II Pathology and Immunology Chapter 3 Mycobacterium tuberculosis The Organism....................................................................................................... 39 John M. Grange Chapter 4 Genotyping and Its Implications for Transmission Dynamics and Tuberculosis Control..................................... 55 Laura F. Anderson Chapter 5 Histopathology....................................................................................................................................................... 79 Helen C. Wainwright SECTION III Diagnosis Chapter 6 Immunodiagnosis of Tuberculosis Infection.......................................................................................................... 95 Ajit Lalvani, Manish Pareek and Katrina Pollock Chapter 7 Diagnosis of Tuberculosis.....................................................................................................................................111 Luis E. Cuevas Chapter 8 Tuberculosis Clinical Immunology.......................................................................................................................117 Robert S. Wallis SECTION IV Clinical Aspects Chapter 9 Respiratory Tuberculosis...................................................................................................................................... 129 Aravind Ponnuswamy Contents

6. viii Contents Chapter 10 Tuberculosis of the Central Nervous System....................................................................................................... 151 Guy Thwaites Chapter 11 Non-Respiratory Tuberculosis.............................................................................................................................. 167 Peter Ormerod Chapter 12 Tuberculosis in Childhood................................................................................................................................... 189 Delane Shingadia SECTION V Treatment Chapter 13 Clinical Pharmacology of the Anti-Tuberculosis Drugs......................................................................................209 Abdullah Alsultan and Charles A. Peloquin Chapter 14 Chemotherapy Including Drug-Resistant Therapy.............................................................................................. 229 Geraint Davies Chapter 15 New Developments in Drug Treatment................................................................................................................ 241 Alexander S. Pym Chapter 16 The Surgical Management of Tuberculosis and Its Complications...................................................................... 253 Richard S. Steyn SECTION VI Tuberculosis in Special Situations Chapter 17 Human Immunodeficiency Virus and Tuberculosis Co-Infection....................................................................... 269 Keertan Dheda and Greg Calligaro Chapter 18 Tuberculosis and Migration.................................................................................................................................. 293 Einar Heldal Chapter 19 Tuberculosis and Poverty: A Clinical Perspective...............................................................................................307 S. Bertel Squire Chapter 20 Multi- and Extreme Drug Resistance: The Experience of India...........................................................................317 Zarir F. Udwadia SECTION VII Prevention Chapter 21 Preventive Therapy .............................................................................................................................................. 329 Jean-Pierre Zellweger

7. ixContents Chapter 22 Bacille CalmetteGuerin and Prospects for New Vaccines against Tuberculosis............................................... 339 Helen McShane SECTION VIII Control Chapter 23 Community Approaches to Tuberculosis Treatment............................................................................................ 353 Kwonjune J. Seung and Michael L. Rich Chapter 24 Control of Tuberculosis in Low-Incidence Countries.......................................................................................... 361 Ibrahim Abubakar and Robert Aldridge Chapter 25 Control of Tuberculosis in High-Prevalence Countries....................................................................................... 377 Jayant N. Banavaliker Chapter 26 The Role of the Tuberculosis Nurse Specialist....................................................................................................405 Christine E. Bell SECTION IX Related Aspects Chapter 27 Non-Tuberculous Mycobacteria.............................................................................................................................419 Jakko van Ingen Chapter 28 Animal Tuberculosis.............................................................................................................................................431 Dirk U. Pfeiffer and Leigh A. L. Corner SECTION X Conclusions Conclusions and Future Developments................................................................................................................ 447 Index.......................................................................................................................................................................................... 453

8. xi It is a privilege to have been invited to write this foreword, as it has been to be associated with some of the major land- marks in tuberculosis research. Those of us living in the West who are working on tuberculosis, either in clinical practice or in research, are probably accustomed to hearing people ask, We dont have tuberculosis anymore, do we?. Sadly, that is not true. Tuberculosis remains everyones problem, and in some countries such as the United Kingdom, recent years have seen an increasing number of cases being reported. And, there are new challenges. Recently, an article in the Wall Street Journal described the arrival of a Nepalese man in the United States with extensively drug-resistant tuberculosis (XDR-TB) who had travelled through 13 countries before arriving in southern Texas. The Stop TB Department of the World Health Organization claims to be working with the US Centers for Disease Control to inform affected countries about people who may have been exposed to this man. Tuberculosis is everybodys problem. But we have come a long way, and 1948 was a landmark year. After centuries of unsuccessful attempts, there was at last an effective treatment, an antibiotic against tuberculosis. A model trial of only 107 patients, conducted by the Medical Research Council (MRC) in the United Kingdom, demonstrated the effectiveness of streptomycin in dramatically reducing death rates, resulting in significant radiographic improvement. But the euphoria was short- lived; the majority of patients developed resistance to streptomycin and, after five years, the death rates in both the study arms were more than 50% and almost identical. Fortunately, two other drugs, isoniazid and para- aminosalicylic acid (PAS), were discovered soon after the discovery of streptomycin; isoniazid remains one of the most effective anti-tuberculosis drugs, and it is inexpensive. PAS and isoniazid supplemented by streptomycin became the standard treatment in the developed world, although in the Third World, thiacetazone replaced PAS as an inexpensive alternative. By the mid-1960s, these two regimens, given for a mini- mum of 18 months, had become the standard modes of treatment worldwide. Both treatments were highly effective in controlled trial conditions, although results in routine practice were a different matter, particularly in Africa. A sur- vey in Kenya reported that only 24% of patients collected 12 months supply of their drugs. Eighteen months was clearly much too long a period to expect good adherence. Around the time I joined Wallace Foxs unit in the mid- 1960s, a new drug appeared that was to lead to the second major landmark in treatment rifampicin. It had both bac- tericidal and sterilising activity and offered the prospect of dramatic shortening of treatment duration. The first and the second East African short-course trials demonstrated that asix-month regimen based on rifampicin and isoniazid was even more effective than the standard 18-month regimen, with relapse rates of less than 3%. Short-course chemotherapy had arrived. Could the same regimen be shortened even further to four months? Unfortunately, the answer was no. Rifampicin was far too expensive for use where it was most needed, and many trials were conducted to assess regimens with only one or two months of rifampicin. But, shorter durations of rifampicin required longer durations of other drugs. In 1993, the World Health Organization went on to recommend an alternative an eight-month regimen based initially on isoniazid and thiacetazone and, subsequently, in 2003, on isoniazid and ethambutol. In 1979, Professor Archie Cochrane opined that TB chemotherapy had the best evidence base of any disease. Unfortunately, that can no longer be said to be true. In 2004, the International Union Against Tuberculosis and Lung Disease and the MRC Clinical Trials Unit published the results of a comparison of the eight-month isoniazid/ethambutol-based regimen and the six-month rifampicin/isoniazid gold standard regimen and found that WHO had been rec- ommending an inferior treatment; this subsequently led to a change in recommendations in 2010 but not before many patients had received sub-standard treatment. There remain some important gaps in our knowledge; two of the most significant challenges we face are the problems associated with treating the large number of HIV co-infected patients and the increasing problem of multidrug-resistant tuberculosis (MDR-TB) for which there is a serious lack of evidence-based guidance. There have been no phase III trials in MDR-TB. The past 10 years have seen an encouraging investment in research into new drugs, vaccines and diagnostics, and there are prospects in the coming decade for significant advances to be made. Six months of treatment for drug-sensitive disease and up to 24 months for drug-resistant disease are much too long; this is evidenced by the poor results obtained in routine treatment in South Africa where favourable outcomes for patients with drug-sensitive disease are well below the 85% target; results for MDR-TB patients co-infected with HIV are less than 50%. There have already been promising advances in diagnostics, offering the prospect of earlier identification and treatment of active disease in suspects that in turn should reduce the infective pool of patients in the community. In the mean- time, this latest edition of Clinical Tuberculosis provides an excellent tool for those working to treat and ultimately defeat the old enemy, covering all aspects from pathology through to diagnosis, treatment, control and prevention. Andrew Nunn MRC Clinical Trials Unit London Foreword

9. xiii The past 20 years have been the most exciting in the long history of tuberculosis (TB) since the introduction of streptomycin to cure the disease. That is how it was long ago (1992) till a letter arrived on my desk from Chapman and Hall asking me to consider launching a new textbook on TB. At that time, there was not a single up-to-date, interna- tionally accepted textbook on TB. Perhaps, it was because, at that point in time, of the general impression all over that the final conquest of TB was happening for the past 10 years. How wrong it was. First, there was ignorance of what was going on in the developing world, and second, the advent of HIV was bringing in a new era of TB. In 1986, the United States realised that it had a problem on hand, as the number of TB cases started to increase once again after more than a century of steady decline. Then, the world slowly began to realise the fact that TB was far from conquered. Unfortunately, almost all the expertise and scientific progress in fighting the disease had been lost. Nowhere was this more apparent than in the United Kingdom where the Medical Research Councils Research Units for TB had been closed. As I wrote in the preface to the first edition, If one wished to find a symbol of the way the developed world has turned its back on the problems of disease in the developing world, then this closure would perhaps be the most poignant. In my search for expertise to write the chapters for the first edition, I scoured the seven seas and the continents. Fortunately, there was still just about enough international expertise left to reawaken the need to drive science in the direction required to re-engage with the problem. This was mainly provided by the International Union against TB which had maintained its scientific integrity and mission against this disease when the rest of the world had given up the fight. There was also just about enough political will, particularly in the United States, to fund such new developments. In fact, a new army of TB workers has been trained and put into action over the past two decades. A sign of this is an adver- tisement for the Stop TB Partnership which was published in the London Times on World TB day (24 March) 2010. Itlists 34 different member organisations. These vary from the two UK-based TB charities, TB Alert and Target TB, through professional bodies, such as the British Thoracic Society and the Royal Colleges of Nursing and General Practitioners, to companies manufacturing and marketing TB drugs, such as Glaxo SmithKline and Genus Pharma. The newly formed All Party Parliamentary Group on tuberculosis is active in bringing the problem of TB into the political forum. TB advocacy groups spurred on by current and former patients are spear- heading the drive for funding and awareness. Unfortunately, the most recent news on the battle against TB is not encouraging. The world economic downturn since 2008 has had a negative impact in the fight against tubercle bacillus. Of late, the Global Fund against AIDS, TB and malaria has not received funding. Many of the Millennium Goals for world health are unlikely to be met by the target year of 2015. It has taken 15 years of very hard work and intense struggle for TB Alert, a relatively young, UK-based TB charity, to achieve a seven-figure annual turnover. Even the English membership of the International Union against Tuberculosis and Lung Disease (IUATLD) has been lost due to non-payment of the constituent member fee. However, as I compile the fifth edition of Clinical Tuberculosis, on the kind request of the publishers, I can virtually cover all the topics required for the book from my own city of Liverpool, as there has been such a rekindling of interest in TB. A well-known and respected colleague said to me at the time I was tackling the first edition, We are living in interesting times. Investment in new diagnostics means that we can now identify and speciate the organism almost within hours of the smear-positive sputum specimen arriving at the lab, and sensitivities to the essential drugs do not take much longer. In general clinical settings, still newer techniques that will give out results in not more than two hours are about to be rolled out. The new interferon gamma release assay (IGRA) blood tests look much more promising than the centenarian tuberculin skin test. We are also on the cusp of a new raft of drug regimens that could probably reduce the length of treatment for the fully sensitive organism to four months, and genuine, new drugs give us hope of much better cure rates in multidrug-resistant (MDR) and extremely drug-resistant TB (XDRTB). We will have to wait longer for a new vaccine, but a number of promising vaccines are in phase I and phase II trials at the moment. All these topics are addressed in the fifth edition. Many wonder in this age of electronic reading and instant updates as to whether there is a place for the traditional textbook. I believe there is. First, although electronic readers have their place, many readers still prefer the reliability and feel of the paper book. Second, in the far-flung parts of developing countries, power supply to read an electronic book may not be easily available. Third, there is a need to keep all aspects of practical clinical information in a single volume for easier access and as a convenient source for those engaged at the coal face of the battle against TB. But for the first time, this edition is also available in electronic format as well. Similar to the previous editions, we have tried to keep the book as concise but as comprehensive as possible. Someofthe fourth edition chapters covering general policy rather than clinical practicalities have been omitted. Authors had been asked to write chapters of the length which can be read comfortably at a sitting no more than 45 minutes to an hour. Preface

10. xiv Preface We have reduced the overall chapter numbers to cut costs. In number, they are now very similar to the first edition,which has been by far the most successful of all editions, going to three print runs in all. The overall structure of the book will be familiar to readers of previous editions. History and epidemiology is followed by the laboratory disciplines including diagnostic tests. These are followed by the clinical sections and treatment chapters. The section on TB in special situations has been expanded. Along with the regular chapter on TB and immigration, and the relatively new chapter on TB and poverty, we have added a chapter on the problem of drug resistance in India, with particular reference to the new extreme forms of drug resistance where virtually no antibiotics are effective. Prevention remains focused on preventive therapy and vaccines. Control is again divided into the developed and developing worlds, as resources for this aspect of TB are so different. Environmental mycobacteria has an exhaustive chapter, as the problem has become increasingly serious in the developed world, and no book on human TB would be complete without a reference to the other living beings with whom we share our planet and our diseases the rest of the animal kingdom. The very recent, controversial badger culling in the UnitedKingdom is receiving special attention. All topics have received a complete rewrite, sometimes with previous authorship but also by new authors. Of the 30 or so authors who contributed to the first edition, only 2 remain in the fifth edition perhaps symbolic of the new army of workers who are carrying the torch in the fight against TB. It is for this very reason that I have involved two much younger colleagues for the fifth edition. Should there be a call for subsequent editions, as I hope there will be, I can pass the baton on to them knowing that it is in safe hands. The past 20 years may have been the most interesting in terms of developments in combating the disease since the discovery of specific antibiotics over 60 years ago, but I do believe the next 20 will be all the more exciting. With the development of new drugs and drug regimens, new diagnostic technology made available to the poorest nations and new vaccines, we have a realistic chance of eliminating TB from the human race within the next 50 years, but to do so we will need political will, funds and determination. In the conclusions chapter to the first edition, I had made a few rash predications. It is interesting to introspect 20 years later and see how wrong or right they were. First the epidemiology: Tuberculosis is likely to increase for the next decade and further due to the impact of HIV. According to WHO, case rates peaked at about 2005, and case numbers peaked some two or three years later: right so far. But, I had predicted an HIV epidemic in Asia of the mag- nitude that we were then experiencing in Africa. I am happy that I have been proved wrong on that score. On treatment front I wrote, The cost of drugs should not be a problem. Thanks to the component of DOTS and the Green Light Committee, drugs are now available free of cost to the poorest countries. There has been a real reduction in case fatalities, and the aim of 85% cure rates is making an impact on disease rates. The co-ordination of disease control at a local level, I wrote about is indeed taking place through the DOTS programme. Right again. What I failed to predict completely is the problem of drug resistance which would emerge as a result of more people coming under the umbrella of drug treatment. This now poses a very real threat to disease control worldwide and promises to reverse the effect treatment has had on reducing mortality unless prop- erly dealt with. The call for more TB workers has indeed been answered, not just in the developed countries but also across the world. New drugs, new diagnostic techniques and new vaccines are very much evident and are undergoing trials. The call for new methods of sensitivity testing are being heeded but not the bioilluminescence technique I alluded to. It is in the area of diagnostics that the real advances have been made, and the implementation of molecular methods aided by sequencing of the genome of the bacteria has given us by far the fastest results in the battle against TB; not fore- seen by me at all at the time, probably reflecting my clinically blinkered and relatively unscientific upbringing. So, about half right which is about what most psepholo- gists seem to score. The future is likely to bring several new drugs and drug regimens into use even within the next five years, and molecular methods of diagnosis and sensitivity testing are likely to be improved over the same time span so that smear-negative- and extra-pulmonary disease can be diagnosed more easily. Because of the nature of the bacteria and the need for assessment of protective efficacy of new vaccines over time, development of a new vaccine is likely to take considerably longer, perhaps another 20 years, time enough to see a big reduction in TB cases for the next generation of TB workers, but not mine. As the case numbers of TB undergo a satisfactory decline, there is a danger that the world may take its eye off the ball and turn away as happened some 30 years ago. Then, as now, we had the opportunity to reduce the disease to negligible levels but failed to do so. As the TB advocates are now saying, even one death from TB is too many. With at least a million and a half deaths in the world from TB, we still have a long way to go. Yet, it can be done within the lifetimes of the younger adults now fighting the disease. When the Millennium Goals were announced in 2000, special funding was earmarked for HIV/AIDS, TB and malaria. Ironically, TB is the one which has been given the least pub- licity and funding. I have little doubt that we could virtually eliminate TB within half a century, but the indifference of the political class in this regard will probably ensure that it will be the last of the Big Three Infectious Diseases to be conquered. Peter Davies Liverpool January 2014

11. xv Ibrahim Abubakar, PhD FFPH FRCP Centre for Infectious Disease Epidemiology Research Department of Infection and Population Health University College London London, UK Medical Research Council Clinical Trials Unit University College London London, UK TB Section, Respiratory Diseases Department Public Health England London, UK Robert Aldridge, MSc MBBS MFPH Centre for Infectious Disease Epidemiology Research Department of Infection and Population Health University College London London, UK TB Section, Respiratory Diseases Department Public Health England London, UK Abdullah Alsultan, PHARM D Department of Pharmacotherapy andTranslational Research College of Pharmacy University ofFlorida Gainesville, Florida, USA Laura F. Anderson, BSc (Hons) MSc byResearch MSc PhD TB Section Respiratory Diseases Department Centre for Infectious Disease Surveillance and Control (CIDSC) Public Health England Colindale London, UK Jayant N. Banavaliker, MD DTCD MBA Rajan Babu Institute for Pulmonary Medicine and Tuberculosis Delhi, India Department of Tuberculosis and Respiratory Diseases Delhi, India South Delhi Municipal Corporation Delhi, India Managing Committee New Delhi TB Centre Chair, TB Alert India Delhi, India Tuberculosis Association of India Delhi, India Christine E. Bell, MSc PGD RGN TB Unit, Department of Respiratory Medicine Central Manchester University Hospitals Manchester, UK S. Bertel Squire, MB BChir MD FRCP Tropical and Infectious Disease Unit Royal Liverpool University Hospital Professor of Clinical Tropical Medicine Centre for Applied Health Research and Delivery Liverpool School of Tropical Medicine Liverpool, UK Jane E. Buikstra BA MA PhD School of Human Evolution and Social Change Arizona State University Tempe, Arizona, USA Greg Calligaro, BSc (Hons) MBBCh FCP MMed Cert. Pulm (SA) Division of Pulmonology Groote Schuur Hospital Lung Infection and Immunity Unit University of Cape Town Cape Town, South Africa Ted Cohen, MD MPH DrPH Division of Global Health Equity Brigham and Womens Hospital Boston, Massachusetts, USA Department of Epidemiology Harvard School of Public Health Boston, Massachusetts, USA Leigh A. L. Corner, BVSc MVSc PhD MANZCVS School of Veterinary Medicine University College Dublin Dublin, Ireland Luis E. Cuevas, MD DTCH MtropMed Tropical Epidemiology Liverpool School of Tropical Medicine Pembroke Place Liverpool, UK Geraint Davies, BM PhD FRCP DTM&H Infection Pharmacology Institutes of Infection & Global Health and Translational Medicine University of Liverpool Liverpool, UK Peter D. O. Davies, MA DM FRCP University of Liverpool Liverpool Heart and Chest Hospital Liverpool, UK Keertan Dheda, MBBCh (Wits) FCP (SA) FCCP FRCP (Lond) PhD (Lond) Lung Infection and Immunity Unit Division of Pulmonology Department of Medicine and UCT Lung Institute University of Cape Town Cape Town, South Africa Christopher Dye, BA DPhil HIV/AIDS Tuberculosis, Malaria and Neglected Tropical Diseases Cluster World Health Organization Geneva, Switzerland Contributors

12. xvi Contributors Stephen B. Gordon, MA MD FRCP FRCPE DTM&H Department of Clinical Sciences Liverpool School of Tropical Medicine Liverpool, UK John M. Grange, MSc MD London Clinic Cancer Centre B2 London, UK Einar Heldal, MD PhD Independent TB Adviser Oslo, Norway Ajit Lalvani, MA DM FRCP FMedSci Tuberculosis Research Centre Imperial College London and Imperial College Healthcare NHS Trust London, UK Helen McShane, FRCP PhD The Jenner Institute University of Oxford Oxford, UK Peter Ormerod, BSc MB ChB MD DSc(Med) FRCP FRCPEd FRCPGlas Chest Clinic Royal Blackburn Hospital Blackburn Lancashire, UK Lancashire Postgraduate School of Medicine and Health University of Central Lancashire Preston Lancashire, UK Manchester University Manchester, UK Manish Pareek, DTM&H MSc MRCP PhD University of Leicester and University Hospitals Leicester NHS Trust Leicester, UK Charles A. Peloquin, PHARM D FCCP Department of Pharmacotherapy and Translational Research College of Pharmacy University of Florida Gainesville, Florida, USA Emerging Pathogens Institute University of Florida Gainesville, Florida, USA Dirk U. Pfeiffer, Tierarzt, Dr.med. vet. PhD MANZCVSc DipECVPH Veterinary Epidemiology The Royal Veterinary College University of London London, UK Katrina Pollock, MA MRCP PhD Imperial College London and Imperial College Healthcare NHS Trust London, UK Aravind Ponnuswamy, MD FRCP(EDIN) MRCP (RESPMED-UK) Countess of Chester Hospital NHS Trust Countess of Chester Health Park Chester Cheshire, UK Alexander S. Pym, MD PhD MRCP KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH) Nelson R. Mandela School of Medicine Durban, South Africa Michael L. Rich, MD PhD MD MPH Division of Global Health Equity Brigham and Womens Hospital Boston, Massachusetts, USA Harvard Medical School Boston, Massachusetts, USA Partners In Health Boston, Massachusetts, USA Charlotte A. Roberts, BA MA PhD SRN FSA Department of Archaeology Durham University Durham, UK Kwonjune J. Seung, MD Division of Global Health Equity Brigham and Womens Hospital Boston, Massachusetts, USA Harvard Medical School Boston, Massachusetts, USA Partners In Health Boston, Massachusetts, USA Delane Shingadia, MBChB MPH MRCP FRCPCH Great Ormond Street Hospital for Children London, UK Richard S. Steyn, MS FRCSEd(C-Th) FIMCRCSEd MRCGP DRCOG Heart of England NHS Foundation Trust Birmingham Heartlands Hospital Bordesley Green East Birmingham, UK Guy Thwaites, MA MBBS MRCP FRCPath PhD Oxford University Clinical ResearchUnit Ho Chi Minh City, Vietnam Nuffield Department of Medicine Oxford University Oxford, UK Zarir F. Udwadia, MD DNB FRCP (London) FCCP (USA) Hinduja Hospital and Research Center Mumbai, India Jakko van Ingen, MD PhD Department of Medical Microbiology Radboud University Medical Centre Nijmegen, The Netherlands Helen C. Wainwright, MBChB FFPath (SA) Division of Anatomical Pathology Faculty of Health Sciences University of Cape Town Cape Town, South Africa National Health Laboratory Services D7 Laboratory Groote Schuur Hospital Observatory Cape Town, South Africa Robert S. Wallis, MD FIDSA Department of Medicine Case Western Reserve University Cleveland, Ohio, USA Rutgers-New Jersey Medical School Newark, New Jersey, USA Jean-Pierre Zellweger, MD TB competence Centre Swiss Lung Association Berne, Switzerland

13. Section I Background

14. 3 1 INTRODUCTION Tuberculosis is now a conquered disease in the British Isles and the rest of the industrialised world. [1] How wrong can one be? In the late 1980s, we thought that tuberculosis (TB) was an infection that had been controlled and almost eradicated from the developed world. However, emergence and re-emergence of infectious diseases plague the developed and the developing world today, and the medical profession struggles to cope [2]. In 2010, there were 8.8 million incident cases of TB, although the absolute number is said to have been declining since 2006 [3]. However, TB has the potential to develop frequency rates with the status of the big killer again as we live through the twenty- first century [4]. TB was as important in our ancestors world as it is today; of course, the difference between past and present is that, potentially, we now have drugs to successfully treat the The History of Tuberculosis from Earliest Times to the Development of Drugs Charlotte A. Roberts Department of Archaeology, Durham University, Durham, UK Jane E. Buikstra School of Human Evolution and Social Change, Arizona State University, Tempe, AZ, USA CONTENTS Introduction.................................................................................................................................................................................... 3 Evidence for the Presence of TB in the Past.................................................................................................................................. 4 Diagnosis of TB in Skeletal and Mummified Remains............................................................................................................. 4 Historical and Pictorial Data..................................................................................................................................................... 5 The Antiquity of TB from a Global Perspective............................................................................................................................ 6 What Led to TB Appearing in Human Populations?................................................................................................................ 6 Animals................................................................................................................................................................................ 6 Humans, Urbanisation and Industrialisation.................................................................................................................................. 7 Skeletal Remains from the Old World...................................................................................................................................... 7 The Mediterranean............................................................................................................................................................... 7 Northern Europe................................................................................................................................................................... 8 Asia and the Pacific Islands.................................................................................................................................................. 8 Summary of Data from the Old World...................................................................................................................................... 8 Skeletal Remains from the New World..................................................................................................................................... 9 North America...................................................................................................................................................................... 9 Mesoamerica........................................................................................................................................................................ 9 South America.................................................................................................................................................................... 10 Summary of the Data from the New World............................................................................................................................ 10 Historical and Pictorial Data........................................................................................................................................................ 10 Historical Data........................................................................................................................................................................ 10 Artistic Representations.......................................................................................................................................................... 10 Biomolecular Evidence for TB from Ancient Skeletal Remains................................................................................................. 11 Overview of Data from Ancient Human Remains....................................................................................................................... 11 TB in the Nineteenth and Twentieth Centuries............................................................................................................................ 12 Conclusion................................................................................................................................................................................... 12 Acknowledgements...................................................................................................................................................................... 13 References.................................................................................................................................................................................... 13

15. 4 Clinical Tuberculosis disease, health education programmes to prevent TB from occurring, and mechanisms and infrastructure to ensure that poverty is not a precursor to the development of the infection. Of course, having coping mechanisms does not mean that TB will be controlled. In some respects, they can com- plicate the situation; one could argue that because one of the major predisposing factors for TB is poverty, if poverty could be alleviated then TB would decline, as would many other diseases [5]. Our ancestors perhaps may have been in a better position to combat TB, assuming they recognised that poverty led to the infection. They certainly did not have to deal with one of the key predisposing factors today human immunodeficiency virus (HIV) [6], or so we assume. Today, the combination of poverty, HIV and drug resistance makes for a challenging and terrifying situation for many people. The cause of TB, its associated stigma, and the different political regimes and cultures around the world can vary considerably, which then affects the treatments provided, the opportunity for access to and the success of those treatments and the implementation of preventive measures [7,8]. We also have to consider the possibility that men, women and children with TB (or any health problem) may be treated differently [9]. Here, we focus on the long history of TB as seen mainly in skeletal remains. First, we will: consider the primary evidence for TB in the past in the remains of people themselves chart the distribution of the infection through time from a global perspective, and consider historical data for the presence of the disease in the distant past. We will also examine remarkable new developments from biomolecular analyses of the tubercle bacillus in human remains that are currently illuminating aspects of the history of TB. Finally, we argue that looking at TB from a deep-time perspective can aid in understanding the problem today. EVIDENCE FOR THE PRESENCEOF TB IN THE PAST Scholars studying TB in our ancestors draw on a number of sources. The primary evidence derives from people themselves (Figure1.1) who were buried in cemeteries through- out the world that have been excavated over the years and that contribute to the understanding of humankinds long history. Secondary sources of evidence flesh out the skeletal remains that we study. For example, we might consider historical sources that document TB frequency at particular points in time in specific parts of the world something we cannot glean from the skeletal remains. Written accounts will also tell us something about whether attempts were made to treat TB and how. Illustrations in texts may indicate that the infection was present in the population and also show the deformity and/or disability that accompa- nied it. The following sections consider this evidence in more detail, highlighting the strengths and limitations of our data. Diagnosis of TB in Skeletal and Mummified Remains Being able to securely identify TB in human remains obtained from an archaeological site proves the presence of the disease in a population. This compares with a written description of the infection whose signs and symptoms may be confused with other respiratory diseases. Although historical sources may provide us with more realistic estimates of TB frequency in the past, we have to be sure that the diagnosis was precise. We would argue that this is not always possible. It has been suggested that in the 1940s and 1950s, the skeletal structure was affected in approximately 3%5% of people with pulmonary TB (PTB), but this rose to around 30% for extrapulmonary TB [10]. The spine is most affected, with the hip and knee being common joints that are involved. Skeletal damage is the end result of post-primary TB spread- ing haematogenously or via the lymphatic system to the bones. Without biomolecular analysis, we cannot identify TB in the skeletons of those people who suffered primary TB. Initial introduction of TB into a population will lead to high and rapid mortality because of the lack of previous exposure; no bone damage would be expected. As time goes by and generations have been exposed to TB, we might expect to see it in their skeletons. In humans, TB caused by Mycobacterium tuberculosis and Mycobacterium bovis can cause skeletal damage, but there are suggestions that the latter is much more likely to do this [11]. Skeletal evidence indicates a chronic long-term process that people could have endured for many years, also suggesting that they had a relatively robust immune system [12]. However, diagnosis of TB in skeletal remains can be challenging. True pathological lesions have to be distinguished from normal skeletal variants and changes dueto post-mortem damage. Some circumstances, such as very dry, waterlogged and frozen environments, may preserve whole bodies very well[13]. If soft tissues are preserved, the potential amount of retriev- able data can be impressive, and diagnosis of disease can be easier. Nevertheless, most archaeological evidence for TB is provided by skeletal rather than mummified remains [14]. Disease can affect the skeleton only in two ways, through bone formation and in bone destruction, although both can be FIGURE1.1 Skeleton in the ground before excavation.

16. 5The History of Tuberculosis from Earliest Times to the Development of Drugs found together. In studies of palaeopathology, such changes are recorded for each bone of the skeleton, their distribution pattern noted and differential diagnoses provided. Because the skeleton can react only in limited ways to disease, the same changes can occur with different diseases. This is why providing a detailed description of the lesions and a list ofpossible diagnoses, based on the presence and distribution of the lesions, is essential if diagnoses are to be verified and/ or re-evaluated in the future. This point is emphasised repeat- edly [12,1416]. Recognition of TB relies mainly on the presence of destructive lesions in the spine, termed Potts disease after Percivall Pott, the nineteenth-century physician who first described the changes. The bacilli focus on the red bone marrow, and there is gradual destruction of the bony tissue. Jaffe [10] indicates that 25%50% of people with skeletal TB will develop spinal changes. Once the vertebral integrity is lost, the structure collapses and angulation (kyphosis) of the spine develops (Figure1.2), sometimes followed by fusion of vertebrae (ankylosis). Other parts of the skeleton may also be affected, for example, the hip and knee joints (Figures 1.3 and 1.4), and other non-specific changes can occur that may be related to TB [10,1723]. Most palaeopathologists will diagnose TB using spinal evidence. However, it is not possible to detect all people with TB using this approach. Over the last 10 years or so, methods developed in biomolecular science have been applied to the diagnosis of disease in skeletal and mummified remains. This approach, discussed in more detail later in this chapter, includes considering human remains without any evidence of disease, as well as those with pathological changes. TB has been the main focus of biomolecular studies, with its diagnosis based upon identifying ancient DNA and mycolic acids of the tubercle bacillus [24,25]. Although there can be inevita- ble problems of survival and of extraction of ancient biomolecules from human remains, this new line of evidence has already significantly revised our models of humanpathogen (TB) co-evolution. Historical and Pictorial Data We are not historians or art historians and, therefore, we are not trained in the analysis and interpretation of texts and illustrations related to the history of disease and medicine.FIGURE1.2 Spinal tuberculosis. FIGURE1.3 Probable joint tuberculosis. FIGURE1.4 New bone formation on the visceral surface of ribs.

17. 6 Clinical Tuberculosis Even so, we recognise that historical sources can generate interpretative problems. The signs and symptoms of TB may include shortness of breath, coughing up blood, anaemia and pallor, fatigue, night sweats, evening fevers, pain in the chest and the effects of associated skeletal changes (for example, kyphosis of the back and paralysis of the limbs). Clearly, all these features, visible to an author or artist, could be associated with other health problems. For example, pallor may be seen in anaemia, shortness of breath in chronic bronchi- tis and coughing up blood in cancer of the lung. Likewise, kyphotic deformities of the back (Figure 1.5) may be the result of osteoporosis of the spine or trauma. Biases abound in written sources including the interpretation of death rates said to reflect TB. For example, Hardy [26] reminds us that because TB was associated with stigma in the nineteenth century, it was not always recorded as the cause of death. People could have had more than one condition contributing to their death, and we must also not assume that those who diagnosed disease in the past were competent to makeacor- rectdiagnosis. Eventoday, some causes listed on death cer- tificates may not be correct [27]. Despite these problems, we will consider some of this evidence following our discussion of skeletal data. THE ANTIQUITY OF TB FROM A GLOBAL PERSPECTIVE Before embarking on a temporal and global perspective of TB, we should emphasise that North America and parts of Europe have received much more archaeological attention than many other parts of the world [28]. There are many regions into which palaeopathologists have not yet ventured and, therefore, evidence for TB is to date absent from these areas. This does not mean that the disease did not existthere in the past, just that the evidence has not been sought. This presents a challenge to scientists who wish to trace the origin, evolution and transmission of TB globally. With this caveat in mind, we first consider the factors that were probably important in the development of TB in past human populations. What Led to TB Appearing in Human Populations? Animals The human form of TB (M. tuberculosis) is transmitted via droplet infection. M. bovis can be transmitted from animals to humans via the gastrointestinal tract, but it can also be contracted by humans through droplet infection from animals. Thus, there is an opportunity for transmission in situations where infected meat and/or milk are being consumed by humans and where humans live or work in proximity to infected animals. In hunting and gathering groups, population density is generally low, and, therefore, it is likely that the animal to human form of transmission would be the most common. Our assumption, until recently, has been that humans contracted TB from infected animals, probably cattle, when these animals were domesticated about 10,000 years ago in the eastern Mediterranean [29]. Here and elsewhere, people moved from hunter-forager subsistence regimes to those more reliant on growing crops and on keep- ing animals. In the Near East, for example, domesticated sheep and goats were present by 8000 bc; by 6500 bc, and this occurred in Northern Europe, the Mediterranean and India [30]. 1000 BC 4000 BC 1st C BC1st C AD 40003500 BC 72506160 BC 1st C BCGermany 54504775 BC Hungary 49704600 BC FIGURE1.5 Distribution map of occurrences of skeletal tuberculosis in the world, excluding Europe (light stars = evidence that needs to be verified; dark stars = definite evidence).

18. 7The History of Tuberculosis from Earliest Times to the Development of Drugs In the New World, domestication is believed to have been established in Central Mexico by 2700 bc, in the eastern United States by 2500 bc and South Central Andes in South America by 2500bc [31]. Assuming that domesticated animals were infected by TB, and if animal to human transmission is accepted, a potential for transmission was clearly present. However, hunter-gatherers could have contracted the disease through capture, butchery and consumption of their kill. Corroborating data from Kapur etal. [32] suggest that mycobacterial species first appeared 15,00020,000 years ago, long before domestication; Rothschild etal. [33] have revealed M. tuberculosis complex ancient DNA in the remains of an extinct, long-horned bison from North America dated to 15,870 bc (230 years). Brosch etal. [34] have fur- thermore indicated, based upon the genomic structure of tubercle bacilli, that M. tuberculosis did not evolve from M. bovis. Other researchers suggest that TB is the culmination of a global history originating in Africa, thereby affecting our hominine ancestors and extending more than three million years in the Old World [35]. HUMANS, URBANISATION AND INDUSTRIALISATION Today, transmission of the human form of TB requires close contact with those infected. Because earlier peoples lived in small, mobile groups, they seldom formed settled communities [36]. With the development of agriculture, population density increased rapidly, thus enabling density-dependent diseases such as TB to flourish. Even so, it was not until the late medieval period (twelfth to sixteenth centuries ad) that the disease really increased in Europe [4]. During this period, conditions were ideal for a marked increase in TB. Poverty, the development of trade and the migration of people from rural communities to urban centres (usually for work) enabled the transmission of TB to previ- ously unexposed people. In addition, working with animals and their products also may have exposed populations to the infection. For example, processing animal skins in the tan- ning industry, working with bone and horn and processing food products from animals all placed people at risk for the infection. Working in industries that produced particulate pollution, such as in the textile trade, also irritated the lungs and probably predisposed people to TB. The post-medieval period and the Industrial Revolution provided potentially explosive conditions for TB. Of special interest here is the suggestion that people who have been urbanised for a long time become resistant to TB through natural selection [37]. This may explain the decline of TB starting in the late nineteenth and early twentieth centuries [38]. We might also ask what people consumed in the past and whether their diet was balanced and nutritious. Quality of diet affects immune systems and how strong their resistance is to infection. If people become malnourished, they are more susceptible to TB; for example, iron and protein are important for immune function and infection outcome in TB, and diet may influence the potential for TB to disseminate from the lungs to the skeleton [39]. Skeletal and dental evidences suggest that health tends to deteriorate with increasing social complexity and the development of agriculture [4042], and diets were less varied. People eat less protein, which is needed to produce antibodies to fight infection, and wheat lacks certain amino acids. As is the case today, many factors would have influ- enced the prevalence of TB in the past, especially population density and poverty. Animals initially thought to have been central to the development and maintenance of TB in humans probably became a key factor more recently, rather than at the time of domestication (see Chapter28). Skeletal Remains from the Old World It can be argued that archaeological human remains are the primary evidence for estimating the timing of TBs first appearance, but it is emphasised that biomolecular models predict co-evolution over a much longer time period when compared with the skeletal evidence for the disease [32,35]. We can define the Old World as the world that was known before the European presence in the Americas, comprising Europe, Asia and Africa [43]. Most of the evidence comes from Europe, reflecting the intensity of study by palaeopathologists there as compared with the rest of the Old World. In some areas, this may be due to non-survival of human remains, non-excavation and particular funerary rites that do not preserve remains well [4]. However, those Old World areas with no evidence may truly be areas with no TB. We can divide extant data into three broad areas in the Old World, which reflect similar climate and environmental features: the Mediterranean, Northern Europe, and Asia and Pacific islands. The Mediterranean Italy has the earliest evidence of skeletal TB in the world, although earlier unpublished evidence has been recently reported for Northern Europe (see the next section). A female skeleton aged around 30 years at death is dated to 3800 bc (90) and comes from the Neolithic cave of Arma dellAquila in Liguria [44]. In the Near East, there are early skeletons with TB from Bab edh-Dhra in Jordan, dated to 31502200 bc [45], although Israel does not show evidence of the disease until ad 600, at the monastery of John the Baptist in the Judean Desert [46]. Egypt reveals evidence of TB dated to 4000 bc [47], although there is no definite evidence from sub-Saharan Africa. Data on TB in human remains have been published since early last century [48]. The most widely cited data are from the mummy Nesperehn, excavated in Thebes, where a psoas abscess and spinal changes were recorded, which established TBs presence in Egypt between 1069 and 945 bc [47]. In 1938, Derrys summary [49] indicated that the earliest occurrence dated to 3300 bc, although Morse etal. [47] record evidence from Nagada dated to as early as 4500bc. In Egypt, there has been considerable research on soft tissue evidence for TB. For example, Nerlich etal. [50] and

19. 8 Clinical Tuberculosis Zinketal. [51] isolated and sequenced DNA from lung tissue of a male mummy found in a tomb of nobles (15501080 bc), providing a positive diagnosis for TB. Spain comes next in chronological sequence with possible TB in skeletal remains dated to the Neolithic [52]. TB appears in Greece by 900 bc [53]. Since Angels work, there have been very little skeletal data on TB from Greece,but by the fifth century bc, Hippocratic writings described the infection [54]. France, like Lithuania and Austria (Northern Europe), reveals TB around the fourth century ad [5557]. Evidence has appeared in early, late and post-medieval southeast France, but Northern France has probably seen the most extensive palaeopathological effort [55], with nearly 2500 skeletons being examined from 17 sites dated to between the fourth and twelfth centuries ad. Twenty-nine skeletons with TB were identified, and most came from urban sites. Other Mediterranean countries, such as Serbia [58], Turkey [59] and Portugal [60], provide the first evidence of the infection much more recently in the medieval period (from around the twelfth century ad). At that time, there appear to be significant numbers of groups with TB [4]. It should also be noted that controversial datafromIsrael dated to 72506160 bc have been published [6162]. Northern Europe In Northern Europe, the Neolithic site of Zlota (5000 bc) in Poland reveals some of the earliest published evidence for TB [63]. As in many other European countries, the frequency of the disease increased during the later medieval period. Data from the Bronze Age site of Manych, in southern Russia, suggest TB was present by 1000 bc [64], but there is much more palaeopathological work to be done in that huge country. Recently, unpublished data have been presented from Germany and Hungary, suggesting early evidence dated to 54504775 bc and 497046 bc, respectively [65,66]. In Denmark, the presence of TB begins during the Iron Age (5001 bc) at Varpelev, Sjlland [67]. In Britain, the first evidence has been recovered from an Iron Age site at Tarrant Hinton, Dorset, dated to 400230 bc [68]. Austria and Lithuania have skeletal evidence by the fourth century ad. For Austria, this coincides with the late Roman occupation. Britain has had a long history of palaeopathological study and, therefore, the evidence for TB is much more plentiful there than in other countries. Of particular interest in Britain is research that contradicts the idea that TB in rural human populations was most likely the result of transmission from animals. Ancient DNA analysis at the rural medieval site of Wharram Percy suggests that TB was the result of M. tuberculosis and not M. bovis [69]. In Lithuania, extensive work has documented the frequency of TB in skeletal remains [70], with the record beginning at the late Roman site of Marvel. In addition to diagnostic skeletal lesions, remains from Marvel also produced positive results for the M. tuberculosis complex [71]. Over time, TB frequencies increased, along with population density and intensification of agriculture. Jankauskas [72] suggests that cattle probably transmitted the infection to humans, and in the early medieval period, he found that people appeared to be surviving the acute stages of the infection. By the seventh century ad, Norway and Switzerland fea- ture in the history of TB [73], followed by Hungary, and then by Sweden and the Netherlands during the eleventh to thirteenth centuries ad, respectively. There also has been extensive published work in Hungary documenting the frequency of TB over time [65,66,74]. Clearly, TB was fairly common in the seventh to eighth centuries and also in the fourteenth to seventeenth centuries; an obvious gap in the evidence in the tenth century may be due to the Hungarian populations semi-nomadic way of life at that time (burial sites not identified). Skeletal and mummified remains from Hungary that display TB have also been subject to extensive biomolecular research, which has allowed the confirmation of possible tuberculous skeletons [75,76]. In Sweden, an extensive study of more than 3000 skeletons from Lund dated to between ad 990 and 1536 showed TB of the spine in one individual (ad 10501100), although more than 40 had possible TB in one or more joints [77]. The Czech Republic also provides its first evidence of TB during the later medieval period [78]. Asia and the Pacific Islands Asia and the Pacific islands reveal TB in skeletal remains much later than the Mediterranean and Northern European areas. China has evidence from a mummy dated to between 206 bc and the seventh century ad [79], although the first written description of TB treatment is dated to 2700 bc [80], with the first accepted description of the disease dated to 2200 bc [79]. Japan has skeletal evidence dated to 454 bc to ad 124; Korea has evidence from the first century bc [81,82] and Thailand has evidence dated to the first two centuries ad [83]. Papua New Guinea and Hawaii [8486] produce data much later (pre-European, i.e. pre-late-fifteenth century ad), with possible TB being recorded on Tonga and the Solomon Islands. Summary of Data from the Old World Although the Old World data for skeletal TB appear quite plentiful, there are many areas where there is no evidence (Figures 1.5 and 1.6). This may be because: It really does not exist even though extensive skeletal analysis has been undertaken. Skeletal remains are not traditionally studied in a particular country. Disposal of bodies at a specific time may not preserve them well enough for the evidence to be observed (e.g. cremation in Bronze Age Britain). Skeletal remains do not survive burial because of the climate or environment in a specific geographic area, for example, the freezing cold climate of Finland or the acidic soils of Wales or Scotland.

20. 9The History of Tuberculosis from Earliest Times to the Development of Drugs For some time periods in certain countries, no skeletal remains have been excavated (e.g. the Roman period in Poland). On the basis of the evidence published to date, we see that TB has an early focus in the Mediterranean and Northern European areas. There are later appearances in Asia and other parts of Northern Europe and the Mediterranean. However, it is not until the hazards of urban living and the increase in population size and density of the later medieval period [87,88] that we see a rise in the frequency of the disease in most places. In addition, at this time, a practice known as Touching for the Kings Evil was developing the monarch could apparently cure a TB victim by touching them on the head and giving them a gold piece [89]. Whether all people touched were tuberculous is debatable. Skeletal Remains from the New World In the New World, particularly in North America, skeletal remains have been studied for a considerable time. For example, the first reported cases of TB were in 1886 [90], although they have since been critically reviewed [9]. By the mid-twentieth century, evidence for the disease had increased considerably in eastern North America [92], the North American Southwest [93] and South America [94]. Some have raised doubts concerning the presence of TB in the New World prior to the sixteenth century [91], but current evidence, both skeletal and biomolecular, confirms that TB was present in the prehistoric Americas. A major argument for its absence in prehistoric populations was the suggestion that sufficiently large population aggregates did not exist. However, the existence of very large prehistoric communities effectively counters this argument [4,95]. For example, estimates of population size at Cahokia in the Central Mississippi Valley, circa ad 1100, have ranged from 3500 [96] to 35,000 [97], with a population density of 2127 individuals per square kilometre [96]. Although there have been doubts about the need for large populations in order for TB to flourish [98], there were certainly wild and domesticated animals that could have provided a reservoir for the infection. The evidence from the Americas can be divided into north, central and southern areas. Most of the evidence comes from North and South America. North America There are two areas of North America where the skeletal evidence for TB derives eastern North America, especially the mid-continent, and the Southwest [95]. Both these areas were large population centres in late prehistory, that is, before ad 1492. However, eastern North America provides most of the data, with four sites producing more than 10 individuals with TB: Uxbridge [99], Norris Farms [100], Schild [101] and Averbuch [102]. This may reflect not only the intensity of skeletal analysis there but also the frequency of destructive burial practices along with casual disposal of the dead in the Southwest. However, the earliest evidence of TB in North America does derive from the Southwest during the same time that there were major population concentra- tions in large pueblos (permanent agricultural settlements) [103]. For example, the site of Pueblo Bonito had more than 800 rooms, with some of the sites having buildings up to five stories high [104]. All the evidence in North America thus post-dates ad 900 and is more recent than that in SouthAmerica. Mesoamerica Despite large numbers of people living in Mesoamerica before European contact, along with considerable skeletal analysis, there is a virtual absence of TB until very late prehistory [4]. This may be explained by poor preserva- tion in some areas of Mesoamerica, but there have also been excavations and analysis of very large well-preserved cemeteries with no evidence of TB forthcoming [105]. One explanation for the absence of TB is that people were dying in Mesoamerica before bone changes occurred. However, similar stresses are also identified in North America where evidence of TB exists [102]. One could also argue that those with TB, manifested by Potts disease of the spine, were buried away from the main cemetery or disposed of in a different way to those without the disease. In Mesoamerica, we also know that people with hunchbacks (the deformity seen in spinal TB) appear to have been awarded special status, as depicted on painted ceramics [106], and that their treatment in society may have been very different to that of the rest of the population, including their final disposal [99]. 200 BC 3800 BC Neolithic Neolithic 900 BC 49704600 BC 54504775 BC FIGURE1.6 Distribution map of occurrences of skeletal tuberculosis in Europe (light stars = early evidence).

21. 10 Clinical Tuberculosis South America The earliest evidence for TB in the New World is seen in South America in Peru [107], Venezuela [108], Chile [108] and Colombia [109], with the oldest evidence recovered from the Caserones site in northern Chiles Atacama Desert [110]. Three individuals with TB were recorded and dated originally to around ad 290 by Allison etal. [109], but Buikstra [95], in considering radiocarbon dating problems in coastal environments, dates them to no earlier than ad700. Within the larger South American sites, it is interesting to note that more males than females are affected (as is seen generally today), whereas in North American sites the sexes are equally affected [4]. Although males and females herded, caravans groups of travellers were com- posed of males; a possible reason for the South American asymmetry would be that males were placed more at risk due to their proximity to camelids while engaged in long distance trade [4]. Stead etal. [111] also suggest that prehistoric TB in the Americas is likely due more to the bovis organism from infected animal products. M. bovis, compared with M. tuberculosis, is also 10 times more likely to produce skeletal damage. Thus, in North and South America, we see TB increasing after about ad 1000 and into the early historic period [112,113]. Summary of the Data from the New World The earliest evidence of skeletal TB in the New World comes from South America by ad 700, with later appearances in North America. This suggests a transmission route of south to north, although Mesoamerica generally does miss the encounter until relatively late prehistory. One model suggests transmission by sea, coincident with material evidence of trade between western Mexico and Ecuador [4]. The only relatively early Mesoamerican sites with multiple skeletons cases of Potts disease are found in western Mexico. Although it has been suggested that TB in the Americas may have been caused by M. bovis rather than M. tuberculosis as a result of contact with camelids [4], and possibly mostly the result of ingestion of infected products, ideas are changing. Much more research remains to establish the nature of ancient TB in the New World [114], including skeletal and biomolecularstudies. HISTORICAL AND PICTORIAL DATA Although we would argue that the presence of TB in past communities should rely primarily on evidence from skeletal or mummified remains, including biomolecular studies, there are large bodies of written and illustrative evidence that have contributed to tracing the evolution and history of this infectious disease. However, these data are less convincing than those derived from human remains. Unfortunately, the clinical expression of pulmonary TB may mimic other lung diseases such as cancer and pneumonia, and kyphotic deformities of the spine could be caused by spinal conditions other than TB. We also have to remember that authors and artists often write about and depict the most disturbing diseases (especially those that are visually dramatic), so they may not always include TB in their renderings. Thus, using historical sources as an indicator for the presence and frequency of TB remains hazardous, and what is represented in these sources may provide a biased portrayal of what diseases were present at any point in time. Historical Data In the Old World, a Chinese text (2700 bc) provides a description of possible TB in the necks lymph nodes and in blood expectoration [115], while the Ebers Papyrus (1500 bc) also describes TB of the lymph glands. In India, the Rig Veda, of the same date, describes phthisis, and a possible example of TB from Mesopotamia (675 bc) has also been described [80]. Numerous references are encoun- tered in classical antiquity ranging from Homer (800 bc) through Hippocrates (460377 bc) to Pliny (first century ad); Arabian writers during the ninth to eleventh centuries ad also suggested that animals may be affected by the dis- easealong with humans. The late medieval period in Europe produced considerable written evidence. For example, Fracastorius (1483 1553), in De Contagione, was the first to suggest that TB was due to invisible germs carrying the disease. From the beginning of the seventeenth century, we receive the impression (in England at least) that TB was becoming very common. The London Bills of Mortality report that 20% of deaths in England by the mid-1600s were due to TB [116]. TB was also associated with romanticism and genius. By the eighteenth century, appearing pale and thin was considered attractive, and TB allowed this to happen [117]. For example, the heroines in some of the famous operas, such as La Traviata and Mimi, were beautiful women with TB [117]. Authors were said to have been especially inspired during fevers. During the nineteenth century, many authors and artists died of TB, thus perpetuating the myth that genius was associated with the disease. At a time when much of the population in Europe was succumbing to TB, this is hardly surprising. When historical data are available, they can potentially provide a window on rates of TB, but the numbers of those actually dying from TB may be inaccurate. This could be due to many reasons, including non-diagnosis (some due to the stigma attached to TB and the effect on lifes prospects) and misdiagnosis. Until 1882, when the tubercle bacillus was identified, diagnosis was based on the analysisof signs and symptoms [118]. Later, sputum tests and radiography played their part, but a post-mortem examination is the only sure way of achieving a diagnosis of cause of death. Artistic Representations Artistic representations come in a variety of forms, including paintings, drawings, reliefs and sculpture. However,

22. 11The History of Tuberculosis from Earliest Times to the Development of Drugs we must remember that artistic conventions must be considered, that artists may be biased in what they portray and that depiction may not be accurate and will be dependent on the artists interpretation and skills. There appear to be two types of possible depictions of TB, the kyphotic spine and pale, thin, tired young women [119]. The former is more commonly represented than the latter. In North Africa, Morse etal. describe spinal deformities in plastic art dating before 3000 bc [47], and similar appearances are seen in Egyptian (3500bc) and North American contexts. A figurine on a clay pot from Egypt (4000bc) has for a long time been identified with spinal TB and emaciation, but the spinal deformity is in the cervical region (rare in TB) and we have already noted the possible differential diagnoses for such kyphotic deformities. In TB, it is important to note that angular deformities are more common than those that are more rounded [91]. In the later and post-medieval periods in Europe, we see more illustrations of deformed spines, such as those by Hogarth in London. In Central America, of course, we have already seen similar evidence on pot- tery [106]. Although potential evidence exists for TB in the past, in writings and in art, the interpretation of such data, until more recent times, is more problematic than the skeletal evidence. BIOMOLECULAR EVIDENCE FOR TBFROM ANCIENT SKELETAL REMAINS Biomolecular evidence for TB from human remains is a rapidly emerging analytical method for interpreting the origin, evolution and palaeoepidemiology of the disease. The study of ancient biomolecules using polymerase chain reaction (PCR) as a tool for diagnosing disease has had a short history, spanning the past 20 years or so (for a summary of the use of aDNA analysis in human remains, see Brown and Brown [120] and Stone [121]. Although there are certainly quality control issues to consider in ancient DNA analysis [122124], it has allowed theories about the origin and evolution of infectious disease, especially TB, to be explored. The most common research problems addressed have been confirmation of diagnoses [125,126], diagnosis of individuals with no pathological changes from TB [127] and identification of the organism that caused TB in humans [128130]. Research diagnosing TB using ancient DNA analysis started in Britain and the Americas. In 1993, Spigelman and Lemma documented the amplification of M. tuberculosis complex DNA in British skeletal remains [131]. Around the same time, Salo et al. [24] successfully amplified M. tuberculosis DNA from the South American site of Chiribaya Alta; a calcified subpleural nodule was noticed during the autopsy of a woman who had died 1000 years ago. A 97 base pair segment of the insertion sequence (IS) 6110, which is considered specific to the M. tuberculosis complex, was identified and directly sequenced. Three other sites have yielded the same M. tuberculosis complex ancient DNA, two in eastern North America (Uxbridge and Schild) [132] and one in South America (SR1 in northern Chile) [133]: in Uxbridge (ad 14101483) a pathological vertebra from an ossuary site; in Schild (ad 10001200) a pathological vertebra from a female; and in Chile (ad 800) an affected vertebra of an 11- to 13-year-old child. In the Old World, most biomolecular research to date has been focused on samples from skeletons and mummies from Britain, Lithuania and Hungary. For example, Gernaey et al. confirmed a diagnosis of TB in an early medieval skeleton from Yorkshire, England with Potts disease using ancient DNA and mycolic acid analyses [25]. Taylor etal. provided positive diagnoses for skeletons from the fourteenth century site of the Royal Mint in London [125,134]. Gernaey etal. established that 25% of the population buried at a post-medieval site at Newcastle in north- eastern England had suffered from TB, although most had no bone changes typical of the disease [127]. In Hungary, Plfi et al. and Haas et al., using ancient DNA analysis, confirmed a number of TB diagnoses in remains dating back to the seventh and eighth centuries ad up to the seventeenth century [126,135], and analysis of four eighteenth- to nineteenth-century mummies from Vac (two with TB) revealed positive results for three of them. Fletcher etal. also analysed TB aDNA in a family group from the same site [130]. In Lithuania, Faerman etal. have also confirmed diagnoses of TB in skeletal remains, including individuals with no diagnostic osseous changes [136]. The use of biomolecular analyses to identify TB in human remains is beginning to answer questions impos- sible to contemplate prior to the early 1990s (e.g. on TB bacterial strains). However, it is clear that this and related fields hold significant future potential [137,138]. One promising line of study focuses on estimating which species of the M. tuberculosis complex infected humans over time in different regions of the world. A second branch of study identifies whether the strains of the organism are the same today as in the past; that is, it compares the phylogenetic relationships of organisms causing TB in the past and present and estimates how the organisms have evolved. Both these areas of research are currently receiving attention from the authors, as well as other scholars around the world [139]. OVERVIEW OF DATA FROMANCIENT HUMAN REMAINS Clearly, there is much skeletal evidence for TB from around the world, with most data deriving from North America and Europe. An early focus for the infection appears in Germany, Hungary, Italy, Poland and Spain in the Neolithic and in Egypt from 4000 bc, but TB does not increase with any real frequency until the later and post- medieval periods in the Old World. This latter observation is corroborated by historical sources. There is very little evidence, if at all, in Asia, most likely reflecting the lack of intense skeletal analysis over the years. In the New World,

23. 12 Clinical Tuberculosis TB appears for the first time in South America by ad 700 and is not seen until around ad 1000 in North America, largely bypassing Mesoamerica. The current biomolecular evidence suggests that M. tuberculosis did not evolve from M. bovis. In the prehistoric Americas, population size and aggregation such that TB could flourish via droplet infection. However, in Europe and the Americas, wild and domesticated animals may also have been a reservoir of infection. TB IN THE NINETEENTH AND TWENTIETH CENTURIES We have thus far considered the evidence for TB in populations from very far distant eras. To bring us to the introduction of antibiotics in the mid-twentieth century, we must now turn to the records of TB in the late nineteenth and early twentieth centuries. In the eighteenth century, John Bunyan referred to TB as the captain of all these men of death [140]. By the beginning of the nineteenth century, TB was the leading cause of death in most European countries, reaching up to 500800 cases per 100,000 population [141]. During the Victorian period in Britain, it was one of the main causes of death [142]. In the late 1800s, the start of the Industrial Revolution in Britain and rapid urbanisation, including rural to urban migration, favoured the spread of TB. By the mid-nineteenth century, the con- cept of the sanatorium had been established. Fresh air, a good healthy diet, rest and graded exercise was the regime offered to TB sufferers, with surgery such as lung col- lapse and rib resection being undertaken for some. Patients were isolated from their families in an attempt to control the spread of the infection. The first sanatorium was opened in Germany in 1859, with many more founded over the next 100 years. In 1882, Robert Koch first described the tubercle bacillus, and in 1895, Conrad Roentgen discovered the x-ray, which provided a new method for diagnosing TB. By 1897, the theory of transmission of TB via droplet infection was established [143], and by the early twentieth century, it was known that animals could contract the infection. By the second half of the nineteenth century and into the twentieth, there was an obvious decline in TB [144]. This is largely attributed to improvements in living conditions and diet, although Davies etal. have shown that none of the other poverty-related diseases showed such a decline, thus making interpretations difficult [38] (but see Barnes etal. [37]). An anti-tuberculosis campaign, which included controls on the quality of meat and milk, started soon after Koch discovered the bacillus [118]. In 1889, the Tuberculosis Association was established in the United States; in the 1890s, the League Against Tuberculosis was founded in France to encourage the control of TB in Europe. In 1898, the National Association for the Prevention of Tuberculosis and other Forms of Consumption (NAPT) was established in Britain as part of an international movement. The International Union against TB was founded in 1902 to encourage a system of control; this included the notification of all cases, contact tracing, and the provision of dispensaries and sanatoria. Mass radiography during the two world wars allowed higher detection rates, while reha- bilitation schemes, the BCG vaccination in the 1950s (in Britain), health education and pasteurisation of milk were all seriously considered [118]. This trend continued with the introduction of antibiotics in the mid-twentieth century. Although TB has been with us for thousands of years and despite once being thought of as a conquered infection, it still remains a plague on a global scale. CONCLUSION The history of TB has been traced through the analysis and interpretation of evidence from human remains derived from archaeological sites around the world. Although there may be biases in these data with respect to tracing the origin, epidemiology and long history of TB, these are the most reliable sources we have at our disposal. The origin in Northern Europe of Old World TB nearly 8000 years ago and its appearance in the Americas by ad 700 truly illustrate TBs antiquity. We have seen that in both contexts, TB increased with human population size, which allowed transmission of the infection through exhaled and inhaled droplets. Infection of humans by wild and domesticated animals was also a risk. TB continued to increase over time, with high frequencies in Europe during the Industrial Revolution of the 1800s. In the late nineteenth and early twentieth centuries, a decline preceded the introduction of antibiotics in Europe and North America. The reasons for this pattern remain speculative. Improvements in living conditions and diet (and its quality), better diagnosis, health education, vaccination and immuni- sation, pasteurisation of milk and isolation of people with TB from the uninfected may all have helped to lower the rate of TB. We have seen that skeletal evidence can provide us with a global picture of this ancient malady from its very earliest times. It can also direct us to the areas of the world that have revealed the earliest evidence, and we can thus begin to explore the epidemiological factors that allowed the infection to flourish. We can see that the factors that influ- enced TB frequencies appear very similar to those today (poverty, high population density, urban situations, poor access to health care, infected animals and certain occupa- tions). How much trade and contact, and travel and migration, contributed to the tuberculous load in past populations is yet to be established. Of course, HIV, acquired immune deficiency syndrome (AIDS) and antibiotic resistance were not issues with which our ancestors had to contend with. Biomolecular studies of TB in the past will continue to contribute to our understanding of the palaeoepidemiology of this infection, by identifying the causative organisms andtheir difference from the strains of TB today. We antici- pate that palaeopathological research in TB will also help our understanding of TB today and hopefully contribute to its decline [145].

24. 13The History of Tuberculosis from Earliest Times to the Development of Drugs ACKNOWLEDGMENTS Our thanks go to the many researchers listed in Roberts and Buikstra [4] who gave freely their time and data during the writing of this book. REFERENCES 1.Smith ER. The retreat of tuberculosis 18501950. London: Croom Helm, 1988. 2.Harper K and Armelagos GJ. The changing disease-scape in the third epidemiological transition. Int J Environ Res Public Health 2010;7:67597. 3. WHO (World Health Organization). Global tuberculosis control. Geneva: WHO, 2011. 4. Roberts CA and Buikstra JE. Bioarchaeology of tuberculosis: global perspectives on a re-emerging disease. Gainesville: University Press of Florida, 2003. 5.Wilkinson R and Pickett K. The spirit level. Why equality is better for everyone. London: Penguin Books, 2009. 6.Pawlowski A, Jansson M, Skld M, etal. Tuberculosis and HIV co-infection. PLoS Pathog 2012;8:e1002464. 7. Vecchiato NL. Sociocultural aspects of tuberculosis control in Ethiopia. Med Anthropol Q 1997;11:183201. 8. Walt G. The politics of tuberculosis: the role of power and process. In: Porter JDH and Grange JM (eds.). Tuberculosis: an interdisciplinary perspective. London: Imperial College Press, 1999, 6798. 9.Mukherjee A, Saha I, Sarkar A, and Chowdhury R. Gender differences in notification rates, clinical forms and treatment outcome of tuberculosis patients under the RNTCP. Lung India 2012;29:1202. 10. Jaffe HL. Metabolic, degenerative and inflammatory diseases of bones and joints. Philadelphia: Lea and Febiger, 1972. 11.Stead WW. Whats in a name? Confusion of Mycobacterium tuberculosis and Mycobacterium bovis in ancient DNA analysis. Paleopathol Assoc Newslett 2000;110:1316. 12.Wood JW, Milner GR, Harpending HC, and Weiss KM. The osteological paradox: problems of inferring prehistoric health from skeletal samples. Curr Anthropol 1992;33:34370. 13. AufderheideAC. The scientific study of mummies. Cambridge: Cambridge University Press, 2003. 14.Roberts CA and Manchester K. The archaeology of disease, 3rd edn. Stroud: Sutton Publishing, 2005. 15. Buikstra JE and Ubelaker D (eds.). Standards for data collec- tion from human skeletal remains. Arkansas: Archaeological Research Seminar Series, 1994, 44. 16.Ortner DJ. Theoretical and methodological issues in palaeopathology. In: Ortner DJ and Aufderheide AC (eds.). Humanpaleopathology. Current syntheses and future options. Washington, DC: Smithsonian Institution Press, 1991, 511. 17.Schultz M. The role of tuberculosis in infancy and childhood in prehistoric and historic populations. In: Plfi G, Dutour O, Dek J, and Huts I (eds.). Tuberculosis. Past and present. Szeged: Golden Book Publishers, 1999, 5037. LEARNING POINTS Evidence of TB in history comes from two sources: primarily from the remains of the people themselves and secondarily from written and illustrative evidence. The skeletal structure will be affected in 3%5% of untrea

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