Smallpox is an acute,
contagious disease caused by the variola virus, a member of the genus Orthopoxvirus, in the Poxviridae family (see the image
below). Virologists have speculated that it evolved from an African rodent
poxvirus 10 millennia ago. Because of the absence of an animal vector,
communities had to reach a critical population (estimated at 200,000 around
3000 BCE) before endemic smallpox could be established. The name is derived
from the Latin word for "spotted" and refers to the raised bumps on
the face and body of the patient. (See Etiology.)
The history of
smallpox is remarkable not only because of the spectacular devastation it
wreaked upon civilization since the dawn of humankind, but also for the
astounding achievement of modern medicine, which eradicated this plague through
the concerted efforts of global vaccination (see the image below). (See
Treatment and Medication.)
The earliest evidence
of smallpox comes from ancient Egypt circa 1157 BCE, where the mummified
remains of a pockmarked Ramses V were uncovered. International traders spread
smallpox throughout the Old World during the 4th-15th centuries CE, while
European explorers and conquerors brought the disease to the Western Hemisphere
in the early 16th century.
Smallpox directly and
profoundly influenced the course of human history. Its tremendous morbidity and
mortality led to indiscriminate killing of kings and warlords and tipped the
balance of power with regularity in Europe and elsewhere. As a result of
smallpox infection, whole civilizations, including the Incas and the Aztecs, were
destroyed in a single generation, and efforts to ward off the disease indelibly
affected the practice of religion and medicine.
Characteristics of variola virus
The variola virus is a
large, brick-shaped, double-stranded DNA virus that serologically cross-reacts
with other members of the poxvirus family, including ectromelia, cowpox,
monkeypox, vaccinia, and camelpox. Unlike other DNA viruses, the variola virus
multiplies in the cytoplasm of parasitized host cells.
Smallpox only
naturally infects humans and does not exist in a carrier state. Experimentally
infected cynomolgus macaques (Macaca fascicularis) develop ordinary or hemorrhagic smallpox
depending on the size of the inoculum. The
virus can survive in the environment for a short period, and it is most stable
at low temperatures and low humidity. Variola is spread most efficiently by
means of inhalation and less efficiently by means of direct contact with scabs
or pustular material from skin lesions. (See the images below.) Swinepox (Suipoxvirus genus of the related Poxviridae family)
may be spread by pig lice in addition to direct contact
Types of smallpox
The 2 predominant
variants of variola, major and minor, differ greatly in their mortality rates
(30% vs 1%, respectively). Variola major was the predominant endemic strain
throughout the world, and by the end of the 18th century, it was responsible
for approximately 400,000 deaths a year in Europe. In patients who recovered
from the disease, blindness was common, and disfiguring scars were nearly
universal.
During the first half
of the 20th century, all outbreaks of smallpox in Asia and most in Africa were
due to variola major. Variola minor was endemic in some countries in Europe,
North America, South America, and many parts of Africa.
Variola major smallpox
has 4 subtypes, as follows:
·
Ordinary smallpox -
The most common form, which accounts for 90% or more of smallpox cases
·
Modified smallpox - A
mild form that develops in previously vaccinated persons
·
Flat smallpox
(malignant smallpox) - A severe variety of smallpox in which lesions do not
project above the skin surface
·
Hemorrhagic smallpox
(fulminant smallpox) - A rare, very severe, highly fatal variety of smallpox in
which hemorrhages develop in the skin and mucous membranes
Variola minor is less
common and much less virulent; it was previously found mainly in South Africa,
South America, Europe, and Australia.
Other types of
smallpox include the following:
·
Variola sine eruptione
(variola sine exanthemata) - Another less common form of smallpox
·
Pulmonary form of
smallpox - Characterized by severe symptoms, cyanosis, and bilateral
infiltrates; has been described in individuals with little or no smallpox
immunity; the mortality rate of this type is undetermined
·
Pharyngeal form of
smallpox - Develops in immunized individuals; this form presents with a spotty
enanthem over the soft palate, uvula, and pharynx
·
Influenzalike form of
smallpox - Rarely results in a rash
The pharyngeal and
influenzalike forms are relatively mild, usually affect individuals who have
been previously immunized, and do not cause mortality.
Immunity
Cellular immunity and
humoral immunity are elicited in response to variola infection. Neutralizing
antibodies can be detected during the first week of clinical illness, whereas
hemagglutination-inhibition and complement-fixation antibodies are found in the
second to third weeks. Neutralizing antibodies persist for many years or
decades after infection, whereas levels of hemagglutination-inhibition and
complement-fixation antibodies generally decrease within a year.
Cell-mediated immunity
likely plays an important role in controlling disease; virus-specific cytotoxic
T cells are detectable in lymphoid organs as early as 4 days after infection.
These cytotoxic T cells are believed to limit viral spread by causing lysis of
infected cells in the reticuloendothelial system and the skin.
The relative
importance of the cellular immune response against smallpox has been
demonstrated in animals. Studies show that mice with defective T cells are able
to generate normal humoral responses to a viral challenge, yet they die when
exposed to Orthopoxvirus concentrations that are sublethal in healthy mice. Studies
in rodents and sheep have demonstrated memory in the form of virus-specific,
cytotoxic lymphocyte immune responses that occur long after the initial variola
infection.
Because of potential
bioterrorism, interest in smallpox pathogenesis has increased. Protein analysis
indicates that the variola virus G1R protein binds to cellular nuclear factor
kappa-B (NF-kB), thereby inhibiting its function in cell signalling.The G1R
protein is highly conserved among pathogenic orthopoxviruses and is absent from
the less-pathogenic vaccinia strains, thus suggesting that it may serve as a
molecular therapeutic target. One report identified a novel peptide with the
ability to inhibit vaccinia virus cell entry.
Other studies
developed a method of reliably classifying species of variola virus into major
and minor species by genotype using novel real-time polymerase chain reaction
(PCR) assay probes Further investigation into genetic variations
between species of variola virus may reveal variable response to therapeutic
targets.
History of inoculation
Intentional
inoculation with subvirulent strains of variola to protect against variola
major (variolation) began in India sometime before the first millennium CE.
This practice spread throughout the Old World and eventually reached Europe in
the early 18th century. Although variolation was capable of inducing lifelong
immunity in vaccinated individuals, the practice was a risky procedure, and
those inoculated had a mortality rate of approximately one tenth that of
individuals with naturally occurring disease. Furthermore, treated individuals
were capable of transmitting disease to untreated individuals for some time
after variolation.
In one of the major
accomplishments in modern medicine, Edward Jenner demonstrated in 1796 that an
individual could be protected against disease. The skin could be inoculated
with pustular material containing the cowpox virus, an orthopoxvirus closely
related to variola. Although the heterologous immunity induced by vaccination
(from the Latin word vacca, meaning cow) was not
lifelong, this approach was significantly safer than variolation, and
vaccination quickly spread throughout the world. In subsequent decades, the
strain of virus used was sustained by means of arm-to-arm inoculation or
maintained as dried material on threads.
Over time, the virus
mysteriously changed from its original cowpox form to the strain of vaccinia
used in current vaccines. In the latter half of the 19th century, the practice
of growing virus for vaccines on the flank of calves was adopted to lessen the
risk of transmitting other human diseases (eg, syphilis) during vaccination.
In the late 1940s,
large-scale production of freeze-dried vaccine enabled mass vaccination
campaigns and, eventually, the global eradication of smallpox. In the latter
half of the 1960s, the World Health Assembly intensified its efforts to
eradicate the disease by using highly potent and stable vaccine, by rapidly
identifying outbreaks, and by performing ring vaccination in all contacts of a
person who was infected. (See Treatment and Medication.)
The last case of
endemic smallpox occurred in Somalia in 1977, and the last recorded case in
humans occurred in England in 1978; this final case resulted from an accidental
laboratory infection. In 1980, the World Health Organization (WHO) officially
declared that smallpox had been eradicated. Currently, the only remaining known
variola virus isolates are frozen in closely guarded repositories at the US
Centers for Disease Control and Prevention (CDC) in the United States and at
the VECTOR Institute in Russia.
After the disease was
eliminated from the world, routine smallpox vaccination was stopped. The
long-term consequence of eradication is that much of the world's population is
now unvaccinated and at risk for smallpox infection. Currently, nearly half of
the US population has not been vaccinated and has no immunity to vaccinia or
variola. The remainder of the population was vaccinated 30 or more years ago
and may retain partial protection from the disease.
Bioterrorism
Smallpox is a
high-priority (category A) agent for bioterrorism, defined as follows by the
CDC (see the PDF file below):
·
Easily disseminated or
transmitted from person to person
·
High mortality rate
and potential for significant public health effect
·
Probable instigator of
panic and social disruption
·
Special actions
required for public health preparedness
