Smallpox: The Triumph over the Most Terrible of the Ministers of Death

Smallpox was always present, filling the churchyard with corpses, tormenting with constant fear all whom it had not yet stricken, leaving on those whose lives it spared the hideous traces of its power, turning the babe into a changeling at which the mother shuddered, and making the eyes and cheeks of the betrothed maiden objects of horror to the lover [1]. Smallpox has been one of humankind's greatest scourges since time immemorial. Even illnesses as terrible as the plague, cholera, and yellow fever have not had such a universal and persistent impact. Smallpox is believed to have appeared at the time of the first agricultural settlements in northeastern Africa, around 10 000 BC [2]. It probably spread from Africa to India by means of Egyptian merchants in the last millennium BC [3]. The earliest evidence of skin lesions resembling those of smallpox is found on the faces of mummies from the time of the 18th and 20th Egyptian Dynasties (1570 to 1085 BC) and in the well-preserved mummy of Ramses V, who died as a young man in 1157 BC [4-6]. The first recorded smallpox epidemic occurred in 1350 BC during the Egyptian-Hittite war. The illness was passed to the Hittite population by Egyptian prisoners and affected soldiers and civilians alike. The Hittite King Suppiluliumas I and his heir, Arnuwandas, were victims; their civilization fell into sharp decline [2]. During the epidemic in Athens in 430 BC, Thucydides noted that those who survived the disease were later immune to it [7]. These observations were reiterated by Rhazes (Abu Bakr Muhammad Ibn Zakariya al-Razi), to whom we owe the first medical description of smallpox, De variolis et morbillis commentarius, which was written in about AD 910. Rhazes also noted that the illness was transmitted from person to person [8]. His explanation of why survivors of smallpox do not develop the disease a second time is the first theory of acquired immunity. The Fall of Empires: Variola Rex and the Course of History Smallpox greatly affected the development of western civilization. The first stages of the decline of the Roman Empire, around AD 180, coincided with a large-scale epidemic: the plague of Antonine, which killed between 3.5 and 7 million persons [9, 10]. The Arab expansion, the Crusades, and the discovery of the West Indies all contributed to the spread of the illness. Unknown in the New World, smallpox was introduced by Spanish and Portuguese conquistadors. It decimated the local population and was instrumental in the fall of the empires of the Aztecs and the Incas. When the Spanish arrived in 1518, Mexico had about 25 million inhabitants; by 1620, this number had diminished to 1.6 million [11]. A similar decrease occurred on the eastern coast of what became the United States, where the advent of smallpox had disastrous consequences for the native population [12], and the disease continued to be spread through the relentless process of European colonization [13]. The devastating effect of smallpox gave rise to one of the first examples of biological warfare. In a letter written to Colonel Henry Bouquet in 1763, Sir Jeffrey Amherst, commander-in-chief of British forces in North America, suggested grinding the scabs of smallpox pustules into blankets that were to be distributed among disaffected tribes of Indians [14, 15]. The slave trade also contributed to the introduction of the illness in the Americas because many slaves came from regions of Africa in which smallpox was endemic [16]. Princes and Peasants Smallpox made no distinctions. It affected all ages and socioeconomic classes. It killed Marcus Aurelius in AD 180; the first Abbasid caliph, Abbul al-Abbas al-Saffah (the blood shedder), in 754; King Thadominbya of Burma in 1368; the Aztec emperor Ciutlahuac in 1520; King Boramaraja IV of Siam in 1534; the King and Queen of Ceylon and all of their sons in 1582; Prince Baltasar Carlos, heir to the Spanish throne, in 1646; William II of Orange and his wife, Henrietta, in 1650; Emperor Ferdinand IV of Austria in 1654; Emperor Gokomyo of Japan in 1654; Emperor Fu-lin of China in 1661; Queen Mary II of England in 1694; King Nagassi of Ethiopia in 1700; Emperor Higashiyama of Japan in 1709; Emperor Joseph I of Austria in 1711; King Louis I of Spain in 1724; Tsar Peter II of Russia in 1730; Ulrika Eleanora, Queen of Sweden, in 1741; and King Louis XV of France in 1774. During the 18th century, four reigning European monarchs died of the disease, and the Habsburg line of succession to the throne changed four times in four generations because of the deaths of heirs [2]. Citizens were equally at the mercy of the illness. In the late 18th century in Europe, 400 000 people died of smallpox each year and one third of the survivors went blind [3]. The word variola (smallpox) was used for the first time by Bishop Marius of Avenches (near Lausanne, Switzerland) in AD 570. It came from the Latin word varius, meaning stained, or from varus, meaning mark on the skin [17]. In England, the term small pockes (pocke meaning sac) was first used at the end of the 15th century to distinguish the illness from syphilis, which was then known as great pockes [18]. The dread that smallpox inspired is graphically described by Macaulay [1]: that disease was the most terrible of all the ministers of death. The Speckled Monster The symptoms of smallpox-or the speckled monster, as it was known in 18th-century England-appeared suddenly and included high fever, chills or rigors, cephalagia, characteristic dorsal-lumbar pain, myalgias, and prostration. Nausea and vomiting were also common. After 2 to 4 days, the fever relented and a rash appeared on the face and inside the eyes; the rash would subsequently cover the whole body. These maculopapular skin lesions evolved into vesicles and pustules and finally dried into scabs that fell off after 3 or 4 weeks [19]. This sequence of events was characteristic for variola major. Other clinical forms of the disease existed. Persons with fulminating smallpox (purpura variolosa) had mucocutaneous hemorrhages that preceded the appearance of the characteristic skin lesions [19, 20]. In malignant smallpox, the rash had a slow evolution characterized by pseudocropping, subconjunctival hemorrhages, and death when lesions on the face and limbs were confluent. In benign smallpox, the evolution of the rash differed from that of the malignant variety; this form was also less extensive [19, 20]. Modified smallpox (varioloid) occurred in persons who were partially protected by vaccination and was usually benign. Variola sine eruptione was smallpox without a rash and occurred predominantly in vaccinated persons [19, 20]. Variola minor (alastrim, Kaffir-pox) was a mild form of smallpox caused by a less virulent strain of the virus and was endemic in Africa and South America [19]. The case-fatality rate associated with smallpox varied between 20% and 60% and left most survivors with disfiguring scars [21, 22]. Many persons went blind as a result of corneal infection. The case-fatality rate in the infant population was even higher; among children younger than 5 years of age in the 18th century, 80% of those in London and 98% of those in Berlin who developed the disease died [23]. The case-fatality rate also varied according to the nature of the attack-it ranged from almost 100% in fulminating smallpox to 0.5% to 2% in variola minor [24]. The ravages of smallpox were apparent in 18th-century Europe, with case-fatality rates ranging from 20 to 400 per 100 000 per year, and it is said that smallpox was responsible for 10% of deaths in Europe during that century [25]. The incidence rate varied greatly, but during epidemics it was as high as 37.5% in Boston in 1752 [26], 43.1% in Hastings in 1730 and 1731, and 92.7% in Chester in 1775 [25]. In Copenhagen between 1750 and 1800, the annual incidence rate ranged from 875 to 1750 per 100 000; in London between 1685 and 1801, it ranged from 313 to 2355 per 100 000; and in Sweden between 1774 and 1798, it ranged from 341 to 1024 per 100 000 [25]. The incidence rate was so high that the disease was regarded as universal or almost universal, and many authorities believed that everyone would eventually develop it [8, 25, 27]. As recently as 30 years ago, smallpox was endemic in 31 countries, between 10 and 15 million persons developed smallpox yearly, and more than 2 million persons died of smallpox each year [3]. The Art of Variolation That survivors of smallpox became immune to the disease was common knowledge. As a result, physicians and others intentionally infected healthy persons with smallpox organisms in the hope that the resulting infection would be less severe than the naturally occurring illness and would create immunity. Children were exposed to organisms from persons with mild cases of smallpox, and various forms of material from persons with smallpox were administered to healthy adults in different ways. This method of immunization was named variolation and involved taking samples (vesicles, pus from pustules, or ground scabs) from patients in whom the disease had been benign and introducing this material into other persons through the nose or skin [28]. In China, powdered scabs of smallpox pustules were blown into the nostrils of healthy persons through a tube [29]. In India, variolation took several forms, the most common of which was the application of scabs or pus from a person with smallpox to the intact or scarified skin of a healthy person [30]. In China, 100 years before Edward Jenner, healthy persons took pills made from the fleas of cows to prevent smallpox; this is the first recorded example of oral vaccination [31]. The technique of variolation was spread by the caravaners (merchants traveling by caravan to sell their wares); for these persons, protection against smallpox was obviously a great advantage. Variolation was known and practiced frequently in the Ottoman Empire, where it had been introduced by Circas