Smallpox

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