populations, seeking gold and other treasures. Decades later, Spanish soldiers, priests, explorers, and opportunists, whose number had increased dramatically by then, made their way north to what is now the United States. These newcomers may have brought cases of TB with them, specifically from the Euro-American lineage (the predominant lineage in North and South America), who then spread the disease to the Aboriginal populations of North America.
The arrival of European contacts from different sources harboring M. tuberculosis, did not lead to an instant, widespread epidemic of TB among susceptible Native Americans and Canadians: there was too much country and too few invaders. When nascent colonies started to enlarge, and Europeans began to mix with the Natives, smallpox and measles were far more frequent and deadly than TB.
An interesting study by Pepperell et al. [49] documents an unfamiliar sequence of low-level spread of TB from incoming migrants. These authors observed that a single Euro-American lineage M. tuberculosis – with a characteristic DS6Quebec genomic deletion – was at its highest circulating frequency in both Aboriginal populations in Ontario, Saskatchewan, and Alberta, and in French Canadian residents in Quebec. In addition, substantial contact among these populations occurred during a defined historical period of fur trading from 1710 to 1870. The results of historical and genetic analyses show that for around 100 years, small, widely scattered indigenous groups became infected by M. tuberculosis, thanks to an infrequent number of human migrants who were infected with low numbers of tubercle bacilli. Furthermore, large-scale TB epidemics did not appear in these communities before the late 19th and 20th centuries [49].
New Observations: Knowledge about susceptibility to the development of TB after exposure to M. tuberculosis includes several risk factors, most of which have been recognized for decades: malnutrition, inadequate ventilation, and overcrowding; once TB infection has occurred mental and/or physical stress, and impaired immunity exacerbate the likelihood that disease will occur. To a greater or lesser extent, all of these factors are related to warfare. Much more recently, whole genome sequencing and phylogenetic analyses have demonstrated more genetic diversity of human-adapted MTBC than previously believed [50]. As already described, 7 lineages, each having a number of sublineages, have been shown to govern intrinsic bacterial forces that affect the pathogenicity of tubercle bacilli. These new factors have increasing public health importance.
The East-Asian lineage, which includes the famous Beijing strain, has spread in successive global waves during the last 200 years, first during the Industrial Revolution, later during World War I (WWI), and lastly associated with the epidemic of HIV infection [51]. According to some, Beijing strains are allegedly endowed with “selective advantages,” including enhanced pathogenicity and/or virulence, and increased progression from infection to disease. Recent studies showing considerable variation among different Euro-American sublineages in the frequency of transmission of contacts to TB among index patients – from 15.7% in RD145 to 1.8% in RD219 – clearly indicate that further studies are needed to document the impact of “bacterial factors on transmissibility and pathogenicity” of human MTBC [52].
Epidemic Tuberculosis
During the 16th century, most of Europe was just beginning to recover from the devastating population losses that occurred during the 14th century pandemics of bubonic plague, which were exacerbated by local famines and wars. England’s population was 2.1 million inhabitants in 1400, half the number estimated in 1348 [53]. During the next 100 years, population growth in England had resulted in 4.1 million people by 1570, and a further increase to 4.8 million in 1600. The majority of the English in the early Middle Ages were subsistence workers, farmers, and laborers, eking out life despite wretched harvests, dreadful climates, and prevalent sickness. Local magistrates took care of business on behalf of wealthy nobles and landed gentry. Workers were widely dispersed throughout the countryside; towns were small and scarce: obviously unfavorable conditions for the spread of TB. Feudal society declined, however, in the 13th and 14th centuries due in part to the rise of a thriving merchant population that established sophisticated trading networks throughout England and Europe and weekly markets and fairs that promoted greater access to commercial goods, the expansion of towns, and the development of an urban artisan population that catered to local needs. Expanded trade and communication probably hastened the spread of TB at the time.
Consequently, during the next century, agricultural practices became more efficient, requiring fewer laborers and less physical input. Food became cheaper, wages rose a trifle; industrialization advanced and towns began to increase in size and number. Meanwhile, from 60,000 to 70,000 inhabitants in 1500, London, already by far the largest city in England, kept making room for ever-increasing numbers of people, causing the population to grow to 250,000 at the end of the 17th century [54]. And to make matters worse, these indigents, often desperately poor and undernourished, had to survive packed into abysmal living conditions: London became a model of crowd diseases. So, by the year 1631, as shown in Figure 2, 15% of all deaths in the city of London that year were attributed to TB [55]; and for the next nearly 200 years, the death rate from TB in the city of London remained enormous, peaking at around 25%, and finally beginning to decline around 1830.
A schematic model showing the trend of mortality from TB in Western Europe from 1740 to 1985 is illustrated in Figure 3 [56]. Death rates from TB peaked at the astronomic value of 1,000/100,000 population in 1800, and then declined at a fairly constant rate for more than 100 years, until the abrupt upsurge that occurred during and immediately after WWI, which was in part lengthened by the Spanish influenza pandemic that lasted until around 1920. Finally, the model illustrates the arrival in 1952 of “triple therapy,” which heralded the steep decline of TB mortality resulting from effective chemotherapy [56].
No one is quite sure what triggered the initial reduction in TB mortality that began around 1800. (Note that both the year and country of the decrease in death rates from TB varied from location to location, but from whatever peak was finally identified, mortality began to go down, with a few wrinkles but fairly consistently and for well over the succeeding 100 years.) In 1800 in Germany, there was no obvious cause for the decline, and it took place at least 82 years before Robert Koch discovered M. tuberculosis. One of the most frequently cited reasons for the reduction remains a rising standard of living, which includes better housing, improved nutrition, higher wages, and lower costs, when and if these actually occurred; public health efforts were meager at the time but may have helped somewhat; and there was the dawning realization that TB was a contagious disease that warranted isolation of sick patients.
The ups and downs of TB mortality varied considerably from one country to another during the 19th century: in Great Britain, it declined; in Ireland and Norway, it increased first; but in France mortality stayed “extremely high” the entire century [54]. During the 17th, 18th, and 19th centuries in Western Europe and then in the 18th and 19th centuries in the Eastern US, TB was by far the most important cause of death, and it remained the highest or one of the highest causes of mortality in several countries, including the US until around 1900. But once TB death rates started going down, they kept steadily decreasing until interrupted by WWI and then again by WWII.
The Industrial Revolution began in England in the mid-18th century and then spread to the rest of Western Europe. While the first and more