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Smallpox in Europe before the

Seventeenth Century:
Virulent Killer or Benign Disease?

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[N his History of Epidemics in Britain, in 1891, Charles

Creighton argued a century ago that the historical con-
troversy over smallpox actually involved two some-
what different questions. The first considered the an-
tiquity of the disease itself, and whether it was in fact
known to earlier civilizations and medical writers prior
to its first clear description by Rhazes in the tenth century.1 This aspect
of the controversy had long predated Creighton, and had been discussed
at length by numerous writers. 2 It is still to this day a question of active
interest among medical historians.3 Variola viruses have long afflicted
human communities. The second major aspect of the smallpox con-
troversy, most clearly stated and developed by Creighton himself, has
received little attention. This concerns the question of whether virulent
smallpox was present in Europe between the tenth and sixteenth cen-
turies. Creighton concluded that it was not, and demonstrated persua-
sively that "the history of smallpox in Britain is that of a disease coming

1. Rhazes, A Treatise on the Small-Pox and Measles, trans. William A. Greenhill, Med. Classics, 4:
22-84, 1939- James Moore, The History of Smallpox, London, Longman, Hurst, Rees, Orme and
Brown, 1815, pp. 1121F., reviews earlier Islamic writings on smallpox.
2. See, Moore, (n. 1) Smallpox; William Woodville, The History of the Inoculation of the Smallpox
in Great Britain, London, J. Phillips, 1796; August Hirsch, Handbook of Geographical and Historical
Pathology, trans. Charles Creighton, London, New Sydenham Society, 1883, vol. 1; and Robert
Willan, Miscellaneous Works Comprising An Inquiry into the Antiquity of The Small-pox, Measles and
Scarlet Fever, ed. Ashby Smith, London, T. Cadell, 1821.
3. See Donald R. Hopkins, Princes and Peasants: Smallpox in History, Chicago, University of
Chicago Press, 1983; Cyril W. Dixon, Smallpox, London, Churchill, 1962; and Peter Razzell, The
Conquest of Smallpox, Firle, Sussex, Caliban Books, 1977.

Acknowledgement: The authors are particularly grateful to Drs. Frank Fenner and D. A. Henderson
for their valuable comments and suggestions on early versions of this paper.

[ 147]
148 Journal of the History ofMedicine : Vol. 42, April 1987
gradually into prominence and hardly attaining a leading place until the
reign of James I." 4
Creighton, an opponent of the germ theory of disease, linked the
history of smallpox to the history of syphilis, the great pox, in his late
nineteenth-century campaign against Jennerian vaccination. He was per-

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suaded that none of the evidence for smallpox in Britain before 1561
could withstand close historical scrutiny. Nevertheless, the contention
that smallpox is a most ancient disease of man is separable from the
argument that the virulent form was seen in distant times. Dixon, in
fact, felt that Creighton was emotionally attached to the sixteenth-cen-
tury appearance of smallpox in Britain, but that it was "not impossible
for the disease to have been present sporadically in Europe and England
before the eleventh century, only to disappear and not recur in England
until the late fifteenth or early sixteenth century. " 5 The thesis of this
review is that what Creighton observed for Britain can also be shown
for the European continent in general: virulent smallpox did not appear
until early modern times, and gradually replaced an earlier endemic and
relatively avirulent form of the disease. Our research suggests that this
transition occurred by only sporadic incursions of the deadly disease
during the fifteenth and sixteenth centuries and that the virulent virus
attained dominance throughout Europe during the seventeenth century.
Most of the evidence presented here comes from England and Italy,
with only occasional reference to sources in France, Germany and Spain,
where fewer data are available in print. Given the highly infectious nature
of smallpox, however, and the widespread movement of commerce and
of armies during the late medieval-early modern period, it is quite un-
likely that virulent smallpox could have existed in some European coun-
tries and failed to cross the borders of England and Italy. The authors
are aware of the difficulty of proving that virulent smallpox did not exist
solely through the absence of positive data, but the historical and
epidemiological implications of our thesis appear to be sufficiently sig-
nificant to justify the hypothesis advanced. Data to modify our conclu-
sions may yet be uncovered by further archival research.
4. Charles Creighton, A History of Epidemics in Britain, 2 vols., Cambridge, Cambridge University
Press, 1891, 1, 440, and 2, 434.
5. Dixon, (n. 3) Smallpox, pp. 191—192. Creighton thought less of Jenner than most, and was
an active antivaccinationist. See Creighton, (n. 4) Epidemics, 2, 5621F, and his Jenner and Vaccination,
London, Sonnenschein, 1889. Thus Creighton's views on the antiquity and severity of smallpox
might have been biased, but Genevieve Miller, The Adoption of Inoculation for Smallpox in England
and France, Philadelphia, University of Pennsylvania Press, 1957, p. 282, credits him with "writing
with remarkable objectivity for one who was an active antagonist of vaccination."
Carmichael & Silverstein : Smallpox in Europe 149
First, a brief note on the clinical and microbiological varieties of small-
pox. Variola major has been one of the major scourges of mankind during
the eighteenth to the twentieth centuries. Even where inoculation or
Jennerian vaccination against smallpox was practiced, virulent Variola
major with case-fatality rates of 20 to 30% might remain endemic in large

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populations and claim a significant annual toll among non-immunes,
breaking out periodically in epidemic proportion. 6 Variola minor, on the
other hand, only comparatively recently recognized, is a far more benign
disease, involving case-fatality rates usually less than 1%. Yet even the
benign Variola minor might leave permanent facial scarring on some 5%
of its victims.7
The organisms responsible for these two forms of smallpox are anti-
genically identical, and each confers the same substantially lifelong im-
munity that protects against reinfection with either strain of the virus.
This is not to imply, however, that smallpox is represented by only the
highly virulent and the relatively avirulent strains. There are many reports
of widespread epidemics in which strains of intermediate virulence have
been implicated,8 and recent historical studies refer to a mixture of strains
accounting for discrete epidemics in a given time or place.9
Instances of varying strains of smallpox were apparent to observers as
early as the eighteenth century. For example, there is the famous com-
ment by Wagstaffe in 1722 that, "we have the sort [of smallpox] in which
a nurse cannot kill, and another in which even a physician can never
cure." In 1725, Clinch could say of smallpox that "it is sometimes so
very Mortal, and at other times so very Mild and Favourable. " 10 Careful
historical analyses have similarly shown the evidence for mild and viru-
lent strains in 19th and 20th century mortality statistics.11 Thus, it is
likely that even in modern times mutational events involving the viral

6. See the recent historical example by Anne Hardy, "Smallpox in London: Factors in the decline
of the disease in the nineteenth century," Med. Hist. 2y: 111-139, 1983; and Dixon, (n. 3) Smallpox,
pp. 408-445-
7. Dixon, (n. 3) Smallpox, p. 108; and Abram S. Benenson, "Smallpox," in Viral Infections of
Humans, ed. Alfred S. Evans, 2nd ed., New York, Plenum, 1982, pp. 544-545.
8. See Creighton, (n. 4) Epidemics, 2, 544ff.; and Razzell, (n. 3) Conquest, pp. 34-35. For more
scientific views of the variation in the virulence of smallpox strains, see K. R. Dumbell and F. Huq,
"Epidemiological implications of the typing of Variola isolates," Trans. Royal Soc. Trap. Med. and
Hyg., 6g: 303-308, 1975; and Benenson, (n. 7) "Smallpox," p. 546.
9. Marc Dawson, "Smallpox in Kenya, 1880-1920," Soc. Sci. Med., iy. 245-250, 1979.
10. William Wagstaffe, "A letter to Dr. Freind, shewing the dangers and uncertainty of inoculating
the smallpox," London, S. Butler, 1722; and William Clinch, "An Historical Essay on the Rise and
Progress of the Smallpox, (1725)," cited in Razzell, (n. 3) Conquest, p. 130.
11. Hardy, (n. 6) and Dawson, (n. 9).
150 Journal of the History ofMedicine : Vol. 42, April
genome may have produced strains of Variola virus with intrinsic viru-
lence anywhere between the most benign Variola minor and the most
severe Variola major. All of these strains have been eradicated in man as
the result of the recent World Health Organization eradication cam-

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Even if we were to assume little change in the virulence of smallpox
before 1800, before the modern rise of population and the industrial
revolution, individual clinical cases of smallpox could have been strik-
ingly diverse because host responses vary widely.13 A particularly dra-
matic case of smallpox, such as that of Theodoras Prodromus in twelfth-
century Constantinople, who claimed, "I almost had my soul spitted out
on account of this disease," may give little direct information about the
clinical severity of Variola virus at the population level.14 Mild cases of
"pox," such as St. Catherine of Siena's affliction in 1363, have, on the
other hand, been ascribed to chickenpox because the illness was compli-
cated only by her poor nutritional status.15 Theodoras was left scarred,
St. Catherine was not.
Confusion with chickenpox raises some particularly difficult problems
in retrospective diagnosis of smallpox. The last naturally occurring case
of smallpox in the world happened in 1977 to a hospital cook in Somalia
who had had brief contact with two infected children. He was hos-
pitalized before the appearance of a rash with the diagnosis of malaria
and released as the rash was erupting, with a diagnosis of chickenpox.16
The disease was not identified until another four days elapsed, even
though a classic centrifugal rash appeared, with lesions concentrated on
the face and extremities, including the palms and soles. In smallpox all
12. Donald A. Henderson, "The history of smallpox eradication," in Times, Places, and Persons,
ed. Abraham M. Lilienfeld, Baltimore, Johns Hopkins University Press, 1980, pp. 90-108.
13. Benenson, (n. 7) Viral Infections, pp. 556-557.
14. Pan S. Codellas, "The case of smallpox of Theodoras Prodromus," Bull. Hist. Med., 20:
207-215, 1946. On the sixth and seventh days of his "double tertain fever" Theodoras wrote, "my
own body is showered with hailstones from the top of the head to the nails of the toes, which are
unblessed. Yes, I do call them hail on account of their color being white and of the shape being
spherical. The body is heated violently through and through with extraordinary torches from the
fever." These lesions became "murderous pustules," and then "closely packed bubbles."
15. Arrigo Levasti, My Servant, Catherine, trans. Dorothy White, Westminster, Maryland, New-
man Press, 1954, p. 28: "Not a grave illness, but her face, hands, skin were covered with pustules.
Catherine feared it might be divine chastisement, and her fever rose. Lapa [her mother] was terribly
worried. It was an illness common to children, but Catherine was nearly eighteen years old, and
for an adult it might be fatal. She was afraid, moreover, that a body so weakened with fasting and
penance might not hold out against the high fever."
16. Benenson, (n. 7) Viral Infections, p. 541. The epidemiological picture was confusing, too.
The cook, Ah Maow Maalin, "exposed 161 persons to smallpox, 91 of them face to face. None of
these contacts developed smallpox."
Carmichael & Silverstein : Smallpox in Europe 151
of the bullae and pustules are at the same stage of development or matu-
ration. The rash of chickenpox, on the other hand, involves "crops" of
lesions at different stages—new pustules beside healing ones—and a cen-
tripetal distribution, with the greatest concentration of pocks on the
trunk. And chickenpox does not leave scars. But this kind of diagnostic

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information is rarely encountered in historical or medical records from
the period we discuss, so the differentiation between the two diseases is
For most of the premodern era, one has to rely on literary accounts
or on medical texts in order to document the occurrences of smallpox
infection. Much of the evidence is so brief and ambiguous that certainty
in a retrospective diagnosis is impossible. Individual case studies have
often been the best way to locate sure evidence of Variola infection.
Nevertheless very few sources give adequate testimony from which to
document the recurrence of killing smallpox epidemics. Accounts before
1500 that we have located, however, suggest that smallpox was not a
virulent infection.
The first clear description of smallpox is that of the Islamic physician
Rhazes in the tenth century. He clearly states that very few persons escape
smallpox infection, by which we may infer the endemicity of the disease.
But equally clearly, Rhazes treated the disease as an almost salutary child-
hood distemper, which assisted in the inevitable transition from the
"moist" blood of childhood to the more mature, "drier" blood of adult-
hood. A conscientious proponent of Hellenic humoral medicine, Rhazes
suggested that this excess moisture was assisted in its escape by the
dermal features of the disease, and compared it to the fermentation of
I say then that every man, from the time of his birth till he arrives at old age,
is continually tending to dryness; and for this reason the blood of children and
infants is much moister than the blood of young men, and still more so than of
old men . . . Now the smallpox arises when the blood putrefies and ferments,
so that superfluous vapors are thrown out of it and it is changed from the blood
of infants, which is like must, into the blood of young men, which is like wine
perfectly ripened;. . . and the smallpox itself may be compared to the fermen-
tation and the hissing noise which takes place in must at that time. And this is
the reason why children, especially males, rarely escape being seized with this
disease, because it is impossible to prevent the blood's changing from this state
into its second state, just as it is impossible to prevent must... from changing.17
17. Rhazes, (n. i) Treatise, p. 29.
152 Journal of the History of Medicine : Vol. 42, April
Nowhere in Rhazes' writing do we find a hint that the assistance
rendered by smallpox infection to the normal physiological maturation
may be associated with any undue danger to the host. Rather, the descrip-
tion of smallpox in the tenth century Islamic world is that of a benign,
endemic childhood disease. Fatalities usually involved the occasional in-

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fected adult, and clinically mishandled cases.
The description of smallpox by Avicenna in the century following
Rhazes once again treated the disease as a benign and almost physiologic
process. Avicenna proposed a somewhat different pathogenesis than had
Rhazes, suggesting that the disease involved the fermentation and putre-
faction of that trace of menstrual blood contaminant with which each
individual was supposed to be tainted in utero. Thus, the skin lesions
associated with smallpox were once again assumed to provide the path-
way of expulsion of this contaminant, leading to an implicitly benign
humoral purification of this previously tainted blood.18
In one form or another, these Galenist views of smallpox pathogenesis
were adapted by physicians in Europe for the next 500 years, and Euro-
pean authors during this period generally did not appeal to their own
differing experience with the disease, in either individual patients or in
epidemic mortality.19 An excellent example of this is the sixteenth-cen-
tury view of smallpox provided by Girolamo Fracastoro in his book On
Contagion and Contagious Diseases. Fracastoro followed Avicenna in his
view of pathogenesis:
the pustules presently fill up with a thin sort of pituita and the matter is relieved
by these very means . . . for this ebullition is a kind of purification of the blood;
nor should we scorn those who assert that infection contracted by the child
from the menstrual blood of the mother's womb is localized by means of this
sort of ebullition and its putrefaction, and the blood is thus purified by a sort
of crisis provided by nature. That is why almost all of us suffer from this malady,
since we all carry in us that menstrual infection from our mother's womb. Hence
when this process has taken place, the malady usually does not recur because
the infection has already been secreted in the previous attack.20
Fracastoro, not once but several times commented on the benign and

18. Avicennae Arabum Medicorum Principis, Latin trans, by Gerard of Cremona, Venice, 1608, 2,
19. For a review of the theories of smallpox pathogenesis see Arthur M. Silverstein, "A history
of theories of acquired immunity," Cell. Immunol., 51: 151—167, 1980.
20. Girolamo Fracastoro, De Contagione et Contagiosis Morbis et Eonim Curatione, trans. W. C.
Wright, New York, Putnam, 1930, pp. 60-63. See also Charles and Dorothea Singer, "The scientific
position of Girolamo Fracastoro," AMU. Med. Hist., r. 1—37, 1917.
Carmichael & Silverstein : Smallpox in Europe 153
almost salutary aspects of smallpox infection. In discussing other infec-
tions, Fracastoro was unafraid to contradict medical tradition, noting the
novelty of typhus, sweating sickness, and syphilis to his generation, and
the relative increase in the virulence of phthisis. Presumably Fracastoro
would have noted virulent smallpox if it had been a part of his experience

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in urban Italy.
This is not to say, however, that smallpox was never fatal before the
late sixteenth century. In a lengthy book devoted entirely to smallpox,
written forty years after Fracastoro's, Aemilius Campolongus reviewed
at length the humoralist view of smallpox pathogenesis.21 Agreeing with
authors dating back to Rhazes, he pointed out that the favorable resolu-
tion of the disease occurred when the "bad humor" was separated from
the body and expelled through the skin, but that when it was retained
within, it might corrupt the blood and vital organs and prove lethal. But
the impression is left that the latter course is the rare exception, and
indeed Campolongus advised the physician to take care not to employ
any treatment that might assist internal retention. Much the same ap-
proach was taken in another contemporary account by Donato, and in
other treatises of pestilential fevers that devoted a chapter to smallpox.22
Similarly, in more rural sixteenth-century England medical authors
recognized smallpox, and that it might lead to facial scars, for remedies
are given for their removal. But again, the implication was that the
disease was not dangerous. As Phayer says in his Book of Children: "For
yf thys disease, which shuld be expelled by a natural action of the body
to the long healthe afterward of the padent, were by force of medicine
cowched in agayn, it were even ynough to destroye the chyld."23
The medical view of smallpox in sixteenth-century France was similar
to that in England and Italy. It is interesting to compare the description
of smallpox presented by Ambroise Pare with his description of plague
and syphilis. He devoted seventy-three pages in his collected works to

21. Aemilius Campolongus, De Variolis Liber, Venice, 1586.

22. Marcello Donato, De Variolis et Morbiliis, Mantua, 1569. See also Nicola Massa, Liber deFebre
Pestilential!, Venice, 1540, fol. 63v-68r; Franciscus Alphanus, OpusdePeste, Febre Pestilentiali et Febre
Matigna necnon de Variolis et Morbiliis, Quatenus nondum Pestilentes Sunt, Naples, 1577; and Feliciano
Betera, Malignarum Variolarum et Obiter Etiam Petechiarum Tractatio, Brescia, 1591.
23. Thomas Phayer, The Regiment of Life, Added a Treatise of the Pestilence, The Booke of Children,
London, 1546, repr. Norwood, New Jersey, W. J. Johnson, r976. Phayer defines "varioli the
measyls, and morbilli called of us the small pockes." Creighton examined and dismissed Phayer's
account as one probably derived from continental sources. A similar view of the avirulence of
smallpox is provided by Andrew Borde, The Breviary of Helthe, London, 1547, repr. New York,
Da Capo, 1971.
154 Journal of the History of Medicine : Vol. 42, April 1987
plague, calling it "a disease coming from the ire of God, serious, tempes-
tuous, hateful, monstrous, . . . a mortal enemy of the life of man."
Similarly, he devoted thirty-eight pages to syphilis, with an introduction
that provided a hideous list of the complications attendant upon this
disease. But to smallpox (together with measles) he devoted a mere four

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and one-half pages. Pare's treatise was written for surgeons, who may
have had little interest in the problems confronting general physicians,
but he himself was well-informed about medical opinions, and restated
the common assumption that the chief importance of smallpox was that
it so often presaged plague: "Because smallpox and measles are like the
forerunners, heralds, and messengers of plague . . . it seemed to me well
to write something here about them, so that by this treatise the young
surgeon might be more amply and perfectly instructed about [plague]. " 24
One might easily construct an argument that the medical profession
was conservative and excessively dependent upon its authorities, espe-
cially on Avicenna, and so one might not expect to find contradiction of
the Arabic picture of benign smallpox before the sixteenth century in its
writings. But even if one turns to strictly non-medical accounts by
chroniclers and diarists of Europe, sure instances of killing smallpox
epidemics are very difficult to find. One cannot but wonder why a
disease so lethal in the eighteenth century caused neither demographically
appreciable losses nor much concern to those living before the sixteenth
Most of the accounts collected in the nineteenth century, and cited
repeatedly in secondary and tertiary histories of smallpox in Europe,
suggest a history of smallpox epidemics from classical antiquity through
the meager accounts of early medieval chroniclers.25 Most are troubled
by imprecise descriptions of "spreading or herpetic Anthrax," pustules,
redness, dysentery, and fluxes of all sorts, many furthermore occurring
during famine times. Multiple infections, mixed epidemics, and even
mycotoxicoses associated with spoiled grain are as likely explanations as
a single, lethal smallpox epidemic. Most highly lethal infectious diseases
claim infants and children in great numbers, particularly in societies
where the young comprise a large segment of the population. Smallpox
was poorly distinguished or distinguishable from other infections
throughout the earlier middle ages.
24. Les Oeuvres d'Ambroise Part, 5th ed., Paris, 1598, p. 726.
25. For the major secondary sources see (n. 2) and the mercifully brief summary by Dixon, (n.
3) Smallpox, pp. 187-191.
Carmichael & Siherstein : Smallpox in Europe 155
The significant point about smallpox is not its existence, but its exis-
tence in a mild form. If we survey a variety of strictly contemporary
accounts in Western Europe from 1300 to 1500, in the populous regions
(Italy, Spain, the Paris region, and the areas around London), only one
lethal smallpox epidemic can be found, among either children or adults.26

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This was reported from Paris in 1444, then a city of no more than 3 5,000.
The bourgeois chronicler stated clearly that 6000 people were affected
and of these "many died."27
In comparison to the records from the earlier Middle Ages, those from
the fourteenth and fifteenth centuries are much more complete and infor-
mative. The evidence for recurrent epidemics of smallpox can be dis-
cerned among them, but much of it testifies to the presence of a relatively
avirulent strain. There are seven Italian reports of smallpox in the four-
teenth century. Three of these epidemics are reported from Tuscany (in
1335 in Florence,28 killing "many children," and two accounts from
Siena in 1363,29 coinciding with St. Catherine's infection). Outside Tus-
cany, one epidemic of smallpox was reported from Naples (1336), one
from Vicenza (1386) and one from Bologna (1393). But 1363 and 1386-
92 were years of plague as well.30 Florence saw "pestilential pustules" in
1390, as did many Tuscan cities, which suggests that cases of smallpox
may not have been well distinguished from plague cases.31 In some places
cases of smallpox were not unnoticed amid the spectacular bubonic
plagues of this era. At best the evidence suggests that noticeable pustular
epidemics were occurring only at rather lengthy intervals, even in popu-

26. Alfonso Corradi, Annali delle epidemie occorse in Italia, 5 vols., repr. Bologna, Forni, 1974,
conveniently surveys most of the continental literature as well as the north Italian data.
27. A Parisian Journal, ed. and trans. Janet Shirley, Oxford, Oxford University Press, 1968, p.
359, (see pp. 28-29 for estimates of Parisian population). "There was the most dreadful outbreak
of smallpox this year that anyone could remember, from the middle of August till after St. Andrew's
day, especially afFecting young children; more than six thousand people in Paris suffered from it
during this period. Many of them died of it and many died after they had recovered from this
accursed smallpox. A lot of grown men and women of all ages fell ill of it, in Paris especially."
Shirley accepts an estimate of 70-80,000 for the population of Paris in the early fifteenth century,
and believes the chronicler reported 6000 cases of smallpox—not deaths.
28. Corradi, (n. 26) Annali, 4, 32.
29. Ibid., 4, 61; and Levasti, (n. 15) Servant. See also Cronica Sanese di Neri Donato, Rerum
Italicarum Scriptores, vol. 15, original edition, Milan, 1735, p. 241; and Matteo Villani, Cronica,
ed. F. Dragomanni, 2 vols., Florence, 1846, 2, 305.
30. Corradi, (n. 26) Annali, 1, 234-239.
31. See Ann G. Carmichael, Plague and the Poor in Early Renaissance Florence, New York, Cam-
bridge University Press, 1986, pp. 11-13. The Crascia morti registers are fairly complete in listing
all deaths in Florence. There are no systematic under-registrations, even among infants. See David
Herlihy and Christiane Klapisch-Zuber, Les toscans el leurs families, Paris, SEVPEN, 1978, pp.
156 journal of the History of Medicine : Vol. 42, April 1987
lous regions, and were still not virulent enough to be differentiated from
more lethal epidemics of bubonic plague.
One could as easily claim that many epidemics ascribed to smallpox
in the pre-1500 period were misdiagnoses themselves. For example, the
earliest fifteenth-century smallpox epidemic reported in Italy was that in
Bologna in 1465.32 The diarist in this case noted that the autumn months

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saw many cases of "fever, smallpocks and pneumonias." Considering
that 1464-1468 were undisputedly years of plague throughout northern
Italy, many diagnostic confusions were possible. Gottfried discovered
one particularly lethal epidemic in England in 1462, that could not be
ascribed to plague, but he found no secure examples of smallpox in the
fifteenth century.33 Classic smallpox should have been distinguishable,
in epidemics if not in individual cases, from plague. Unless one is pre-
pared to reevaluate entirely the extent to which plague affected urban
Europe in the fifteenth century, one cannot hope to argue a secure case
for virulent smallpox epidemics during plague years. Evidence for
epidemics of smallpox apart from plague is exceedingly rare in the cen-
turies just before 1600.
Finally, and perhaps most significantly, urban mortality registers do
occasionally report causes of death. The Florentine Books of the Dead
recorded burials in a populous (36,-40,000) city, at the hub of commercial
affairs. Diagnoses of cause-of-death are provided only during plague
years, and they testify to three visitations of smallpox: 1424-25, 1430,
and 1439.34 The interval here is much closer than that postulated for
fourteenth-century epidemics, but the total number of deaths ascribed
to smallpox during the thirty-five years from 1424 to 1458, (including
these three "epidemic" years) was eighty-four deaths! Since a diagnosis
of smallpox presumably protected families from being treated as harshly
as they might be if plague were the diagnosis, one would not necessarily
expect the disease to be underreported. Similarly, smallpox was one of
the contagions popularly expected to precede plague, and thus a certain
value in identifying these cases could be seen in their predicting the major

32. Corradi, (n. 26) Annali, [1465], "febbri, vajuoli, e pneumonih."

33. Robert S. Gottfried, Epidemic Disease in Fifteenth-Century England, New Brunswick, Rutgers
University Press, 1979, pp. 51, 62-63, and 105. Gottfried finds the "pox" of 1462 especially
destructive in the "north country," and that mortality peaked in the early spring, which was
uncharacteristic of plague. He concluded that "there is little doubt that England also felt the ravages
of typhus, smallpox and influenza in the fifteenth century," but separately indexed "pox" and
"smallpox." The only severe epidemics other than plague which he could identify were "flux"
(dysentery), "sweat," and the French pox.
34. See Carmichael, (n. 31) Plague and the Poor, pp. 11-15.
Carmichael & Silverstein : Smallpox in Europe 157
pestilence. Such cases cannot be found in Florentine records. Neverthe-
less from 1424 to 1458, there is no discerniblerisein cool season mortality
except for the expected, occasional increase in deaths among the aged.
Morbidity from smallpox perhaps was widespread, but high case fatality
rates appear not to have characterized the infection.
A similar situation is seen in the sixteenth century in the parish register

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of All Hallows London Wall. Here, not only the cause, but the age at
death is recorded. During the twenty-five year period between 1574 and
1598, only twelve persons were recorded as having died of smallpox in
this parish, ten of whom were under seven years of age. 36 Here too, we
seem to have an endemic childhood disease of no great mortality, rather
than the great killer that smallpox was to become in the next century.
Throughout the Middle Ages and into early modern times, numerous
epidemics occurred that might or might not have been smallpox. Their
characterization by more modern writers usually depended upon
whether they sought to prove either the antiquity or the novelty of the
disease. Thus Woodville cites the ancient prayer contained in the Harleian
Collection of manuscripts in the British Museum, "Defend me from the
fire and power of smallpox, and against the loathsome pox, " 37 which
indicated to him that "the inhabitants lived in continual dread of this
disease. " 38 On the other hand, the existence of saints for pustular diseases
may not document recurrent virulent epidemics. In analyzing the legend
that holds the fifth century Bishop of Rheims, St. Nicaise, to be the
patron saint of smallpox, Moore suggests that when a new disease ap-
peared on the scene in early times, a suitable saint was found and stories
were then invented that he had suffered from the disease, to make the
case more plausible. These, Moore suggests, are hagiographic legends
which cannot be verified, and might likely be untrue. 39
Creighton attaches much significance to the expressions of the trou-
bled conscience of Master Richard Allington, Esq., who summoned to
his deathbed on November 22, 1561, the Master of the Rolls and several
lawyers, saying, "Maisters, seing that I must nedes die, which I assure
you I never thought wolde have cum to passe by this dessease, con-
35. Thus, in 1398 Giangaleazzo Visconti believed that cases of measles and smallpox presaged
plague, and ordered that officials should inquire about the presence of these diseases in Milan. See,
Aldo Bottero, "La peste in Milano nel 1399-1400, e l'opera di Gian Galeazzo Visconti," Atti e
memorie dell'accademia di storia dell'arte sanitaria, ser. 2, 8: 19, 1942.
36. Cited in Razzell, (n. 3) Conquest, p. 113.
37. Dixon, (n. 7) Smallpox, p. i87ff.
38. Ibid., p. 190.
39. Moore, (n. 1) Smallpox, p. 97ff.
158 Journal of the History ofMedicine : Vol. 42, April 1987
syderinge it is but the small pockes." It is Creighton's view that Al-
lington's words give the first genuinely English account of smallpox in
Britain, although Dixon contends that "if he did die of smallpox, the
disease which he had previously thought to be so mild was probably the
chickenpox. " 41

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In assessing the circumstantial evidence on the extent to which a society
might view a disease as serious or of little consequence, the absence of
its mention may be as significant as its presence. Shakespeare, whose
works make mention of almost every aspect of the human condition,
nowhere makes reference to smallpox or its facial scarring.42 Either di-
rectly or metaphorically, Shakespeare mentions almost every other phys-
ical or mental ailment of significance in Elizabethan England, including
such infectious diseases as syphilis (pox), plague, leprosy, and consump-
tion. 43 He even uses "measels" in Coriolanus, Act III, Scene I, but here
to denote leprosy. While we must be cautious about overemphasizing
the significance of this "negative finding," it is difficult to conceive that
the virulent smallpox of the following century, with its devastating effects
upon beauty, would have escaped his keen eye and sharp pen.


Italian Chronicle References to Smallpox, 1300-1600

Years Number of References
1300-1400 7
I400-1500 4
1500-1550 7
1550-1600 38
SOURCE: Alfonso Corradi, Annali delle epidemie occorse in Italia
(repr. Bologna, Forni, 1973), vol. I, IV, V.

Table I reflects the number of accounts of smallpox in a fairly thorough

survey of all Italian chroniclers and diarists from 1300 to 1600, and the
pattern of smallpox reporting is clear. Major epidemics of smallpox
begin to occur in the mid-sixteenth century. The earliest reference to a

40. Creighton, (n. 4) Epidemics, 1, 460.

41. Dixon, (n. 7) Smallpox, p. 191.
42. John C. Bucknill, The Medical Knowledge of Shakespeare, London, Longman, i860.
43. Mary C. Clarke, The Complete Concordance to Shakespeare, London, n.d.
Carmichael & Siluerstein : Smallpox in Europe 159
virulent epidemic of variola unmixed with plague or typhus is that of
Naples in 1544: "few [children] who had smallpox escaped, and there
were five or six thousand dead children, with many other deaths among
adults."44 The first sizeable epidemic in Venice was in 1570-71, claiming
almost 10,000 victims; the epidemic had swept through Rome in 156c).45

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In the smaller inland town of Mantua, smallpox killed many in 1586.46
Until the early 1570s no separate mention was made of smallpox mortal-
ity in most of northern Italy. Within the first five years of that decade,
eight major epidemics of smallpox were reported, with additional de-
scriptions of malignant pustules and high childhood mortality that begin
to resemble the Variola major of the next two centuries.
Pieter van Foreest recorded epidemics of smallpox combined with
measles in Alkmaar in 1551 and in Delft in 1562-63, attacking primarily
children. In the former epidemic, Foreest provided no precise estimates
of deaths, although he pointed out that certain treatments led to sudden
death. He had to go back some twenty-five to thirty-five years to find
other smallpox epidemics, and indeed recorded that smallpox was known
locally as kindtsflecken, kinderenpocken, and kindtsbletteren. Some epidem-
ics, he speculated, were extremely mild and some were severe.47 In 1555
smallpox in Valencia killed "many" but all contemporary medical
treatises emphasized its secondary importance to plague and typhus.
Spanish accounts in 1564, and throughout the 1580s and 1590s hint of
smallpox intermixed with other epidemics in their descriptions of pustu-
lar eruptions. In 1600 an "extravagant" epidemic of smallpox befell
Galida, similar to one seen there in 1585 and 1586.48 Measles and small-
44. Corradi, (n. 26) Annali, 1, 484. See also 1, 479-480 for note of the cluster of scholarly medical
treatises on smallpox in the 1540s; all are conventional, based on Arabic descriptions. For the late
1560s epidemics see 5, 480.
45. Corradi, (n. 26) Annali:, 1, 569, 573, 577-578, and 580; 4, 330-331; and 5, 480. Richard
Palmer, "The Church, leprosy and plague in medieval and early modern Europe," in The Church
and Healing, ed. W. J. Sheils, Studies in Church History, no. 19, Oxford, Blackwell, 1982, p. 79,
n. 2, notes thousands of deaths from smallpox in Venice, 1570, "known only from statistics in the
Venetian civic death registers."
46. See Lorenzo del Panta, he epidemic nella sloria demografica italiana, Turin, Loescher, 1980, pp.
67-68; and Corradi, (n. 26) Annali, 5, 330-331 and 392. An earlier epidemic in Mantua speaks to
the changing epidemiology of smallpox in the sixteenth century. Giovanni Battista Susio, Tralto che
sia giovevole rimedio il trare del sangue nelle volgare varuole,ferse et pettecchie, Venice, 1571, pp. 87-89,
notes a recent (1568) epidemic of measles and smallpox together in Mantua, himself witnessing the
infection of many adults by smallpox. Nevertheless, the mortality was not great unless mixed with
another disease, particularly influenza.
47. Pieter van Foreest, Observalionum et curationum medicinalium, Frankfort, 1634, liber VI, Obs.
xli, xlii, and xliv. The episodes are also recorded in Corradi, (n. 26) Annali, 1, ad annum.
48. Joaquin Villalba, Epidemiologia Espaiiola, 2 vols., Madrid, 1803, 1, 96 and 103, where a
description of plague in Barcelona illustrates how smallpox may have been confusing some clinical
160 Journal of the History of Medicine : Vol. 42, April 1987
pox combined to enhance the severe mortality in Paris in 1580, atypically
causing adult, as well as child, mortality.49
The most familiar evidence on the history of epidemics is that for
England and especially for London, gleaned from the listings of the
causes of death contained in the Bills of Mortality.50 These were instituted

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starting in 1629 and, except for missing records between 1636 and 1646,
provide a fairly accurate account of the comings and goings of the more
severe epidemics.
Only in 1632 do the Bills of Mortality provide the first clearcut evi-
dence of a moderately severe smallpox epidemic, when the proportion
of non-plague deaths attributed to smallpox jumped from a background
level of less than 1% to 5.6%. Again, in 1634, virulent smallpox returned



35 '50 '60 '70 '80 1690

Figure 1. The rise of smallpox mortality in England from 1629-88. The solid line plots the
proportion of total deaths ascribed to smallpox, while the dashed line approximates the rising
"background" mortality in non-epidemic years.

cases. Tumors and carbuncles were accompanied by pustules all over the bodies of victims, some
turning greenish, others yellow, others black. See also 2, 10.
49. Journal de I'Estoile pour le regne de Henri 111 (1574-1589), ed. Louis-Raymond Lefevre, Paris,
Gallimard, 1943, p. 244, where along with plague and a severe influenza in 1580 "courent force
rougeole et petites v£roles, mane aux grandes personnes, jusques aux veillards qui s'en trouvent
50. John Graunt, Natural and Political Observations made upon the Bills of Mortality, London, 1662,
repr. Baltimore, Johns Hopkins University Press, 1939. With a ten-year gap due to "lack of space,"
Graunt carried the bills from 1629-1660. Those for succeeding years may be found in Creighton,
(n. 4) Epidemics, 2, 4S6ff.
Carmichael & Silverstein : Smallpox in Europe 161
once again to London, claiming 12.4% of all non-plague deaths. The
incursions of smallpox in London between 1629 and 1688 are presented
graphically in Figure 1, where the percentage of total deaths ascribed to
smallpox are plotted for each year from 1629 through 1688. Before
considering the implications of this graphical presentation, several points
should be noted: 1) the break in the curve between 1636 and 1647, which

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John Graunt omitted from his compilation; 2) the break in the curve
during the years 1665-66, when the great London plague distorted all
mortality figures; 3) the/fact that, save for the effects of the plague, there
was a parallel increase in both total deaths per year and total population
in London; and 4) one may estimate, employing Graunt's approach,51
that London had a population in 1630 of some 230,000, so that for some
time prior to this it should have been able to support endemic smallpox
independent of chance importations.52
Setting aside the uncertainty attributable to the missing data from 1637
to 1646, we find that not only does the annual average background
mortality from smallpox rise in the later 1640s to 2 to 3%, in the 1650s
to almost 4%, and by the 1670s and thereafter to over 5%, but epidemics
begin to superimpose themselves with greater frequency on normal en-
demic mortality rates.53 Prior to the initiation of the London Bills of
Mortality in 1629, there is little recorded evidence for significant small-
pox-induced mortality in London, save perhaps for a possible epidemic
in 1612, and the first years in which these records were kept seem to bear
out this conclusion.
Smallpox epidemics contributing greater than 8% of the total deaths
occurred in 1649, 1652, 1655, 1659, 1664, 1668, 1674; a deadly pattern
which would persist in England for nearly two centuries more. There is
little reason to doubt that the seventeenth-century English experience
with the rise of virulent smallpox was repeated on the Continent, and
by the beginning of the eighteenth century smallpox epidemics were
everywhere known, and everywhere feared.

51. Graunt, (n. 50) Observations. Creighton, (n. 4) Epidemics, 1, 473, put the population of London
in 1593-95 at around 152,000, while Graunt estimates it at about 384,000 in 1658 (p. 69). See more
recently Roger Finlay, Population and Metropolis: The Demography of London, 1580-1650, Cambridge,
Cambridge University Press, 1981, p. 5iff.
52. The minimum population suggested by Bartlett able to support endemic measles is put at
some 200,000-250,000, and Frank Fenner has suggested that the figure for smallpox may be
appreciably less (personal communication, 1983). Maurice S. Bartlett, "Measles periodicity and
community size, "J. Roy. Stat Soc, 120: 48-60, 1957; and "The critical community size for measles
in the United States," Ibid., 123: 37-44, i960.
53. Razzell, (n. 3) Conquest, p. 128.
162 Journal of the History ofMedicine : Vol. 42, April 1987
Two points emerge clearly from a consideration of the data in Figure
1. The first is the continually increasing annual background level of
smallpox's contribution to total mortality from 1629 onward, as rep-
resented by the dashed line. It may be seen that during the first years
(and presumably earlier), smallpox was an almost insignificant con-

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tributor to London's death totals, whereas over the next forty to fifty
years the background (non-epidemic year) contribution slowly rose to
4 to 6% of total deaths, and then appeared to level off. This implies that
by the end of the century, some 1,000 to 1,200 smallpox deaths occurred
year in and year out in London alone, reaching 2,500 to 3,000 during
epidemic years. Save for a rather limited proportion of the population
protected by inoculation during the eighteenth century, this picture must
have remained substantially unchanged for another century or more,
until Jennerian vaccination and perhaps other factors reduced the ravages
of smallpox in nineteenth-century England.54
If we are correct in interpreting the data in Figure 1 to indicate that
virulent smallpox first appeared in England during the seventeenth cen-
tury, then we must inquire about the status of the population at risk prior
to its arrival. Here again, the epidemic curve in Figure 1 is highly il-
luminating. We see that as soon as virulent smallpox appeared on the
scene, there began a cycle of epidemic recurrence with almost monoto-
nous regularity, returning at an average interval of less than four years.
But most significant is the height of the epidemic peaks. The first in 1632,
a relatively minor one, accounted for some 5.6% of the total deaths,
while the major epidemic of 1634 accounted for 12.4% of the total. It
will be seen that these two epidemics, and those that followed in the
years thereafter, were neither appreciably less devastating nor more devas-
tating than those which occurred later in the century. If the population
of London on the arrival of virulent smallpox had represented an im-
munologically "virgin soil" (of the type that smallpox and measles found
in the Americas and in the Pacific), then the first epidemics in London
should have been proportionately far greater killers than the later ones. 55
That they were not must be taken as convincing evidence that the popu-

54. See Hardy, (n. 6) "Smallpox in London."

55. James V. Neel, et al., "Notes on the effect of measles and measles vaccine in a virgin-soil
population of South American Indians," Amer. J. Epidemiol., pi: 418-429, 1970. See the classic
description by Peter Lud wig Panum, "Observations made During the Epidemic of Measles on the
Faroe Islands in the Year 1846," Med. Classics, y. 803-886, 1939, and Alfred W. Crosby, "Virgin
soil epidemics as a factor in the aboriginal depopulation in America," William and Mary Quart., 3rd
ser, 33: 289-299, 1976.
Carmichael & Siherstein : Smallpox in Europe 163
lation of London at the beginning of the seventeenth century had no
smaller proportion of smallpox-immunes than it did at the end of that
century. If these data are trustworthy, then only an explanation based
upon the gradual replacement of an endemic, relatively avirulent, strain
of smallpox by a more virulent form fits the Bills of Mortality.

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Analysis of the demographic data contained in the Bills of Mortality
permits one further clue to be gleaned, this time about the degree of
virulence of this "new" smallpox strain that appeared in England during
the seventeenth century. Accepting Graunt's estimates,56 we see for
example that around 1658 the total population of London was some
384,000, and was increasing by approximately 4,500 per year. With a
total annual mortality of some 15,000 per year, almost 20,000 new
individuals must have been added each year through birth and immigra-
tion. It may be reasonably estimated by standard demographic techniques
that some 10,000 of these were newboms, 57 all of whom would be
non-immunes, whereas the remaining 10,000 or so would be immigrants
from the moderately isolated countryside, perhaps half of whom might
be non-immunes. Given the endemicity of smallpox in London, few
would escape infection. Therefore, we may predict that all of these non-
immunes would appear sooner or later in the smallpox morbidity totals,
so that during this period some 15,000 cases of smallpox might be
expected each year on average. Since the average of smallpox deaths for
the ten years surrounding 1658 was about 1,000 per year, we may calcu-
late a case-fatality rate of approximately 6.5%. If indeed virulent and
avirulent smallpox strains coexisted at this time, and all of the deaths are
attributed to the virulent strain, then the case-fatality rate for the latter
should be increased, perhaps by as much as a factor of two. This implies
a virulence for mid-seventeenth century smallpox not too far out of line
with some of the deadly strains which ravaged the world during the
succeeding two centuries, a strain worthy to bear the name Variola major.
By the end of the seventeenth century, when smallpox had taken its
place as one of the leading and recurrent factors in English mortality
tables, the medical view of the disease had changed radically. Now
Sydenham could discuss in detail the heavy toll exacted by its epidemic
recurrences, and could present case histories of the most severe forms of

56. Graunt, (n. 50) Observations, p. 69.

57. Edward A. Wrigley and Roger S. Schofield, The Population History of England, 1541-1871,
Cambridge, Massachusetts, Harvard University Press, 1981, p. i66ff.
164 Journal of the History ofMedicine : Vol. 42, April 1987
the disease.58 Polymath Martin Lister reported to the Royal Society in
I judge the Small pox so much raging at present not to be the Season, or
temperature of the year, but from the Infection wholly; that also being an Exotic
Disease of the Oriental People, and not known to Europe, or even Asia Minor, or

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Africa at all, till a Spice trade was opened by the later Princes of Egypt to the
remotest ports of the East Indies whence it originally came, and where it rages
more cruelly at this day than with us.59
Beginning in the early seventeenth century, smallpox did in fact begin
to appear with increasing frequency in the writings of England's poets.60
In 1602, Thomas Spillman, perhaps describing an isolated case, wrote:
Cruel and unpartiall Sicknesse
Sword of that Arch-Monarke Death,
That subdues all strength by weaknesse,
Whom all Kings pay tribute breath.
Are not these thy steps I tracke,
In the pure snow of her face.61
Again, in 1616, the year of Shakespeare's death, Benjonson published
"An Epigram to the Smallpox," in which he says:
Envious and foule Disease, could there not be
One beautie in an Age, and free from thee?
. . . Thought'st thou in disgrace
Of Beautie, so to nullifie a face.62
Having lost his wife to smallpox in 1628, Bishop Richard Corbet wrote

58. Thomas Sydenham, The Whole Works, trans. John Pechey, 5thed., London, 1712, pp. 78-104,
165-172, 268-301, 439-445.
59. Martin Lister, "A discourse concerning the rising and falling of the Quicksilver in the Barome-
ter; and what may be gathered from its great rise in Frosty weather, as to a healthy or sickly season;
presented to the Royal Society March 20, 1683," Phil. Trans. Roy. Soc, no. 165 (November 20,
1684), reprint ed., Amsterdam, DeGraaf, 1963-64, pp. 793-794. We are very grateful to Professor
Richard S. Westfall for supplying this reference. By the mid-eighteenth century, this historical
position was challenged, and smallpox placed among the ancient diseases. See, Thomas Thompson,
An Enquiry into the Origin, Nature, and Cure of the Smallpox, London, A. Millar, 1752, p. 3.
60. Vincent J. Derbes, "Smallpox in English Poetry of the 17th Century," Arch. ofDermatol., yj:
430-432, 1958.
61. Thomas Spillman, in Hyder E. Rollins, ed., A Poetical Rhapsody, Cambridge, Massachusetts,
Harvard University Press, 1931, vol. 1, 222 [cited in Derbes, (n. 60)].
62. Ben Johnson, "Epigrams," 2nd folio in The Forest Underwood [cited in Derbes, (n. 60)].
Carmichael & Silverstein : Smallpox in Europe 165
Oh thou deform'd unwoeman-like Disease,
Thou plowst upfleshand bloud, there sow'st pease
And leav'st such printes on Beauty, that dost come
As clouted shon dew on aflooreof lome;

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Thou that of faces hony-combes dost make.63
These writings, along with the increasing mention of smallpox in
private letters and other records during the course of the seventeenth
century, as reviewed in greater detail by Creighton and by Dixon, imply
the growing recognition of smallpox as both a disfiguring and a deadly
disease—a sentiment that was not generally evident during the preceding
The data reviewed above strongly suggest that smallpox was endemic
throughout Europe during the fifteenth and sixteenth centuries, but that
it was a relatively nonlethal disease. The few epidemiologic records that
are available show that the normal background mortality ascribable to
smallpox was quite low until the seventeenth century. If Variola major
did exist in Europe during this period, then it must have been represented
by only very occasional and highly isolated epidemics, which seemed to
lack the persistence, the centrifugal spread, and the periodicity of return
so characteristic of the virulent smallpox of a later age. As mysterious
as their rapid disappearance is the provenance of these isolated outbreaks.
Were they accidental introductions from some extra-European source of
a virulent strain of the virus, or were they local mutants of increased
virulence? In either case, they appear not to have succeeded in finding
an ecological niche in the midst of the less virulent endemic strains then
But while Europe was being spared the ravages of deadly smallpox
during the sixteenth century, a disease that was undoubtedly smallpox
had been introduced into the New World by the Conquistadors, and
would within a generation or two destroy from one-third to one-half of
the indigenous population.64 Here, for perhaps the first time, was a
virulent smallpox that would command the 10-30% or more case-fatal-
63. Jack A. W. Bennett and Hugh R. Trevor-Roper, The Poems of Richard Corbett, Oxford,
Clarendon Press, 1955, [cited in Derbes, (n. 60)].
64. Esther W. Steam and Allen E. Stearn, The Effect of Smallpox on the Destiny of the American
Indian, Boston, Humphries, 1945; Percy M. Ashbum, The Ranks of Death: A Medical History of the
Conquest of America, New York, Coward-McCann, 1947; Alfred Crosby, The Columbian Exchange:
Biological and Cultural Consequences of 1492, Westport, Connecticut, Greenwood, 1972.
166 Journal of the History of Medicine : Vol. 42, April ig87
ity rate that would become the norm for Variola major throughout the
world two centuries later. The fact that it struck an immunologically
virgin population rendered it especially destructive, but not because the
disease is intrinsically more deadly in the naive recipient—all smallpox
infections occur in previously uninfected hosts with little or no immunity.

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Rather, the greater overall morbidity and therefore mortality in such a
population so disrupts the society as to lead to a complete breakdown
in food production and distribution, and in the other normal social struc-
tures and functions that might otherwise help the sick individual to
survive.65 Similar virgin soil effects leading to excessive mortality in
smallpox, measles, and other infections would later be described in
greater detail.66
What can we conclude about the nature and origin of the agent respon-
sible for this deadly sixteenth-century epidemic in the Western Hemi-
sphere? So long as virulent smallpox was conceived to be rampant
throughout the populated world of the fifteenth century it appeared
reasonable to believe, with Crosby, 67 that it was introduced directly from
Spain by the Spanish, or else carried by slaves from Africa, as most other
accounts have it. But if, in fact, only a relatively benign smallpox was
present in Spain and the rest of Europe at this time, then the former view
may be untenable. If, however, as seems more plausible, virulent small-
pox did exist in Africa and find its way thence to the New World, then
we may wonder why it was not brought during the sixteenth century
to the seaports of Spain, Portugal and Holland, in the course of their
extensive traffic with Africa; nor does the virulent disease appear to have
been returned to Europe from the Americas during this period. In each
of these instances, account must be taken of the probable immunity that
almost all European sailors would have had to this widespread endemic
childhood disease.
Several other possible explanations come to mind to account for the
apparent coexistence of virulent smallpox in the Americas and relatively
avirulent forms of the disease in Europe at this time, each of which
suggests interesting lines of speculation and research for the historian of
epidemic disease. Should the smallpox virus indeed have undergone
repeated mutations in its virulence during modern times, as the epidemi-
ologic data hint, then perhaps virulent smallpox was indeed carried by
the Spanish from one of the isolated outbreaks in Europe that we have
65. Panum, (n. 55).
66. Ibid.
67. Crosby, (n. 64) Columbian Exchange, p. 35-58.
Carmichael & Silverstein : Smallpox in Europe 167
described above, to find in the virgin Indian population the ecological
foothold that it failed to attain in Europe in the presence of endemic mild
disease. Alternatively, it may have been the more benign European form
of the disease that was carried to the Americas, followed by an early
mutation there which exposed a more virulent agent to the Amerindian

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Finally (and historically far more fascinating if perhaps less probable),
the poxvirus that contributed to the high death rates of the indigenous
population of the Americas might even have been the relatively avirulent
European strain of smallpox itself. It is well known that the Amerindian
population is genetically quite different from that of Europe, Africa, and
Southeast Asia, due presumably to a marked founder effect.68 Thus,
Amerindians constitute a remarkably uniform population genetically,69
and the gene frequencies of their blood types and other genetic markers
differ sharply from those of other populations.70 If there should exist
single genes or gene complexes that predispose the individual to suffer
an increased mortality from an otherwise avirulent strain of smallpox,
such as appears to exist in slight measure for poliomyelitis and other viral
infections,71 then the response of Europeans and Amerindians to the
same agent might be quite different. The relatively inbred Amerindian
population, never having experienced smallpox during their isolated res-
idence in the Western Hemisphere, might hyper-respond to even the
mild European strain of the disease, with case-fatality rates of 20 to 30%
or more. Such a situation would result in a rapid disappearance of these

68. A "founder effect" relates to the restricted gene pool that exists in an isolated population that
descends from a limited number of ancestors. See, Aldur W. Erikson, ed., Population Structure and
Genetic Disorders, New York, Academic Press, 1980.
69. Frederick S. Hulse, The Human Species: An Introduction to Physical Anthropology, New York,
Random House, 1963, p. 346; James V. Neel and F. M. Salzano, "A prospectus for genetic studies
on American Indians," in The Biology of Human Adaptability, ed. Paul T. Baker and Joseph S. Wiener,
Oxford, Clarendon Press, 1966, p. 249.
70. Arthur E. Mourant, Ada Kopec and Kazimiera Domaniewska-Sobczak, The ABO Croups:
Comprehensive Tables and Maps of World Distribution, Springfield, Illinois, Charles C. Thomas, 1958,
pp. 268-270.
71. Just as significant genetic predispositions for certain diseases have been identified in the major
histocompatibility complex (see, e.g., John J. Van Rood, Ren£ R. P. deVries, and B. A. Bradley,
"Genetics and the biology of the HLA system," in Martin E. Dorf, ed., The Role of the Major
Histocompatibility Complex in Immunobiology, New York, Garland Press, 1981, pp. 59-113, so there
is the suggestion that there may be a genetic contribution to respond to polio infection with a more
severe, paralytic disease. See, for example, Murray C. Pietsch and Peter J. Morris, "An association
of HL—A3 and HL-A7 with paralytic pohomeylitis," Tissue Antigens, 4: 50-55, 1974; and W. van
Eden, et al. "Differential resistance to paralytic poliomyelitis controlled by histocompatibility leuko-
cyte antigens, "Jour. Infect. Dis., 147: 422, 1983. The broad subject of genetic control of resistance
has been reviewed by Margo A. Bnnton and Neal Nathanson, "Genetic determinants of virus
susceptibility," Epidemiol. Rev., y. 115-139, 1981.
168 Journal of the History of Medicine : Vol. 42, April ig8j
deleterious genes from the indigenous gene pool, 72 so that very quickly
the native population would respond to new outbreaks of smallpox just
as would the European population, for both genetic as well as im-
munologic reasons.73 In this regard, it would be highly interesting to
know whether there was any change in the age-specific case-fatality rate

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among Amerindians later in the sixteenth century, compared with those
experienced during the initial outbreak.
During the centuries or even millennia preceding 1600 A.D., virulent
smallpox may well have ravaged the Far East, India, or Africa, but the
information reviewed above suggests that it did not do so in Europe.
Except for a few outbreaks in the fifteenth and sixteenth centuries, widely
scattered in both space and time and quite atypical of the Variola major
that would spread throughout Europe during the seventeenth century,
most medical, epidemiologic, and literary evidence points to the presence
earlier of only a relatively mild endemic form of the disease. But while
Europe appears to have been spared from virulent smallpox during the
sixteenth century a deadly strain of this virus attacked the indigenous
population of the new world, raising questions once again about the
provenance of the lethal strain and the genetic susceptibility of its isolated
target population. It may be assumed that the Variola major that became
dominant in Europe during the seventeenth century resulted either from
a mutation, or from the introduction of a new strain from Africa or the
Orient. The speculations advanced in this review pose a number of
interesting questions for both the historian and the epidemiologist.
Department of History Institute of the History of Medicine
Indiana University Johns Hopkins University
Bloomington, Indiana 47405 School of Medicine
Baltimore, Maryland 21205

72. One need only recall here the rapidity with which the rabbits in Australia were genetically
selected to resist the lethal myxomatosis virus, introduced to control their population; see Frank
Fenner, "Myxomatosis," Brit. Med. Bull., ty. 240-245, 1959; and, W. R. Sobey, "Selection for
resistance to myxomatosis in domestic rabbits (Oryctolagus cuniculus), "Jour. Hyg., 67:743-754, 1969.
For other examples, see F. B. Hutt, "Genetic resistance to infection," in Resistance to Infectious
Diseases, ed. Robert H. Dunlop and Harley W. Moon, Saskatoon, University of Saskatchewan
Press, 1970, pp. 1—11.
73. This last speculation leaves open, of course, the question of the provenance of the virulent
smallpox that spread throughout Europe in the seventeenth century, and the mechanism by which
it was able to displace the earlier, more benign form of the disease. Whether it resulted from a viral
mutation or was imported from Asia, as the "McNeill hypothesis" (William H. McNeill, Plagues
and Peoples, New York, Anchor Press, 1976) would suggest, is currently impossible to say. It is
interesting that in modern times Variola minor appears to have been able to displace Variola major in
many places: see, e.g., Dixon, (n. 6) Smallpox, p. 203ff.