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
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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 tuber- culosis, either in clinical practice
or in research, are probably accustomed to hearing people ask, We
dont have tubercu- losis 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
tuber- culosis (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 coun- tries 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 tuberculo- sis. 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 strep-
tomycin 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 treat-
ment worldwide. Both treatments were highly effective in controlled
trial conditions, although results in routine prac- tice 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 chemother- apy 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 regi- mens 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/etham- butol-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 associ- ated 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 diagnos- tics, offering the
prospect of earlier identification and treat- ment 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
strepto- mycin 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 bring- ing 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 num-
ber 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 text- book. 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
diagnos- tic 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 anti- biotics are effective.
Prevention remains focused on preventive therapy and vaccines.
Control is again divided into the developed and devel- oping
worlds, as resources for this aspect of TB are so differ- ent.
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 con- trol 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 num- ber 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 infec- tion. 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 immu- nodeficiency 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
consider- ably, which then affects the treatments provided, the
oppor- tunity 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 his-
torical 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 them- selves
(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 skel- etal 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 indi- cate
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 previ- ous 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 patho- logical lesions
have to be distinguished from normal skel- etal 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 pres- ence 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, meth- ods 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 diagno- sis 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
biomol- ecules 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 asso- ciated 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 ani- mals. Thus, there is an opportunity for transmission in
situ- ations 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, popula- tion 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, prob- ably 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 ani- mals were infected
by TB, and if animal to human trans- mission 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 mil- lion 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 commu- nities [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 nine- teenth 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 impor- tant 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 popula-
tion 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 palaeo-
pathologists 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 dis- ease 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 earli- est
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 pos- sible 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 cen-
turies 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, sug- gest 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. tuber- culosis and not M. bovis [69]. In
Lithuania, extensive work has documented the fre- quency 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 pro- duced 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 peo- ple 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 fre- quency 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 confirma- tion 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 skel- etal analysis has been
undertaken. Skeletal remains are not traditionally studied in a
particular country. Disposal of bodies at a specific time may not
pre- serve 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
skel- etal 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, skele- tal 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, espe- cially 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 pro- vides 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 defor-
mity seen in spinal TB) appear to have been awarded spe- cial
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 tubercu-
losis 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 recov- ered 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 prob-
lems in coastal environments, dates them to no earlier than ad700.
Within the larger South American sites, it is inter- esting 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 pre-
historic TB in the Americas is likely due more to the bovis
organism from infected animal products. M. bovis, com- pared 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 appear- ances 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 skel- etal
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 defor- mities 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 pos- sible
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 consider- able 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 begin- ning 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 con- sidered 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, includ- ing 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 depen- dent 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 peri- ods 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 skel-
etal 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 sum- mary 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 mum- mies 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 popu- lation 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 seven- teenth 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 prom- ising 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 pres- ent 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
biomolecu- lar 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 drop- let
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 popula- tions from very far
distant eras. To bring us to the introduc- tion 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 coun-
tries, reaching up to 500800 cases per 100,000 popula- tion [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 bacil- lus, 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 sec- ond 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 mak- ing
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 estab- lished 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 noti- fication 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,
epi- demiology and long history of TB, these are the most reli-
able 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 earli- est 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 migra- tion,
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
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untrea