TUBERCULOSIS 0272-5231/97 $0.00 + .

20

THE ORIGIN AND

ERRATIC GLOBAL SPREAD
OF TUBERCULOSIS
How the Past Explains the Present and
Is the Key to the Future

William W. Stead, MD, MACP

"The student who dates his knowledge of
tuberculosis from Koch may have a
v e y correct but a v e y incomplete
appreciation of the subject"
SIR WILLIAM OSLER, 18923q
"The past is the key to our future."
LOUIS LEAKEY**
One can discuss the history of tuberculosis
in a variety of ways-i.e., tuberculosis in his-
tory, evolution of treatment, discovery and
use of antibiotics, and so on. I have chosen to
take a long view of the disease, starting with
the origin of the family Mycobacteriaceae and
describing the type of evolutionary forces that
could have given rise to Mycobacterium tuber-
culosis, the causative agent for human tuber-
culosis. Although some of the pieces of the
puzzle are missing, this hypothetical scenario
is supported at a number of points by firm
scientific evidence gained from recent genetic
and molecular research. These facts provide
reality checks.
Physicians in the Western world today
know tuberculosis as a chronic infection, par-
ticularly of the lung, and largely affecting the
poor and the elderly.'8, 48 In historic times,
however, it was a potentially fatal subacute
illness of the young2,17as well as a chronic
disease of adults. Persons encountering M.
tuberculosis for the first time must rely on
their innate system of preimmune antibacte-
rial defenses to resist the initial implantation.
If this fails, as shown by conversion of the
tuberculin skin test to positive, cell-mediated
immunity determines whether the infection
heals without incident or progresses to
chronic pulmonary tuberculosis. Unless it be-
comes impaired, this system usually is able
to control a healed infection for life. As a
result of these immune-system variations, the
disease varies widely in its incidence and
clinical course in different individuals and
populations, depending on living conditions
and duration of ancestral selection for resis-
tance to this ancient killer.
THE ORIGIN OF THE
TUBERCLE BACILLUS
The family Mycobacteriaceae antedates evo-
lution of animal life and comprises a number

From the Tuberculosis Program, Arkansas Department of Health; and the Department of Medicine, University of
Arkansas College of Medicine, Little Rock, Arkansas

CLINICS IN CHEST MEDICINE

VOLUME 18 NUMBER 1 * MARCH 1997 65

66 STEAD
of saprophytic soil bacteria that serve a vital
function in decomposing dead vegetable mat-
ter to enrich the soil as part of the life cycle
of plants and trees.23But as early genera of
the animal kingdom evolved, chance muta-
tions of mycobacteria produced species capa-
ble of parasitizing animals as they evolved-
e.g., reptiles, amphibians, fish, and birds.
Much later, as mammals evolved, a mutant
that we call M . bovis appeared that could
parasitize a very wide spectrum of warm-
blooded animals-e.g., rodents, marsupials,
deer, and l i v e s t o ~ kIt. ~remained
~ endemic in expose a family to airborne infection by M .
many species, spreading from prey to preda-
tor, comparable to tularemia today. But with-
out airborne spread within a closed space, it
could not become epidemic.
Similarly, mankind’s earliest experience
with M . bovis probably was quite sporadic
and caused by eating raw or inadequately
cooked game. Because it is only marginally
pathogenic for humans, it would have created
little selective pressure for survival of resis-
tant mutants among its human hosts. The
disease therefore remained endemic for many
centuries, causing an occasional case of tuber-
culous spondylitis, evidence of which has
been found in ancient Egypt and the high
Andes Mountains of Peru.
About 8000 to 10,000 years ago, another
factor was introduced in Europe as humans
there began to domesticate animals’O and to
supplement their diets with meat, milk, and
cheese. Children with a random mutation
that enabled them to metabolize lactose could
be weaned to cow’s or goat’s milk and were
better nourished than their lactose-intolerant
counterpart^.^^ These children would have
had a better chance of surviving and repro-
ducing. It has been speculated, however, that
this advantage from drinking milk increased
the frequency of childhood infection with
milk-borne M . bovis. Although the resulting
infection was often a self-limited enlargement
and draining of the cervical lymph nodes
(called scrofula), it occasionally spread to
other organs and bones and could be fatal.
Whether early exposure to M . bovis con-
ferred protective advantage to European pop-
ulations has been argued. In 1886 M a ~ f a n ~ a~ sporadic disease, because other factors for
noted that individuals with scars from scrof-
ula rarely developed phthisis (chronic pulmo-
nary tuberculosis) as adults.22 In effect, an
episode of M. bovis infection served as a risky
form of vaccination against later tuberculosis,
much as a bout of cowpox appeared to pro-
tect against subsequent smallpox. The long-
term selective effect of the combination of
these two selective factors is reflected in the
significantly greater resistance to tuberculosis
and lactose tolerance in persons of European
Juxtaposition of humans and cattle has
been proposed as a means for the evolution
of M. tuberculosis. During the cold European
winters (Rome is the same latitude as Chi-
cago), humans had to share their houses with
their animals for heat conservation, as well as
security. One coughing cow therefore could
bovis. This created a niche for a mutant more
pathogenic for humans and much less patho-
genic for most other animals. Like M . bovis,
M . tuberculosis could not survive in the envi-
ronment and was dependent upon transmis-
sion from host to host.
The new airborne pathogen placed great
pressure on survival of children, favoring sur-
vival and reproduction of the better-nourished
lactose-tolerant individuals.= Geographic sepa-
ration, whether by desert, sea, or mountains,
isolated other populations from selective pres-
sure from M . tuberculosis for centuries. At the
same time, the prevalence of lactose malab-
sorption in most other areas produced no
pressure to favor development of dairying
and herds of livestock.
The validity of this scenario for the evolu-
tion of M . tuberculosis is attested by modern
studies in bacillary genetics. The various spe-
cies of mycobacteria bear close resemblance
to one another. The DNA of M. bovis and
M . tuberculosis is so nearly identical they are
considered one species, along with M . microti
and M . a f r i c a n ~ r n .Only
~ ~ recently has a ge-
netic marker been discovered that is specific
for M. bovis, but it is not related to the differ-
ence in pathogenicity of M . bovis and M . tu-
berculosis.M
ENDEMICITY OF TUBERCULOSIS IN
INDO-EUROPEANS
Although M . tuberculosis had found its
niche in humans, it must have persisted as
epidemic spread were still missing. In very
susceptible individuals, the disease resem-
bled typhoid fever39,59 and killed its host too
quickly to produce an efficient
Individuals whom chance favored with
greater resistance, however, gradually began
to survive the primary invasion. The more
 THE ORIGIN AND ERRATIC GLOBAL SPREAD OF TUBERCULOSIS
survivors of the primary infection, the greater
the number who developed pulmonary tuber-
culosis and became efficient spreaders of
the organisms. Nonetheless, tuberculosis re-
mained a sporadic endemic disease in Europe
for many centuries.51It presumably presented
a minor environmental hurdle for survival
of children because of occasional contact
with infectious persons, as well as exposure
through drinking contaminated milk. Condi-
tions still were not right to initiate the world’s
first epidemic of tuberculosis.
THE EPIDEMIC CURVE
FOR TUBERCUOSIS
In 1958, GriggZ0pointed out that the shape
of the epidemic curve for tuberculosis is the
same as for any other infectious disease, if
one adjusts the time scale on the horizontal
axis to allow for differences in duration. Epi-
demics all have a rapid ascent as the infection
spreads, slowing as the number of susceptible
subjects is reduced and then a descending
slowly to the baseline as the pool of suscepti-
ble individuals is depleted by death.
History has seen epidemics of smallpox,
measles, and bubonic plague begin, grow, de-
cline, and disappear many times. The thing
that makes this picture difficult to envision in
the case of tuberculosis is that the epidemic
that began in Europe in the eighteenth cen-
tury developed in a population in which
some selection for resistance to it already ex-
isted. Even so, this epidemic still has not com-
pleted one cycle. It is important to realize
that there is not a single worldwide epidemic
0 600
0
15! 500
L.
&
c
400
Q
a 300
.-2
! 2oo
[ /r-\
100
50 100 150
Years
Figure 1. Tuberculosis morbidity and mortality after the infection is established in a population
having no prior experience with it. (Adapted from Grigg ER: The arcana of tuberculosis. American
Review of Tuberculosis and Pulmonary Disease 78:160, 1958, with permission.)
67
of tuberculosis, but many concurrent epi-
demics? 51 having started at different times,
varying from 300 years ago in Europe to as
few as 25 years in Ama~onia.~
Just as the effectiveness of a single bacteri-
cidal antibiotic comes to an end by selection
of resistant mutants for survival and repro-
duction, epidemics of infection end by some
combination of immunity or natural selection
favoring resistant mutants for survival and
reproduction.4ONature provides enough flex-
ibility of the human genome to permit even-
tual adaptation to any lethal threat over many
generations. It therefore can be predicted that
even the acquired immunodeficiency syn-
drome (AIDS) epidemic will subside eventu-
ally, even if no cure is found. The time scale
presumably will be quite long, however.
As can be seen in Figure 1, Grigg’s curve
for a tuberculosis epidemic depicts rates of
tuberculosis exposure, disease, and mortality
over the roughly 300-year duration of the epi-
demic after adequate introduction of the in-
fection into a virgin population.20It should be
noted that, as the epidemic starts, the mortal-
ity rate rises quite steeply, reflecting the rap-
idly fatal course the early cases tend to run.
Although theoretical, this curve is based upon
extensive mortality and morbidity data re-
ported from a number of countries, particu-
larly Great Britain, continental Europe, and
the United States. Note that the descending
limb is much longer and less steep than the
ascending limb and that mortality rate peaks
50 years or more before morbidity peaks.
After about 300 years, the epidemic has
largely run its course, although the incidence
probably will never reach zero.
TB Morbidity
1000
TB Mortality 1 500
200 250 300
68 STEAD
1000 -
0
INDUSTRIAL REVOLUTION
’
0
8
500 - Endemic --
\
E
.-- Epidemic -
m
c
8
a
1600 1700
Figure 2. Tuberculosis morbidity as it changes from an endemic infection to an
epidemic disease, as it did in Europe during the Industrial Revolution.
A point that is not shown in Grigg’s curves
is the considerable delay that M . tuberculosis
experiences in becoming established in a new
population. Whereas introduction of a single
individual with measles or smallpox into a
susceptible population will establish an epi-
demic, this is not true of tuberculosis. In the
absence of treatment, tuberculosis is likely to
kill its first several victims without producing
cavitary pulmonary lesions. It is when a num-
ber of infectious chronic cases are mixed with
a new population for a prolonged period that
an epidemic results.19,57 Even then, the disease
is likely to occur at a very low level (endemic)
for a prolonged period unless crowding of
the population facilitates spread of the infec-
tion. The theoretical shape of such a curve is
shown in Figure 2, with the flat initial portion
representing the endemic phase before the
disease reaches epidemic proportions.
Bubonic plague is another disease in which
an epidemic cannot be initiated by a single
diseased person. The disease becomes epi-
demic either when there is a great release of
fleas because of a rat die-off or when some
cases survive long enough to advance to the
pneumonic stage. These events can greatly
facilitate a rapid increase in the number of
highly infectious cases, initiating an epidemic.
The morbidity and mortality from tubercu-
losis in a population vary with the epidemic’s
progression along this curve.2,51 Gradual de-
clines of morbidity and mortality from the
disease occur in populations that are well
along the descending limb of the curve. Ad-
vances such as the discovery of the tubercle
bacillus, the use of tuberculin skin testing,
the development of the chest radiograph, the
sanatorium movement, the widespread use of
1800 1900 2000
Year
BCG vaccination, two world wars, or even
the advent of effective chemotherapy have
had only minimal impact on the shape of the
curve of the oldest epidemic, that in Western
Europe and the Middle East. A guide to de-
termine the stage of the epidemic in a particu-
lar region is the age of the population most
affected. Early in an epidemic, the disease
takes a heavy toll among children and young
adults. As the epidemic progresses, the group
at greatest risk shifts gradually from the
young to older and older persons. In most
Western countries, prior to the human immu-
nodeficiency virus (HIV) epidemic, tuberculo-
sis had become largely a disease of older peo-
ple, with disease caused by recrudescence of
old infections,4*,53 indicating that new infec-
tions were less frequent. The AIDS epidemic
is changing this picture in many countries
and eventually will in all. This point is dis-
cussed in the article by McCray, Weinbaum,
Braden, et a1 in this issue.
THE BEGINNING OF THE WORLD’S
FIRST TUBERCULOSIS EPIDEMIC
The first point that should be understood
is that there is not one worldwide epidemic
of tuberculosis, but many separate epidemics,
because M . tuberculosis was seeded at very
different times into various populations that
were quite isolated from one another by
desert, sea, mountains or political boundar-
ies.2,51
The tuberculosis epidemic in Europe devel-
oped in a population in which both bovine
and human tuberculosis had been endemic
for centuries. As a result, individuals who
 THE ORIGIN AND ERRATIC GLOBAL SPREAD OF TUBERCULOSIS
became infected commonly survived the pri-
mary stage but often developed chronic pul-
monary tuberculosis, much as we see today.
The population was largely rural but, even in
cities, great crowding was not a major prob-
lem. The essential ingredient for epidemic
spread was introduced with the coming of
the Industrial Revolution in the eighteenth
century, when crowded cities and wide-
spread poverty in Europe set off the
epidemicz,50(see Fig. 2).
In that period, tuberculosis was called the
"Great White Plague." It is not clear whether
this was to distinguish it from bubonic plague
(The Black Death) or because it was limited
to Cau~asians.'~ The incidence of tuberculo-
sis in Europe increased very sharply.20An
uninhibited tuberculosis epidemic generally
reaches its peak in a new population within
50 to 75 years after onset and then shows
a steady, but much slower, decline as more
resistant members are favored for survival
and propagation, gradually enhancing the
"herd" immunity of the population. After
reaching its peak, the rate of decline in inci-
dence generally is about 1% to 2% per year.2o
Widespread chronic infectious pulmonary
tuberculosis in the presence of such a great
population density in the ever-enlarging cities
provided the ideal conditions for airborne
spread of many infections, including tubercu-
losis. The epidemic grew and spread rapidly
through Western Europe. During that time,
virtually everyone in Western European cities
became infected with M. tuberculosis by age
25 to 30 and about 25% of all deaths were
attributable to the disease.I7 The particular
combinations of factors that characterized this
epidemic had never come together previously
anywhere in the world.
Tuberculosis was slow to spread to eastern
Europe because of its much later industrial-
ization and the great difficulty of traveling
over formidable mountain ranges or political
As late as the 188Os, tuberculo-
sis was not commonly seen in Russiaz7and it
is reported to have been relatively uncommon
in India at that time.58
The epidemic was taken to colonial North
America by European settlers.16In Boston, tu-
berculosis mortality was 650/100,000 in 1800
and fell to 400 by 1860.20The death rate for
New York City was 750/100,000 in 1805 and
had fallen to 400 by 1870. The death rate
for Baltimore was 400/100,000 in 1830 and
decreased to about 210 by 1900. Over the
succeeding generations, the death rate de-
69
creased progressively for cities along the
Northeastern seaboard. By 1904, the tubercu-
losis death rate for the United States was 188;
by 1920,100, and by 1969,4/100,000 per year.
As Europeans colonized other geographic
areas over the next two centuries, individuals
with chronic pulmonary tuberculosis carried
the infection to seaports around the world.
Primitive means of travel and hostility to-
ward hinterlanders prevented significant
spread to the interior, however. Tuberculosis
reached the coastal people of Africa and New
Guinea early in the nineteenth century, for
example, but penetrated to the interior of Af-
rica only about 1910 and New Guinea in
about 1950.5As a result, populations of those
areas remain much more susceptible to the
infection than those of European heritage.
There are several analogies for the manner
in which populations acquire resistance to a
serious environmental stress, such as tubercu-
losis was before effective chemotherapy. Per-
haps the easiest to understand is the manner
in which a large population of M . tuberculosis
becomes resistant to isoniazid (INH), a highly
bactericidal drug: The one bacillus in a mil-
lion with a chance mutation providing an
alternate metabolic pathway around the poi-
sonous effect of INH starts the process. As
all susceptible bacilli are killed, the surviving
bacilli are resistant to INH. As these multiply,
the entire population becomes resistant to the
drug. Similarly, the high frequency of sickle-
cell hemoglobin in the African malaria belt
developed through natural selection of carri-
ers of the hemoglobin-S gene because of their
resistance to growth of plasmodia in their red
blood cells. An even more widely distributed
innate resistance to malaria, developed by the
same mechanism, was described by Hill et
aLZ6They have identified a genetic basis for
variation in resistance to infection by M. tu-
berculosis among humans in Gambia, the area
from which most of the American slaves
came over several centuries.z6
When only one or two members of a primi-
tive population become infected with tuber-
culosis, it is likely to pursue a rapid course
to death, resembling typhoid fe~er.3~. 59 This
would be quite unlikely to set off an epi-
demic. Epidemic spread would occur only
when contact with persons with chronic pul-
monary tuberculosis was so common that
enough innately resistant individuals in the
population would survive long enough to de-
velop chronic pulmonary tuberculosis and
become infectious themselves.
70 STEAD
The devastation caused when tuberculosis
does become epidemic in a primitive popula-
tion is exemplified by the experience of many
Native American6 and Alaskan tribes19 and,
more recently, by the experience in New
Guinea5 and the high Amazon territory (A.
de Sousa, personal communication, 1995). In
such areas, the incidence may run as high as
6000 to 8000/100,000 per year and affected
populations may be decimated. Adaptation to
the infection occurs slowly, over 50-75 years,
because it depends upon elimination of sus-
ceptible individuals and survival of random
resistant mutants.24,40
When M . tuberculosis reached Japan in
about 1850, it was slow to take hold. When
rapid industrialization began there in about
1895, with its attendant poverty and crowd-
ing, however, the stage was set for a national
epidemic. That is the subject of a recent book,
The Modern Epidemic by William Johnston, de-
scribing the tuberculosis epidemic in Japan
beginning about 1895. Mortality reached 250/
100,000 per year by 1920, before declining
gradually. It had not yet been controlled in
1950, when it was blunted by the advent of
effective antibiotics against the organism.
Tuberculous spondylitis existed in Egypt as
early as 3700 BC.~OArcheologists also have
found evidence in remains of pre-Columbian
Native Americans in both North and South
America.’, In a recent paper, Salo et a141
claimed identification of DNA from M . tuber-
culosis of the human variety from material
from an exceptionally well-preserved Peru-
vian mummy. It must be remembered, how-
ever, that M . tuberculosis cannot be distin-
guished from M . bovis by the methods those
authors used. That distinction can be made
only in living organisms by showing differ-
ences in biochemical tests and host pathoge-
nicity between the two subspecies. Consider-
ing other evidence that M . tuberculosis, var
hominis, was first brought to this continent by
European explorers and settlers,16it therefore
is much more likely that the specimens found
in the Americas were caused by its predeces-
sor, M . bovis, which almost certainly was
present in the Americas before the arrival of
Columbus.51
Technology was most advanced in Western
Europe, as were navigation, exploration, and
colonization. Because those were the popula-
tions in which tuberculosis had become a
chronic pulmonary disease with great poten-
tial for person-to-person spread, they took the
infection to many populations that had never
before experienced it. If only a person or two
became infected, the disease killed too
quickly to establish itself. But where contact
with Europeans was prolonged enough for
survivors of the primary phase to accumulate,
the infection could become endemic with a
relatively high mortality. Development of an
epidemic, however, depended upon an in-
crease in population density.
TUBERCULOSIS AMONG
NATIVE AMERICANS
Tuberculosis caused by M . bovis probably
was sporadic among Native Americans prior
to European colonization. It is estimated that
the combined population of the North and
South American continents in the immediate
pre-Columbian period was about 60 million,
with only 4 million living in North America.
The largest North American population ten-
ter was at Cahokia, across the Mississippi
River from the present city of St. Louis. It had
a population estimated to number between
25,500 and 43,000.7 Several other population
centers existed in Central and South America.
These population figures are comparable with
those found in neolithic Egypt, Germany,
and France.
Although native Americans did not domes-
ticate herd animals, they must have come into
contact with many animal species known to
be susceptible to M . bovis, such as squirrels,
llama, bison, and deer. Human tuberculosis
caused by M . bovis almost certainly existed
among Native Americans before Columbus
but, without airborne transmission, it must
have been uncommon. Certainly, later evi-
dence indicates it played little role in selection
for resistance to the infection.
Buikstra and Cook7 examined over 1400
prehistoric human skeletons from eight popu-
lation centers in Illinois dating to the period
between 100 BC and 1300 AD. A few skeletons
show deformities compatible with, but not
diagnostic of, tuberculous spondylitis, com-
monly called Pott’s diseuse. Allison et all ob-
served acid-fast bacilli in the lungs of a
mummy from southern Peru (700 AD). Pott’s
disease-like deformities dating to 160 BC have
been found in Peru. The development of en-
demic bovine tuberculosis in that setting is
compatible with the known complex society,
with established agriculture, that existed
there as many as 9000 years ago.
Tuberculosis remained a rare disease with
 THE ORIGIN AND ERRATIC GLOBAL SPREAD OF TUBERCULOSIS
little or no human-to-human spread among
many isolated tribes of native North Ameri-
cans well into the nineteenth century. Jesuit
priests who explored the Great Lakes region
indicated that there were cases of glandular
infection and chronic pulmonary lesions,
probably tuberculous, but such cases were
uncommon. Because Native Americans had
never domesticated cattle, they were lactase
deficient and drank no milk. Scrofula there-
fore was practically nonexistent among the
Native Americans. Such an endemic disease
would have created little selective pressure
on the population.
Sporadic cases of tuberculosis had been ob-
served among the Plains Indians of Western
Canada as early as 1858 and it may be as-
sumed that the disease spread steadily in the
interval up to 1880. Tuberculosis did not be-
come a scourge among the Indians, however,
and it was not the major cause of death until
after they had been settled on the reservations
in the 1880s. This is confirmed by the general
death rate during the period between the be-
ginning of treaty payments in 1874 and the
date of settling on reservations in the 1880~.‘~ the body.
Whenever Native Americans were forcibly
settled in compounds, living in small fixed
huts, a localized outbreak of tuberculosis
was likely to develop. Contact with the sur-
rounding European settlers was frequent and
children were crowded into boarding schools
with virtually no medical care. Under those
conditions, tuberculosis could spread from
settlers with chronic tuberculosis to the na-
tives. When several hundred Apache Indian
prisoners were kept in the Mount Vernon
barracks by the US Army in 1887, for exam-
ple, the overall death rate rose from 54.61
1000 in the first year of imprisonment to
142.8/1000 in the fourth year. The mortality
was largely caused by tuberculosis? sug-
gesting a lack of innate resistance to the infec- lack of ancestral experience with tuberculosis.
tion.
When Native Americans were confined to
reservations, death rates from tuberculosis in-
creased rapidly. By 1886, the tuberculosis
death rate reached 9000/100,000.19These rates
are 10 times higher than ever observed in
Europe at the peak of the epidemic there and,
indeed, are the highest rates ever recorded
anywhere. All of this strongly suggests a very
great susceptibility attributable to lack of an-
cestral experience with the infection, although
Clark” has argued that the great incidence of
the disease in Native Americans was caused
by changes in various ecologic factors.
71
TUBERCULOSIS IN
AFRICAN-AMERICANS
Despite the rapid spread of the tuberculosis
epidemic in Europe and descendants of Euro-
pean ancestry in North America, the disease
spread quite erratically to African-Americans.
When Africans were taken to the United
States as slaves, they apparently brought no
tuberculosis with them.52As they began to
have contact with whites, however, cases of
subacute fatal (typhoidal) tuberculosis devel-
oped. Several such cases in slaves were de-
scribed in detail by Yandel in 1837.59 This
form of the infection did not spread readily
because of the brevity of illness and only
terminal involvement of the lungs. Analo-
gously, we recently reported such a patient
with miliary tuberculosis who infected none
of 55 ward personnel caring for him over a
period of 3 weeks; however, all five tubercu-
lin-negative personnel who attended his au-
topsy were infected.55Organisms isolated from
two of these showed RFLP fingerprints iden-
tical to that of the organisms cultured from
There was a gradual increase in the tuber-
culosis death rate among slaves between 1822
and 1861. Following the Civil War and libera-
tion from slavery, blacks began to move to
cities, where contacts were closer both among
themselves and with Europeans. Tuberculosis
morbidity and mortality rose rapidly; in 1912,
the rate for blacks in the United States
reached 700/100,000.20~ 34 The rate of spread
increased as more survivors of the subacute
illness went on to develop chronic cavitary
pulmonary lesions of much greater infec-
tiousness for associates. Although much of
the devastation was attributable to miserable
social conditions, the subacute and fatal
course of the primary infection attests the
Although native blacks showed much less re-
sistance to tuberculosis compared with British
troops on Caribbean islands, the natives
showed much greater resistance to malaria
and yellow fever, infections that had played
a significant role in selection of their ancestors
for survival and propagation.14a
TUBERCULOSIS IN
SUBSAHARAN AFRICA
Although tuberculosis was known on the
coast of Africa during the period of the Euro-
pean epidemic, it was practically unknown in
72 STEAD
the interior. Very few Europeans reached that
area because of difficult and treacherous
travel and almost certain death because of
indigenous African diseases+.g., malaria,
yellow fever, or schistosomiasis.52 Several
physicians reported its absence from that
area. HirschZ7reported in 1860 that the native
population of an Algerian city of 25,000 was
free of tuberculosis over a period of at least 8
years. Cummins13 reported on his own and
other Army medical officers' experiences and
noted that tuberculosis was almost unknown
in those parts of Africa where the European
influx had not yet 0cc~rred.I~ Both Lich-
tensteinZ9and Livingstone30reported finding
no tuberculosis in parts of South Africa as
late as the first half of the nineteenth century.
In 1867, Budd6 expressed surprise at finding
no tuberculosis in Subsaharan Africa. Finally,
GrzybowskiZ2has estimated, on epidemio-
logic evidence, that tuberculosis could not
have reached that area until about 1910.
Tuberculosis was rare among Africans who
lived in small remote villages and largely out
of doors, where airborne transmission of the
tubercle bacillus was unlikely. When they
were exposed to the disease by close contact
with Europeans, however, they experienced a
high mortality rate from a subacute typhoidal
illness similar to that observed among Native
Americans. When healthy young Senegalese
men were conscripted in defense of France in
World War I, for example, they had their
first experience with tuberculosis while living
under military conditions in close contact
with French soldiers. They were decimated
by subacute disseminated tuberculosis?
Records from one such camp reported 48 tu-
berculosis deaths in 1910, 312 in 1917, and
557 in 1918, clearly an exponential rise in the
number of cases, as occurs in a very suscepti-
ble population.
In 1907, soldiers from the interior of Sudan
were recruited for the Egyptian Army and
lived with Egyptian troops under crowded
military conditions. The Sudanese suffered a
fate similar to that of the Senegalese, whereas
the more resistant Egyptians showed only
chronic pulmonary lesions, with little mortal-
ity,14 strongly suggestive of a considerable
difference in ancestral experience with tuber-
culosis.
Around the turn of the century, European
tuberculosis patients moved in great numbers
to the salubrious climate of the South African
mountains to "take the cure" for their tuber-
culosis. With this influx of infectious cases,
the native population had its first exposure to
tuberculosis. Millar37reported the increasing
frequency of tuberculosis in South Africa in
1908.37Its increase was accelerated when it
reached the natives in the gold mines. To this
day, South African men suffer one of the
highest case rates in the world because of the
combination of crowded living conditions, ex-
posure to silica dust in the gold mines, and
their lack of ancestral experience with the
disease. Miners still must live in crowded
dormitories apart from their families, permit-
ted to return home once a year to impregnate
their wives and infect their whole family with
tuberculosis. The epidemic curve of tubercu-
losis morbidity and mortality in Africa had
not reached its peak before it was turned up
sharply by the advent of HIV infection. The
problem became serious enough that, in 1991,
Stanford45 raised the question, "Is Africa
Lost?"
TUBERCULOSIS IN ASIA AND THE
PACIFIC ISLANDS
As late as 1855, tuberculosis was rare in
the Hawaiian Islands. W i l k i n s ~ nremarked
~~
upon the rarity of tuberculosis in India in the
first half of the nineteenth century and its
gradual increase in the middle years of the
nineteenth century, as population density and
industrialization increased. It is unclear when
India and Asia first experienced tuberculosis.
It is known that the incidence was high to-
ward the end of the nineteenth century and
remains so today. In contrast, tuberculosis
was still unknown in the highlands of New
Guinea5as late as 1951, and 1971 in the high
Ama~on.~
THE MECHANISM BY WHICH A
POPULATION ACQUIRES NATURAL
RESISTANCE TO AN INFECTION
Selection of individuals in a population
who are resistant to a given parasite occurs
only if exposure is very frequent and the re-
sulting disease produces a high mortality
prior to or during the reproductive age, as tuber-
culosis does early in an epidemic.
The evolutionary pressure of infectious
pathogens in the struggle for survival of all
species has been dramatic. The noted histo-
rian William H. McNeilP5calls infectious dis-
eases one of the fundamental determinants of
 THE ORIGIN AND ERRATIC GLOBAL SPREAD OF TUBERCULOSIS
human history. As successive generations are
subjected to an inexorable elimination of the
most susceptible young people, the percent-
age of individuals resistant to that parasite
gradually increases. This is the way infections
such as measles, mumps, varicella, and per-
tussis became benign childhood diseases,
leaving survivors immune for life. Increased
innate resistance to these infections through
natural selection explains the modest child-
hood mortality from these infection^.^^
It is well known that the selective pressure
of some infectious agents has worked to hin-
der the natural selection process from elimi-
nating the genes for inherited diseases that
otherwise would destroy the species. The best
understood example for this in humans is
the compensating advantage provided by the
gene encoding for sickle-cell anemia. Homo-
zygous carriers of this gene die young and
thereby lose out in the reproduction race. The
much more numerous heterozygous carriers
resist malaria better than individuals without
this gene. This resistance of heterozygotes ex-
plains the persistence of the gene in malarial
areas.
More recently, Hill et alZ6observed a group
of West Africans who show resistance to se-
vere malaria that is quite separate from sickle
hemoglobin and is associated with human
leukocyte antigens (HLA) of the plasmodium.
Resistance to malaria on this basis is present
much more frequently in West Africans than
in other racial groups. This supports the con-
cept of natural alteration of susceptibility to
an infectious pathogen by elimination of the
most susceptible members of a population
over many generations. Hillz5now is reported
to have found a genetically based range in
susceptibility to tuberculosis in blacks in
Gambia, West Africa, the area from which
many of the slaves in America came. This is
a potentially important finding.
A study of the descendants of Dutch fami-
lies who had immigrated to Surinam in 184515
showed resistance to typhoid fever and ma-
laria among the 40% of the population that
had survived sequential epidemics of these
two diseases.
A more relevant example of this selective
effect for tuberculosis is the relative resistance
of those of Jewish descent noted by McCarthy
at the Boston Consumptives Hospital in
1912.34He postulated that the forced urban-
ization of those of Jewish descent in crowded
ghettos in Europe during the peak of the tu-
73
berculosis epidemic had selected a subset of
tuberculosis-resistant survivors. OBrien3shas
pointed out that the gene encoding for this
resistance is closely linked to the gene encod-
ing for Tay-Sachs disease, a genetically trans-
mitted fatal disease of young children. Ash-
kenazi Jews who are heterozygous carriers of
this gene represent a good example of a rare
and fatal genetic disease persisting in a popu-
lation because of a genetic advantage that is
closely linked.38Over many generations, the
heterozygous state provided a special advan-
tage of resistance to tuberculosis when expo-
sure was universal in the eastern European
states of Austria, Hungary, Czechoslovakia,
and Yugoslavia.
STUDIES OF MECHANISMS
OF HERD RESISTANCE
TO TUBERCULOSIS
The mechanisms that allow a host popula-
tion to develop natural resistance to tubercu-
losis have been studied by a number of inves-
tigators. Lurie31 used selective breeding
techniques to develop colonies of rabbits that
were either highly resistant or highly suscep-
tible to M . bovis. The highly resistant rabbits
showed localized chronic pulmonary lesions
after inhaling large numbers of M . bovis,
whereas the susceptible rabbits showed rap-
idly progressive generalized spread of infec-
tion after inhaling a much smaller number of
bacilli. More recently, Skamene's group42,56
has shown that resistance of mice to infection
with small doses of M. bovis is under the
control of a single gene. This gene affects the
capacity of the host to restrict proliferation of
tubercle bacilli during the pre-immune, mac-
rophage-laden phase of the infection. The re-
sistance is expressed by mature tissue macro-
phages independently of T, 8, and natural
killer T cells. Skamene and coworkers4*,56 hy-
pothesize that the gene regulates the level
of macrophage activation. Macrophages from
innately resistant mice switch rapidly to the
activated mode, capable of lysing ingested
bacilli. Macrophages from innately susceptible
mice are activated more slowly. Skamene's
group4* has cloned this gene, which may
make it possible to enhance pre-immune re-
sistance to tuberculosis, as I suggested re-
cently.46
The relationship between the protective
gene in the mouse and the expression of
74 STEAD
major histocompatibility (MHC) glycopro-
teins has been explored by several investiga-
tors. These glycoproteins can be expressed
transiently or persistently by mouse macro-
phages. The ingested bacilli grow floridly in
macrophages following transient inhibition,
but not in macrophages expressing more per-
sistent inhibition.
In a study of 41,000 black and white resi-
dents of Arkansas nursing we found
that whites are significantly more resistant
than blacks to infection by M. tuberculosis.
Soon thereafter, Crowle and Elkins12 found
that macrophages from black donors permit
significantly more bacillary replication than
do those obtained from white donors.
McPeek et a135then showed that monocytes
have a pattern of HLA-DR expression consis-
tent with innate resistance to M . tuberculosis
in 70% of whites but in only 30% of American
blacks. This finding is consistent with our
finding52that nonimmune (innate) resistance
is about twice as common in persons of Euro-
pean descent as in African-Americans.
Persons with different MHC types logically
should differ in their susceptibility to some
major pathogens, including tuberculosis. No
significant contribution has yet been shown,
however.
THE PRESENT SITUATION
In the United States today, tuberculosis
among African-Americans usually presents
in a relatively chronic form similar to that
seen among whites, indicating selection for
tuberculosis resistance dating back 15 to 20
generations. This pattern stands in contrast to
the type of tuberculosis described recently by
my group55and observed among Senegalese
troops4 in France and blacks in the United
States 150 years when the tuberculosis
epidemic was just starting among them. At
that time, the disease often was fulminating
in its course and characterized by widespread
extrapulmonary dissemination, easily mis-
taken for typhoid fever59but minimally infec-
tious for others. Although African Americans
as a group have been shown to be less resis-
tant than 52 they too are clearly on
the descending limb of the epidemic curve.
In addition to a systematic difference in
resistance to infection by M. tuberculosis be-
tween persons of European and African heri-
tage, we have found evidence of a difference
in the function of cell-mediated immunity. In
our database of 6200 tuberculosis cases in
Arkansas since 1976, the percentage of blacks
showing extrapulmonary lesions is two to
three times greater than in whites. For the most
serious forms-i.e., miliary spread and menin-
gitis-however, the percentage in blacks is
six times that in persons of European heritage
(Stead, unpublished data, 1996). In addition,
blacks are about twice as likely to have posi-
tive sputum smears. All of this points to a
racial difference in the immune response to
tuberculosis, which is consistent with selec-
tive survival of resistant individuals early in
the epidemic.
There still remain regions of the world
where isolated population groups have had
little or no contact with the tubercle bacillus.
Where conditions and social structures are
very primitive and where a village popula-
tion does not exceed 300 persons, tuberculin
skin testing has shown little or no reactivity
and clinical evidence of tuberculosis is virtu-
ally absent. Examples of such tribes can be
found in the highlands of central New
Guinea3, and among the Yanomami Indians
of the high Amazon in Brazil (A. de Sousa,
personal communication, 1995). One can pre-
dict that such persons, having experienced no
selection pressure from tuberculosis, will be
much more susceptible to infection and seri-
ous disease from M. tuberculosis. Should these
persons migrate to urban areas having a high
incidence of tuberculosis, the risk of death
from tuberculosis will be great. It would be
of great interest to compare such natural re-
sistance, as measured in tissue cultures of
macrophages from a group of natives in Af-
rica, New Guinea, and the Yanomami Indians
of Brazil, where the epidemics are in their
early phase, with macrophages from a group
of blacks and whites from America and west-
ern Europe, where the epidemic is in its de-
scending phase.
Effective chemotherapy for tuberculosis
first became available in the late 1940s. Al-
though it spread rapidly throughout the in-
dustrialized world, its use remains inade-
quate in developing countries, limited by the
cost of drugs and lack of the necessary public
health infrastructure. In addition, its effective-
ness has been quite uneven because of its
improper and irregular use in some devel-
oping countries.21After its introduction, the
rate of decline in incidence accelerated from
1%to 2%/year to 6% to 10% per year in Eu-
rope, Great Britain, Canada, and the United
States, all countries quite far along the de-
 THE ORIGIN AND ERRATIC GLOBAL SPREAD OF TUBERCULOSIS
scending limb of the epidemic curve. Unfor-
tunately, little decline has been seen in many
developing countries because of poverty and
the combination of ineffective national treat-
ment programs as well as their less favorable
position on the epidemic curve.
In the United States, the greatest reduction
in prevalence of tuberculosis infection has
been attributable to a dual national effort over
the past 25 years: (1)to treat each active case
to cure, and (2) to treat all close contacts
prophylactically with isoniazid to prevent
secondary cases. This effort has been highly
successful in most areas, but we are now ex-
periencing a resurgence of the d i ~ e a s eIroni-
.~
cally, however, an unexpected downside of
this success is the very small proportion of
today’s health care workers with effective im-
munity derived from healed infections,
which, in earlier days, enabled them to care
for communicable cases with minimal risk.
Now that multiple-drug-resistant cases of tu-
berculosis are increasing in frequency, only
about 5% of young health care workers have
this very effective immunity against these
dangerous organisms.47
SUMMARY
All infectious epidemics follow the same
form-a period of increase in incidence fol-
lowed by a leveling off as resistance develops
and then a gradual decline. A tuberculosis
epidemic is no different, but instead of its
taking a few months or years, it is measured
in hundreds of years. Development of herd
resistance to an infection is slow because it
results only from elimination of the most sus-
ceptible individuals. Mankind has not yet
seen a complete epidemic cycle, even in west-
ern Europe and the United States. The germ,
M . tuberculosis, evolved through a series of
random mutations from common soil sapro-
phytes over millions of years. The final step
from M . bovis to M . tuberculosis probably oc-
curred when humans shared their homes
with cattle in Europe. After a long period of
endemicity, crowding during the Industrial
Revolution produced a change from an en-
demic infection to a devastating epidemic.
In Europe and America, this epidemic was
nearing its end when it was re-ignited by the
HIV epidemic.
The epidemic in a given population gradu-
ally wanes as only the more resistant individ-
uals survive and reproduce. This genetically
75
based innate resistance manifests as the abil-
ity of macrophages to react quickly to lyse
the M . tuberculosis even before specific immu-
nity has developed, preventing the infection
from implanting and the skin test from con-
verting. In the event some organisms do im-
plant and the tuberculin skin test converts to
positive, the resistant host usually can render
the infection dormant.
The highly susceptible host may develop a
subacute, often fatal, illness with generalized
spread to many organs so it is easily mistaken
for typhoid fever. If the immune system (par-
ticularly the HLA T cell immunity) proves
adequate to gain control of the infection, it
leaves the host clinically well and with
readily mobilized resistance to tuberculosis.
If the control by the immune system is only
partial, the infection may progress as a
chronic infiltrate in a lung that may progress
to cavitation and considerable infectiousness.
CONCLUSION
The study of the epidemiology of tubercu-
losis and the evaluation of various public
health measures to prevent or contain the
disease require an understanding of the tu-
berculosis epidemic curve and the position of
the area under study on that curve. This natu-
ral phenomenon is a much more powerful
influence on the type of disease the germ will
produce and the course of the infection in the
area than any measure humans can institute,
just as river currents can be more powerful
in determining the course of a canoe than the
efforts of even the most vigorous paddler.
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Address reprint requests to
William W. Stead, MD, MACP
Tuberculosis Program
Arkansas Department of Health
4815 West Markham Street
Little Rock, AR 72205-3867