5 курс / Пульмонология и фтизиатрия / Clinical_Tuberculosis_Friedman_Lloyd_N_,_Dedicoat

“germs” carrying the disease. From the beginning of the seventeenth century, the impression (in England at least) is 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.121 TB was also associated with romanticism and genius. By the eighteenth century, appearing pale and thin was considered attractive, especially for women, and TB led to this appearance in many.122 For example, the heroines in some of the famous operas, such as La Traviata and Mimi, were beautiful women with TB.122 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 frequency 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 evading a diagnosis because of the stigma attached to TB and the effect on life’s prospects) and misdiagnosis. Until 1882, when the tubercle bacillus was identified, diagnosis was based on the analysis of signs and symptoms.123 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, 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.124 The former is more commonly represented than the latter. In North Africa, Morse et al. describe spinal deformities in “plastic” art dating to before 3000 bc,53 and similar appearances are seen in Egyptian (3500 bc) and North American contexts. A figurine on a clay pot from Egypt (4000 bc) 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.97 In the later and post-medieval periods in Europe, more illustrations of people with deformed spines are seen, such as those by Hogarth in London. In Central America, of course, similar evidence is recorded on pottery.112 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 TB

FROM ANCIENT SKELETAL REMAINS

Humans may acquire TB from each other, and from other mammals who are infected by bacteria of the MTC or Mycobacterium

tuberculosis complex. The MTC includes three species that are most commonly found in humans (M. tuberculosis, M. africanum, and M. canettii). Other forms, including M. microti, M. bovis, and M. pinnipedi are most commonly found in non-human mammals. Before the development of twenty-first century genomic models, researchers assumed that the more ancient forms included M. bovis, which is either a distinct species or polytypic form that also affects animals such as the oryx, seals, and sea lions. The pathogen, so the story went, was thought to have “jumped” species to humans as pastoralism developed in the Eastern Mediterranean.125 TB in America remained enigmatic, perhaps derived independently from a bovine form of the Americas affecting deer or bison. Speculation also included New World domesticates such as the dog or the guinea pig. Turkeys, possible avian sources, were also kept near households in, for example, the American Greater Southwest, primarily for secondary products such as feathers rather than for meat. Biomolecular evidence for TB from human remains is a rapidly emerging analytical method for interpreting the origin, evolution, and paleoepidemiology 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 25 years or so (for a summary of the use of aDNA analysis in human remains, see Brown and Brown126 and Stone127). Although there are certainly quality control issues to consider in aDNA analysis,128–130 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,131,132 diagnosis of individuals with no pathological changes from TB,133 and identification of the organism that caused TB in humans.134–136 More recently, this has been supplemented by phylogenetic research that has been able to identify different TB strains in archeological human remains, including seal/sea lion strains in South America.137, 138

Research diagnosing TB using aDNA analysis started in the United Kingdom and the Americas. In 1993, Spigelman and Lemma documented the amplification of M. tuberculosis complex DNA in British skeletal remains.139 Around the same time, Salo et al.25 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 aDNA, two in Eastern North America (Uxbridge and Schild)140 and one in South America (SR1 in northern Chile)141: in Uxbridge (ad 1410–1483)—a pathological vertebra from an ossuary site; in Schild (ad 1000–1200)—a pathological vertebra from a female; and in Chile (ad 800)—an affected vertebra of an 11to 13-year-old child.

In the Old World, most biomolecular research to date has been focused on samples from skeletons and mummies from the United Kingdom, Lithuania, and Hungary. For example, Gernaey et al. confirmed a diagnosis of TB in an early medieval skeleton from Yorkshire, England with Pott’s disease using aDNA and mycolic acid analyses.26 Taylor et al. provided positive diagnoses for skeletons from the fourteenth century site of the Royal Mint in London.131–142 Gernaey et al. established that 25% of the

population buried at a post-medieval site at Newcastle in northeastern England experienced TB, although most had no bone changes typical of the disease.133 In Hungary, Pálfi et al. and Haas et al., using aDNA analysis, confirmed a number of TB diagnoses in human remains dating back to the seventh and eighth centuries and up to the seventeenth century,132,143 and analysis of four eighteenthto nineteenth-century mummies from Vac (two with TB) revealed positive diagnoses for three of them. Fletcher et al. also analyzed TB aDNA in a family group from the same site.136 In Lithuania, Faerman et al. have also confirmed diagnoses of TB in skeletal remains, including individuals with no diagnostic osseous changes.144

With the genomic “revolution” of the twenty-first century, new models have identified the human predilected members of the

MTC (M. africanum, M. tuberculosis and basal M. canettii) as being the more genetically complex and therefore the more ancient forms, when compared to M. microti and M. bovis.37 Such models argue for a much longer co-evolution between humans and the MTC more than previously thought, beginning in Africa. Even so, the earliest skeletal evidence for human TB appears in the Eastern Mediterranean, associated with the Neolithic. This increased time depth for human−pathogen co-evolution led researchers to speculate that humans brought a form of the MTC when they migrated from East Asia to North America along the coast, or across the Bering Strait land bridge. More recently, however, it has been demonstrated that the ancient American forms of TB jumped species from pinnipeds—either seals or sea lions—who had brought the pathogen with them as they migrated from the horn of Africa.138 Studies are currently underway to explore the path taken by the pin- niped-derived human TB in the ancient and early colonial Americas.

Thus, in the last edition of this book, the use of biomolecular analyses to identify TB in human remains was beginning to answer questions impossible to contemplate prior to the early 1990s (e.g., on TB bacterial strains). However, it is clear that new methodologies and ideas have moved us forward. This and related fields hold significant future potential.145,146 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.138,147 As Guichón et al. have said, this type of research is “Moving beyond simple confirmatory analysis of diseased bone, researchers are now asking nuanced research questions capable of confronting the debate regarding TB’s origins and evolution.”148

OVERVIEW OF DATA FROM ANCIENT

HUMAN REMAINS

Clearly, there is much evidence from human remains for TB from around the world, with most data derived 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 in those parts of the world. In the New World, 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 contributed to the flourishing of TB 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 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.”149 By the beginning of the nineteenth century, TB was the leading cause of death in most European countries, reaching up to 500–800 cases per 100,000 population.150 During the Victorian period in Britain, it was one of the main causes of death.151 In the late 1800s, the start of the Industrial Revolution in Britain and rapid urbanization, including rural to urban migration, favored the spread of TB. By the mid-nineteenth century, the concept of the sanatorium had been established. Fresh air, a good healthy diet, rest, and graded exercise was the regime offered to people with TB, with surgery—such as lung collapse 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, even ones for children.152

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,153 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.154 This is largely attributed to improvements in living conditions and diet, although Davies et al. have shown that none of the other povertyrelated diseases showed such a decline, thus making interpretations difficult42 (but see Barnes et al.41). An anti-tuberculosis campaign, which included controls on the quality of meat and milk, started soon after Koch discovered the bacillus.123 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 rehabilitation schemes, the Bacillus Calmette Guerin (BCG) vaccination in the 1950s (in Britain), health education, and pasteurization of milk were all seriously considered.123 This trend towards tackling TB continued with the introduction of antibiotics in the midtwentieth 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 archeological 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 TB’s antiquity. We have seen that in both contexts, TB increased with human population size, which allowed transmission of the infection through exhaled and inhaled bac- teria-laden 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 immunization, pasteurization 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 influenced TB frequencies appear very similar to those today (poverty, high population density, urban living, poor access to health care, infected animals, migrating populations, and certain occupations). How much trade and contact, and travel and migration, contributed to the tuberculous load in past populations is yet to be established with certainty, but stable isotope analysis is showing that people were very mobile in the past. Of course, HIV, acquired immune deficiency syndrome (AIDS), and antibiotic resistance were not issues with which our ancestors had to contend. Biomolecular studies of TB in the past will continue to contribute to our understanding of the paleoepidemiology of this infection, by identifying the causative organisms and their similarities and differences from the strains of TB today. We anticipate that paleopathological research in TB will also help our understanding of TB today and hopefully contribute to its decline.155

ACKNOWLEDGMENTS

Our thanks go to the many researchers listed in Roberts and Buikstra4 who gave freely of their time and data during the writing of this book.

REFERENCES

1.Smith ER. The Retreat of Tuberculosis 1850–1950. 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;7:675–97.

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 et al. Tuberculosis and HIV co-infection. PLoS Pathog. 2012;8:e1002464.

7.Mason PH, Roy A, Spilllane J, and Singh P. Social, historical and cultural dimensions of tuberculosis. J Biosco Sci 2016; 48:206–32.

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, 67–98.

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;29:120–2.

10.Mitchell PD. Retrospective diagnosis and the use of historical texts for investigating disease in the past. Int J Paleopath 2011;1:81–8.

11.Jaffe HL. Metabolic, Degenerative and Inflammatory Diseases of Bones and Joints. Philadelphia: Lea and Febiger, 1972.

12.Steyn M, Scholtz Y, Botha D, and Pretorius S. The changing face of tuberculosis: Trends in tuberculosis-associated skeletal changes. Tuberculosis 2013; 93:467–74.

13.Stead WW. What’s in a name? Confusion of Mycobacterium tuberculosis and Mycobacterium bovis in ancient DNA analysis. Paleopathol Assoc Newslett 2000;110:13–6.

14.Wood JW, Milner GR, Harpending HC, and Weiss KM. The osteological paradox: Problems of inferring prehistoric health from skeletal samples. Curr Anthropol. 1992;33:343–70.

15.Aufderheide AC. The Scientific Study of Mummies. Cambridge: Cambridge University Press, 2003.

16.Roberts CA, and Manchester K. The Archaeology of Disease, 3rd ed. Stroud: Sutton Publishing, 2005.

17.Buikstra JE, and Ubelaker D (eds.). Standards for Data Collection from Human Skeletal Remains. Arkansas: Archaeological Research Seminar Series, 1994, 44.

18.Ortner DJ. Theoretical and methodological issues in palaeopathology. In: Ortner DJ, and Aufderheide AC (eds.). Human Paleopathology. Current Syntheses and Future Options. Washington, DC: Smithsonian Institution Press, 1991, 5–11.

19.Ortner DJ. Identification of Pathological Conditions in Human Skeletal Remains, 2nd ed. London: Academic Press, 2003.

20.Schultz M. The role of tuberculosis in infancy and childhood in prehistoric and historic populations. In: Pálfi G, Dutour O, Deák J, and Hutás I (eds.). Tuberculosis: Past and Present. Szeged: Golden Book Publishers, 1999, 503–7.

21.Lewis ME. Endocranial lesions in non-adult skeletons: Understanding their aetiology. Int J Osteoarchaeol. 2004;14:82–97.

22.Kelley MA, and Micozzi M. Rib lesions in chronic pulmonary tuberculosis. Am J Phys Anthrop 1984;65:381–6.

23.Roberts CA, Lucy D, and Manchester K. Inflammatory lesions of ribs: An analysis of the Terry Collection. Am J Phys Anthropol. 1994;85:169–82.

24.Santos AL, and Roberts CA. Anatomy of a serial killer: Differential diagnosis of tuberculosis based on rib lesions of adult individuals from the Coimbra Identified Skeletal Collection, Portugal. Am J Phys Anthropol. 2006;130:38–49.

25.Salo WL, Aufderheide AC, Buikstra JE, and Holcomb TA. Identification of Mycobacterium tuberculosis DNA in a pre-Colum- bia mummy. Proc Natl Acad Sci USA. 1994;91:2091–4.

26.Gernaey A et al. Mycolic acids and ancient DNA confirm an osteological diagnosis of tuberculosis. Tuberculosis 2001;81: 259–65.

27.Müller R, Roberts CA, and Brown TA. Complications in the study of ancient tuberculosis: Non-specificity of IS6110 PCRs. Sci Technol Archaeol Res. 2015; 1(1):112054892314Y.0000000002.

28.Galagan JE. Genomic insights into tuberculosis. Nat Rev Genet. 2014; 15: doi: 10.1038/nrg3664.

29.van Tong H, Velavan TP, Thye T, and Meyer CG. Human genetic factors in tuberculosis: An update. Trop Med Int Health. 2017; 22:1063–71.

30.Hardy A. Death is the cure of all diseases. Using the General Register Office cause of death statistics for 1837–1920. Soc Hist Med. 1994;7:472–92.

31.Payne D. Death keeps Irish doctors guessing. Br Med J 2000;321:468.

32.Buikstra JE, and Roberts CA (eds.). The Global History of Palaeopathology. Pioneers and Prospects. Oxford: Oxford University Press, 2012.

33.Renfrew C, and Bahn P. Archaeology. Theories, Methods and Practice. London: Thames and Hudson, 2012.

34.Smith BD. The Emergence of Agriculture. New York: Scientific American Library, 1995.

35.Kapur V, Whittam TS, and Musser JM. Is Mycobacterium tuberculosis 15,000 years old? J Infect Dis. 1994;170:1348–9.

36.Rothschild BM et al. Mycobacterium tuberculosis complex DNA from an extinct bison dated 17,000 years before present. Clin Infect Dis. 2001;33:305–11.

37.Brosch R et al. A new evolutionary sequence for the Mycobacterium tuberculosis complex. Proc Natl Acad Sci USA. 2002;99:3684–9.

38.Gutierrez MC et al. Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis. PLoS Pathol 2005;1:e5.

39.Brites D, and Gagneux S. Co-evolution of Mycobacterium tuberculosis and Homo sapiens. Immunol Rev. 2015; 264:6–24.

40.Lee RB, and De Vore I (eds.). Man the Hunter. Chicago: Aldine, 1968.

41.Barnes I, Duda A, Pybus O, and Thomas MG. Ancient urbanization predicts genetic resistance to tuberculosis evolution. Evolution. 2011;65:842–8.

42.Davies RPO et al. Historical declines in tuberculosis in England and Wales: Improving social conditions or natural selection? Int J Tuberc Lung Dis. 1999;3:1051–4.

43.Wilbur AK, Farnbach AW, Knudson KJ, and Buikstra JE. Diet, tuberculosis and the paleopathological record. Curr Anthropol. 2008;49:963–91.

44.Cohen MN. Health and the Rise of Civilisation. New York: Yale University Press, 1989.

45.Steckel R, and Rose JC (eds.). The Backbone of History. Health and Nutrition in the Western Hemisphere. Cambridge: Cambridge University Press, 2002.

46.Roberts CA, and Cox M. Health and Disease in Britain. Prehistory to the Present Day. Stroud: Sutton Publishing, 2003.

47.Hanks P. Collins Dictionary of the English Language. London: Collins, 1979.

48.Roberts CA. Old World tuberculosis: Evidence from human remains with a review of current research and future prospects. Tuberculosis 2015;95:S117–21.

49.Canci A, Minozzi S, and Borgognini Tarli S. New evidence of tuberculous spondylitis from Neolithic Liguria (Italy). Int J Osteoarchaeol. 1996;6:497–501.

50.Sparacello VS, Roberts CA, Kerudin A, and Müller R. A 6500-year- old Middle Neolithic child from Pollera Cave (Liguria, Italy) with probable multifocal osteoarticular tuberculosis. Int J Paleopathol. 2017;17:67–74.

51.Ortner DJ. Disease and mortality in the Early Bronze Age people of Bab edh-Dhra, Jordan. Am J Phys Anthropol. 1979;51:589–98.

52.Zias J. Leprosy and tuberculosis in the Byzantine monasteries of the Judaean Desert. In: Ortner DJ, and Aufderheide AC (eds.).

Human Palaeopathology. Current Syntheses and Future Options. Washington, DC: Smithsonian Institution Press, 1991, 197–9.

53.Morse D, Brothwell DR, and Ucko PJ. Tuberculosis in ancient Egypt. Am Rev Respir Dis 1964;90:526–41.

54.Elliot-Smith G, and Ruffer MA. Pottsche Krakheit an einer ägyptischen Mumie aus der Zeit der 21 dynastie (um 1000 v. Chr.). In: Zur Historichen Biologie der Kranzheit Serreger. Leipzig, 1910, 9–16.

55.Derry DE. Pott’s disease in ancient Egypt. Med Press Circ 1938;197:196–9.

56.Nerlich AG et al. Molecular evidence for tuberculosis in an ancient Egyptian mummy. Lancet. 1997;35:1404.

57.Zink A et al. Morphological and molecular evidence for pulmonary and osseous tuberculosis in a male Egyptian mummy. In: Pálfi G, Dutour O, Deák J, and Hutás I (eds.). Tuberculosis: Past and Present. Szeged: Golden Book Publishers, 1999, 371–91.

58.Santoja M. Estudio antropológico. In: Canellada AZ (ed.).

Excavaciones de la Cueva de la Vaquera, Torreiglesias. Segovia: Edad del Bronce, 1975, 74–87.

59.Angel JL. Health as a crucial factor in the changes from hunting to developed farming in the Eastern Mediterranean. In: Cohen MN, and Armelagos GJ (eds.). Paleopathology at the Origins of Agriculture. London: Academic Press, 1984, 51–74.

60.Grmek M. Diseases in the Ancient Greek World. London: Johns Hopkins University Press, 1989.

61.Moyart V, and Pavaut M. La tuberculose dans le nord de la France du IVe à la 62IIe siecle. Thèse pour le Diploma d’état de Docteur en Médecine. Lille 2, U du Droit et de la Santé, Faculté de Médecine Henri Warembourg, 1998.

62.Molnar E et al. Skeletal tuberculosis in Hungarian and French Medieval anthropological material. In: Guerci A (ed.). La cura della mallattie. Itinerari storici. Genoa: Erga Edizione, 1998, 87–99.

63.Blondiaux J et al. Epidemiology of tuberculosis: A 4th to 12th century­ AD picture in a 2498-skeleton series from Northern France. In: Pálfi G, Dutour O, Deák J, and Hutás I (eds.). Tuberculosis: Past and Present. Szeged: Golden Book Publishers, 1999, 521–30.

64.Djuric-Srejic M, and Roberts CA. Palaeopathological evidence of infectious disease in later medieval skeletal populations from Serbia. Int J Osteoarchaeol. 2001;11:311–20.

65.Brothwell D. The human bones. In: Harrison RM (ed.). Excavations at Saraçhane in Istanbul. Volume 1: The Excavations, Structures, Architectural Decoration, Small Finds, Coins, Bones and Molluscs. Princeton: Princeton University Press, 1986, 374–98.

66.Cunha E. Paleobiologia des populacoes Medievals Portuguesasoscasos de Fão e. S. oãoda Almedina. FCT, University of Coimbra, Portugal, unpublished PhD thesis, 1994.

67.Hershkovitz I et al. Detection and molecular characterization of 9000-year-old Mycobacterium tuberculosis from a Neolithic settlement in the Eastern Mediterranean. PLOS ONE 2008;3:e3426.

68.Wilbur AK et al. Deficiencies and challenges in the study of ancient tuberculosis DNA. J Archaeol Sci. 2009;36:1990–7.

69.Gladykowska-Rzeczycka JJ. Tuberculosis in the past and present in Poland. In: Pálfi G, Dutour O, Deák J, and Hutás I (eds.). Tuberculosis: Past and Present. Szeged: Golden Book Publishers, 1999, 561–73.

70.Rokhlin DG. Diseases of Ancient Men. Bones of the Men of Various Epochs – Normal and Pathologic Changes. Moscow: Nauka, 1965. [in Russian].

71. Nicklisch N, Maixner F, Ganslmeier R, Friederich S, Dresely V, Meller H, Zink A, and Alt KW. Rib lesions in skeletons from early neolithic sites in Central Germany: On the trail of tuberculosis at the onset of agriculture. Am J Phys Anthropol. 2012; 149:391–404.

72.Masson M, Bereczk Z, Molnár E, Donoghue HD, Minnikin DE, Lee OYC, Wu HH, Besra GS, Bull ID, and Pálfi G. Osteological and biomolecular evidence of a 7000-year-old case of hypertrophic pulmonary osteopathy secondary to tuberculosis from Neolithic Hungary. PLOS ONE 2013;8(10):e78252.

73.Bennike P. Facts or myths? A re-evaluation of cases of diagnosed tuberculosis in Denmark. In: Pálfi G, Dutour O, Deák J, and Hutás I (eds.). Tuberculosis: Past and Present. Szeged: Golden Book Publishers, 1999, 511–18.

74.Mays S, and Taylor GM. A first prehistoric case of tuberculosis from Britain. Int J Osteoarchaeol. 2003;13:189–96.

75.Mays S et al. Paleopathological and biomolecular study of tuberculosis in a medieval skeletal collection from England. Am J Phys Anthropol. 2001;114:298–311.

76.Jankauskas R. History of human tuberculosis in Lithuania: Possibilities and limitations of paleoosteological evidences. Bull Mém Soc Anthropol Paris. New Ser 1998;10:357–74.

77.Faerman M, and Jankauskas R. Osteological and molecular evidence of human tuberculosis in Lithuania during the last two millennia. Sci Israel Technol Adv. 1999;1:75–8.

78.Jankauskas R. Tuberculosis in Lithuania: Palaeopathological and historical correlations. In: Pálfi G, Dutour O, Deák J, and Hutás I (eds.). Tuberculosis: Past and Present. Szeged: Golden Book Publishers, 1999, 551–8.

79.Morel MMP, Demetz J-L, and Sauetr M-R. Un mal de Pott du cimitère burgonde de Saint-Prex, canton de Vaud (Suisse) (5me, 6me, 7me siècles). Lyon Med. 1961;40:643–59.

80.Pálfi G, and Marcsik A. Paleoepidemiological data of tuberculosis in Hungary. In: Pálfi G, Dutour O, Deák J, and Hutás I (eds.). Tuberculosis: Past and Present. Szeged: Golden Book Publishers, 1999, 533–9.

81.Haas CJ, Zink A, and Molnár E. Molecular evidence for tuberculosis in Hungarian skeletal samples. In: Pálfi G, Dutour O, Deák J, and Hutás I (eds.). Tuberculosis: Past and Present. Szeged: Golden Book Publishers, 1999, 385–91.

82.Pap I et al. 18th–19th century tuberculosis in naturally mummified individuals (Vác, Hungary). In: Pálfi G, Dutour O, Deák J, and Hutás I (eds.). Tuberculosis: Past and Present. Szeged: Golden Book Publishers, 1999, 421–42.

83.Arcini C. Health and Disease in Early Lund. Osteo-Pathologic Studies of 3,305 Individuals Buried in the First Cemetery Area of Lund 990–1536. Lund: Department of Community Health Sciences, University of Lund, 1999.

84.Horácková L, Vargová L, Horváth R, and Bartoš M. Morphological, roentgenological and molecular analyses in bone specimens attributed to tuberculosis, Moravia (Czech Republic). In: Pálfi G, Dutour O, Deák J et al. (eds.). Tuberculosis: Past and Present. Szeged: Golden Book Publishers, 1999, 413–17.

85.Kiple K (ed.). The Cambridge World History of Human Disease. Cambridge: Cambridge University Press, 1993.

86.Morse D. Tuberculosis. In: Brothwell D, and Sandison AT (eds.). Diseases in Antiquity. Springfield: Charles C Thomas, 1967, 249–71.

87.Suzuki T, and Inoue T. Earliest evidence of spinal tuberculosis from the Neolithic Yaoi period in Japan. Int J Osteoarchaeol. 2007;17:392–402.

88.Suzuki T, Fujita H, and Choi JG. Brief communication: New evidence of tuberculosis from prehistoric Korea—Population movement and early evidence of tuberculosis in Far East Asia. Am J Phys Anthropol. 2008;136:357–60.

89.Tayles N, and Buckley HR. Leprosy and tuberculosis in Iron Age Southeast Asia? Am J Phys Anthropol. 2004;125:239–56.

90.Pietruwesky M, and Douglas MT. An osteological assessment of health and disease in precontact and historic (1778) Hawai’i. In: Larsen CS, and Milner GR (eds.). In the Wake of Contact. Biological Responses to Conquest. New York: Wiley-Liss, 1994, 179–96.

91.Pietrusewsky M, Douglas MT, Kalima PA, and Ikehara R. Human skeletal and dental remains from Honokahua burial site, Hawai’i. Paul H Rosendahl Inc. Archaeological, Historical and Cultural Resource Management Studies and Services. Report 246-041091, 1991.

92.Trembly D. A germ’s journey to isolated islands. Int J Osteoarchaeol. 1997;7:621–4.

93.Platt C. Medieval England. A Social History and Archaeology from the Conquest to 1600 AD. London: Routledge, 1997.

94.Dyer C. Standards of Living in the Later Middle Ages. Social Change c.1200–1520, Rev ed. Cambridge: Cambridge University Press, 1989.

95.Crawfurd R. The King’s Evil. Oxford: Oxford University Press, 1911.

96.Whitney WF. Notes on the anomalies, injuries and diseases of the bones of the native races of North America. Annu Rep Trustees Peabody Museum Am Archeol Ethnol 1886;3:433–48.

97.Lichtor J, and Lichtor A. Paleopathological evidence suggesting pre-Columbian tuberculosis of the spine. J Bone Joint Surg 1952;39A:1398–9.

98.Judd NM. The Material Culture of Pueblo Bonito. Washington, DC: Smithsonian Institution Miscellaneous Collections, Vol. 124, 1954.

99.García-Frías JE. La tuberculosis en los antiguos Peruanos.

Actualidad Médica Peruana 1940;5:274–91.

100.Morse D. Prehistoric tuberculosis in America. Am Rev Respir Dis 1961;85:489–504.

101.Buikstra JE. Paleoepidemiology of tuberculosis in the Americas. In: Pálfi G, Dutour O, Deák J et al. (eds.). Tuberculosis: Past and Present. Szeged: Golden Book Publishers, 1999, 479–94.

102.Milner GR. The Cahokia Chiefdom: The Archeology of a Mississippian Society. Washington, DC: Smithsonian Institution Press, 1998.

103.Gregg ML. A population estimate for Cahokia. Perspectives in Cahokia Archeology. Bulletin 10. Urbana: Illinois Archeological Survey, 1975, 126–36.

104.Black FL. Infectious disease in primitive societies. Science. 1975;187:515–18.

105.Pfeiffer S. Rib lesions and New World tuberculosis. Int J Osteoarchaeol. 1991;1:191–8.

106.Milner GR, and Smith VG. Oneota human skeletal remains. In: Santure SK, Harn AD, and Esarey D (eds.). Archeological Investigations at the Morton Village and Norris Farms 36 Cemetery. Reports of Investigations 45. Springfield: Illinois State Museum, 1990, 111–48.

107.Buikstra JE. Differential diagnosis: An epidemiological model.

Yearb Phys Anthropol. 1977;20:316–28.

108.Eisenberg LE. Adaptation in a ‘marginal’ Mississippian population from Middle Tennessee. Biocultural insights from palaeopathology. New York University, unpublished PhD thesis, 1986.

109.Dean JS, Doelle WH, and Orcutt JD. Adaptive stress, environment and demography. In: Gumerman GJ (ed.). Themes in Southwest Prehistory. Santa Fe: School of American Research Press, 1994, 53–86.

110.Cordell LS. Archaeology of the Southwest, 2nd ed. San Diego: Academic Press, 1997.

111.Storey R. Life and Death in the Ancient City of Teotihuacan. Tuscaloosa: University of Alabama Press, 1992.

112.Kerr J. The Maya Vase Book. A Corpus of Rollout Photographs of Maya Vases. New York: Kerr Associates, 1989.

113.Buikstra JE, and Williams S. Tuberculosis in the Americas: Current perspectives. In: Ortner D, and Aufderheide AC (eds.).

Human Paleopathology. Current Syntheses and Future Options. Washington, DC: Smithsonian Institution Press, 1991, 161–72.

114.Requena A. Evidencia de tuberculosis en la América pre-Columbia.

Acta Venezolana 1945;1:1–20.

115.Allison MJ et al. Tuberculosis in pre-Columbian Andean populations. In: Buikstra JE (ed.). Prehistoric Tuberculosis in the Americas. Evanston: Northwestern University, 1981, 49–51.

116.Romero Arateco WM. Estudio bioanthropologico de las momias de la Casa del Marque de San Jorge de Fondo de Promocion de la Cultura, Banco Popular, Bogota. Carrera de Antropologia, Universidad Nacional de Colombia, 1998.

117.Stead WW et al. When did M. tuberculosis infection first occur in the New World? An important question for public health implications. Am J Resp Crit Care Med 2000;151:1267–8.

118.Clabeaux MS. Health and disease in the population of an Iroquois ossuary. Yearb Phys Anthropol. 1977;20:359–70.

119.Pfeiffer S, and Fairgrieve S. Evidence from ossuaries: The effect of contact on the health of Iroquians. In: Larsen CS, and Milner GR (eds.). In the Wake of Contact. Biological Responses to Conquest. New York: Wiley-Liss, 1994, 47–61.

120.Keers RY. Laënnec: A medical history. Thorax. 1981;36:91–4.

121.Lutwick LI. Introduction. In: Lutwick LI (ed.). Tuberculosis. London: Chapman and Hall Medical, 1995, 1–4.

122.Sontag S. Illness as Metaphor. AIDS and Its Metaphors. London: Penguin, 1991.

123.Bryder L. ‘A health resort for consumptives’. Tuberculosis and immigration to New Zealand 1880–1914. Med Hist. 1996;40: 453–71.

124.Clarke HD. The impact of tuberculosis on history, literature and art. Med Hist. 1962;6:301–18.

125.Cockburn A. The Evolution and Eradication of Infectious Disease. Baltimore: Johns Hopkins University Press, 1963.

126.Brown T, and Brown K. Biomolecular Archaeology. An Introduction. New York: Wiley-Liss, 2011.

127.Stone AC. DNA analysis of archaeological remains. In: Katzenberg MA, and Saunders SR (eds.). Biological Anthropology of the Human Skeleton. New York: Wiley-Liss, 2008, 461–83.

128.Cooper A, and Poinar HN. Ancient DNA: Do it right or not at all. Science. 2000;289:1139–41.

129.Wilbur AK et al. Deficiencies and challenges in the study of ancient tuberculosis DNA. J Archaeol Sci. 2009;36:1990–7.

130.Roberts CA, and Ingham S. Using ancient DNA analysis in palaeopathology: A critical analysis of published papers and recommendations for future work. Int J Osteoarchaeol. 2008;18:600–13.

131.Taylor MM, Crossley M, Saldanha J, and Waldron T. DNA from M. tuberculosis identified in Medieval human skeletal remains using PCR. J Archaeol Sci. 1996;23:789–98.

132.Haas CJ et al. Molecular evidence for different stages of tuberculosis in ancient bone samples from Hungary. Am J Phys Anthrop 2000;113:293–304.

133.Gernaey A et al. Correlation of the occurrence of mycolic acids with tuberculosis in an archaeological population. In: Pálfi G, Dutour O,

Deák J, and Hutás I (eds.). Tuberculosis: Past and Present. Szeged: Golden Book Publishers, 1999, 275–82.

134.Taylor GM et al. First report of Mycobacterium bovis DNA human remains from the Iron Age. Microbiology 2007;153:1243–9.

135.Zink AR et al. Molecular history of tuberculosis from ancient mummies and skeletons. Int J Osteoarchaeol. 2007;17:380–91.

136.Fletcher HA et al. Molecular analysis of Mycobacterium tuberculosis DNA from a family of 18th century Hungarians. Microbiology 2003;149:143–51.

137.Müller R, Roberts CA, and Brown TA. Genotyping of ancient Mycobacterium tuberculosis strains reveals historic genetic diversity. Proc Roy Soc. B 2014; 281(1781): 20133236.

138.Bos K et al. pre-Columbian mycobacterial genomes reveal seals as a source of New World human tuberculosis. Nature, 2014;514(7523): 494–7.

139.Spigelman M, and Lemma E. The use of polymerase chain reaction (PCR) to detect Mycobacterium tuberculosis in ancient skeletons.

Int J Osteoarchaeol. 1993;3:137–43.

140.Braun M, Cook D, and Pfeiffer S. DNA from Mycobacterium tuberculosis complex identified in North American pre-Columbian human skeletal remains. J Archaeol Sci. 1998;25:271–7.

141.Arriaza B, Salo W, Aufderheide AC, and Holcomb TA. PreColumbian tuberculosis in Northern Chile: Molecular and skeletal evidence. Am J Phys Anthrop 1995;98:37–45.

142.Taylor GM et al. Genotypic analysis of Mycobacterium tuberculosis from medieval human remains. Microbiology 1999;145:899–904.

143.Pálfi G et al. Coexistence of tuberculosis and ankylosing spondylitis in a 7th–8th century specimen evidenced by molecular biology. In: Pálfi G, Dutour O, Deák J, and Hutás I (eds.). Tuberculosis: Past and Present. Szeged: Golden Book Publishers, 1999, 403–9.

144.Faerman M et al. Prevalence of human tuberculosis in a Medieval population of Lithuania studied by ancient DNA analysis. Anc Biomol 1997;1:205–14.

145.Mehaafy MC, Kruh-Garcia NA, and Dobos KM. Prospective on

Mycobacterium tuberculosis proteomics. J Proteom Res 2012;11: 17–25.

146.Boros-Major A et al. New perspectives in biomolecular palaeopathology of ancient tuberculosis: A proteomic approach. J Archaeol Sci. 2011;38:197–201.

147.Bouwman AS, Bunning SL, Müller R, Holst M, Caffell AC, Roberts CA, and Brown TA. The genotype of a historic strain of

Mycobacterium tuberculosis. Proceedings of the National Academy of Science 2012;109:18511–6.

148.Guichón RA, Buikstra JE, Stone AC, Harkins KM, Suby JA, Massone M, Wilbur A, Constantinescu F, and Martín CR. Pre-Columbian tuberculosis in Tierra del Fuego? Discussion of the paleopathological and molecular evidence. Int J Paleopathol. 2015; 11:92–101.

149.Guthrie D. A History of Medicine. London: Thomas Nelson, 1945.

150.Pesanti EL. A short history of tuberculosis. In: Lutwick LI (ed.). Tuberculosis. London: Chapman and Hall Medical, 1995, 5–19.

151.Howe GM. People, Environment, Disease and Death. A Medical Geography of Britain through the Ages. Cardiff: University of Wales Press, 1997.

152.Roberts CA, and Bernard MC. Tuberculosis: A biosocial study of admissions to a children’s sanatorium (1936–1954) in Stannington, Northumberland, England. Tuberculosis 2015; 95:S105–8.

153.Meachen NG. A Short History of Tuberculosis. London: Staples Press, 1936.

154.Bryder L. Below the Magic Mountain. A Social History of Tuberculosis in 20th Century Britain. Oxford: Clarendon Press, 1988.

155.Glaziou P et al. Lives saved by tuberculosis control and prospects for achieving the 2015 global target for reducing tuberculosis mortality. Bull World Health Organ. 2011;89:573–82.

THE LENGTH AND BREADTH OF

TUBERCULOSIS EPIDEMIOLOGY

Why did tuberculosis (TB) decline in Europe and North America for much of the nineteenth and twentieth centuries but not elsewhere? What is the current direction of the global TB epidemic? How can we improve control of TB epidemics in line with ambitious global policy goals to end TB by 20351? This overview of TB epidemiology is structured around ten such questions about the distribution and control of the disease in human populations (Table 2.1).

The chapter has two more general themes. The first is that we cannot fully address the questions in Table 2.1 without considering the disease agent (M. tuberculosis), the host (humans), and the environment (e.g., migration, living conditions) as dynamic, interacting entities. Conventional tools of epidemiology such as cross-sectional, case−control, cohort studies and experimental trials,2 which often employ molecular methods to analyze and trace strains (i.e., molecular epidemiology), allow us to assess risk factors for infection, disease, and treatment outcomes, but these studies do not usually inform long-term projection of disease trends or population-wide impact of interventions. For instance, a new vaccine found to have a protective efficacy of 70% against pulmonary TB in adults would be a breakthrough for TB control, but by knowing only the protective efficacy, we could not predict the

community-wide impact of a vaccination program over 10 years. That understanding requires a knowledge of events that happen through interactions among individuals and across bacterial and human generations—of processes that can be understood and measured in terms of case reproduction numbers, heterogeneity in transmission, herd immunity, feedback loops, equilibrium, and evolutionary selective pressure.3

The second theme is that ending TB will require epidemiologists to take an imaginative and unrestricted view of the opportunities for intervention. Over the past 25 years, the chemotherapy of active TB, delivered initially under the rubric of the WHO directly observed therapy strategy (DOTS) (first extended as the stop TB strategy4 and now succeeded by the end TB strategy1), has come to be accepted as the cornerstone of good TB management. As a model of delivery, standardization, and evaluation, DOTS represented a major advance in the attack, not just on TB, but also on the principal endemic diseases of the developing world.3–5 However, DOTS did not sufficiently explain how TB programs could improve case detection and cure, especially by addressing broader social (e.g., financial support), behavioral (e.g., tobacco smoking), environmental (e.g., air pollution), and clinical (e.g., HIV) risks. The elimination of TB will depend on this, rather than just improving detection and care for individuals with active disease.

The Global Plan to End TB Strategy (2016–2020), framed by the objective of achieving Universal Health Coverage and nested

Table 2.1  Ten leading questions about TB epidemiology

1.What is the burden of TB worldwide, and which countries are most affected?

2.Why does M. tuberculosis cause epidemics of a lowincidence disease that run over centuries?

3.Why do some people get TB and not others?

4.Why did TB decline in Europe and North America for most of the twentieth century?

5.What factors explain resurgences of TB, like those seen in Africa and the former Soviet countries since 1990?

6.Do differences in M. tuberculosis strains modify the natural history, epidemiology, and control of TB epidemics?

7.How does TB interact with other diseases?

8.How can current tools, including broader interventions that address risk factors for poor health and strengthen health systems, be used to better control TB epidemics?

9.Will TB become resistant to all antibiotics?

10.How can the use of novel tools and pharmacological interventions (e.g., diagnostics, drugs, and vaccines) be informed by lessons learned from the recent implementation of advances (e.g., Xpert MTB/RIF)?

within the Sustainable Development Goals, represents a new plan by which the global community hopes to end TB by 2035.173 The End TB Strategy requires treating 29 million people with TB, preventing 45 million people from getting TB, and averting the catastrophic costs that patients and their families face due to TB. The objective of Universal Health Coverage will address some of DOTS’ prior limitations and ultimately enhance the End TB Strategy not only by drawing attention to cross-cutting risk factors that impact TB (e.g., alcohol) and were previously siloed by most national TB programs, but by incorporating these factors into the global TB reporting infrastructure, highlighting opportunities for targeted interventions. If widely implemented, the plan could result in a reduction in TB deaths by 90% and reduce the incidence rate (defined as the number of new cases per 100,000 population per year) by 80% (<20/100,000) compared to 2015.1,5 As we argue in this chapter, new perspectives, tools, and approaches are needed to accomplish these lofty goals. This requires, but by no means is limited to, drastically accelerating the hitherto slow decline in the epidemic, reducing the incidence of multidrug-resistant (MDR) TB, increasing the targeting of vulnerable populations in a costeffective manner using new tools, and, importantly, empowering national TB programs to better use local epidemiological data for decision making. Ultimately, all of this is underscored by a need to massively increase funding for TB, to support both research and programmatic implementation.6

WHAT IS THE BURDEN OF TB WORLDWIDE, AND WHICH COUNTRIES ARE MOST AFFECTED?

Based on notification reports and surveys, there were an estimated 10.4 million new TB cases in 2016. Assuming lifelong infection, about a quarter of humanity is infected with M. tuberculosis.7 Most

of the estimated cases in 2016 occurred in the WHO Southeast Asian Region (45%) followed by the WHO African Region (25%), where the burden of HIV-associated TB is highest and exceeds 50% in southern Africa. Despite having a lower incidence, extremely populous countries like India nevertheless account for a large proportion of the new cases ( 1 in 5) and TB deaths ( 1 in 4) worldwide.8

Although the overall burden of disease is still large, there has been substantial progress in worldwide TB control. In a reversal of patterns in the 1990s, the global incidence rate of TB has been declining since 2002 and the absolute number of new cases per year has been decreasing since 2006.5 While this represents an achievement, the overall rate of decline in per capita is slow (2% per year), and needs to accelerate (4%–5% per year) to reach the 2020 milestones of the End TB Strategy (Figure 2.1).5,8 Furthermore, some countries and regions (e.g., China, India) are still experiencing an increase in TB incidence and MDR TB.

Over the past two decades, while Asian countries had the most cases, countries in Africa and Eastern Europe have reflected global trends in incidence (Figure 2.1). Countries within sub-Saharan Africa and the former Soviet Union showed the greatest increases in case load during the 1990s and, despite falling case numbers in other parts of the world (principally West and Central Europe, the Americas, and the Eastern Mediterranean regions), were responsible for the overall rise in TB incidence per capita during the late 1990s and early 2000s. However, since 2013, most of the global increase in notifications is driven by India, with an estimated 37% increase from 2013 to 2016.8

TB prevalence (the estimated number of extant TB cases at a specific time) is falling more quickly than incidence (Figure 2.2). At the present rate, the global TB incidence will decrease from125/100,000 to 100/100,000 by 2035 yet, under the Global Plan accelerated investment scenario, it is expected to reach100/100,000 before 2020, before finally reaching elimination levels by 2035 (≤10/100,000).

There were approximately 1.7 million deaths from TB in 2016, of which one in five were in HIV co-infected individuals. TB is the world’s leading killer among infectious agents,5 with an overall estimated case fatality of 16% (deaths among all TB cases/ total number of incident TB cases). Mortality is substantially higher among individuals with untreated HIV-co-infection and for individuals with drug-resistant TB. While these statistics are grim, both regional and global mortality estimates are declining. From 1990 to 2010, global TB mortality had declined by more than one-third in HIV-uninfected patients while the incidence in HIV-infected patients slowly declined (Figure 2.2).8 The Stop TB Partnership goal of halving overall TB mortality rates compared with a 1990 baseline was met by 2015, but not in all regions (most notably Africa).

Although TB is among the top ten overall causes of illness and disability,11 estimation of burden remains imprecise, especially in high-burden countries where precision is most needed.12,13 Since 2002, national surveys of the prevalence of TB disease, which are done in a random cross-section of the population, have been undertaken in well over 20 countries and more are scheduled within the next few years. These surveys provide vital data in high-burden settings, but the world as a whole cannot be feasibly surveyed. Investment in high-quality routine surveillance

Rate per 100,000 population per year

Rate per100,000 population per year

TB incidence

200

150

All TB cases

100

Rate per 100,000 population per year

TB mortality (HIV-negative)

30

20

10

0

and innovative targeted sampling methods that build on systems already in place are needed to produce robust data for assessment and future planning.13,14

WHY DOES M. TUBERCULOSIS CAUSE EPIDEMICS OF A LOW-INCIDENCE DISEASE THAT RUN OVER CENTURIES?

Remarkably, the interaction between M. tuberculosis and humans is relatively low compared to the enormous burden of suffering

in at least three respects. First, as a rule of thumb, untreated sputum smear-positive cases infect 5–10 other individuals each year.15–17 For a prevalence of smear-positive disease of 0.1% (i.e., 100/100,000, a little less than the estimated global average of 122/100,000) an average contact rate of 10 per year would generate an annual risk of infection of 1%. Second, only about 5%–10% of infected individuals (in the absence of other predisposing conditions) develop “progressive primary” disease following infection and this proportion is lower in children and higher in adults.18–20 Third, the progression from infection to disease is slow, averaging 2–4 years.21,22 After 5 years, there is a low annual risk of