Smallpox

Smallpox is the infectious disease produced by Variola major. It was the first infection for which a preventive measure, vaccination, was introduced; it is the first infectious disease that has been eradicated from the wild. A new case of smallpox would almost certainly be a use of a biological weapon, probably as terrorism, and constitute a major worldwide emergency.

By world agreement, only two stocks of the smallpox pathogen exist: in high-security government laboratories in Russia and the United States. There are concerns, however, that there may be cultures elsewhere, and, since it is transmissible from human to human and has substantial morbidity and mortality, there are worldwide preparations for containing and treating an outbreak. The vaccine, while having significant side effects, can reduce the severity of an active case as well as prevent the disease. At least one antiviral drug, cidofovir, is believed active against it, but has not been used in humans.

Smallpox Infection

The virus normally enters the body through the respiratory mucosal surfaces. It can also enter through the skin and rarely enters through the placenta. Relatively few particles (10-100) are needed to infect people with the virus. Once infected, the virus concentrates in the lymph nodes. The primary viremia lasts from the 3rd day from exposure to the 8th or 12th days since infection. During the primary infection, the patient does not have symptoms. After this initial period, the secondary viremia begins and the patient begins to display symptoms. After about the 14th day, the lesions begin to form, at this point the patient is contagious. Eventually the patient dies from toxemia, or blood poisoning, from the amount of infected cells.

Pathophysiology

Smallpox is caused by the variola virus. The variola virus is a member of the genus Orthopoxvirus, which also includes cowpox, monkeypox, orf and molluscum contagiosum. Among animal viruses, poxviruses are some of the largest, rivaling the size of bacteria and have DNA strands that are, on average, 200,000 base pairs (200 kbp). The smallpox virus is a brick shaped virion that is 250 to 300nm long and 250nm high with a diameter of 200nm.

Replication

The poxviruses are unique in the fact that they are able to reproduce in the cytoplasm of a cell, with no need for the nucleus. In fact, poxviruses are the only known virus to be able to do this. The virus replicates in the major organs and uses the filtering organs (lymph nodes, kidneys, spleen and liver) to reproduce and spread.

Immune System Evasion

Two major devices that smallpox use to prevent immune system response have been discovered.

Interlukin-18 blocking

Interlukin-18 (IL-18) is a protein that is produced by macrophages to activate natural killer (NK) and natural killer T cells (NKT). Smallpox, and other poxviruses, block this protein from activating the NK and NKT cells. When the IL-18 protein is not blocked, it causes the production of Interferon-gamma or IFN-&gamma. This research accompanied research revealing how proteins communicate, giving the possibility to create drugs that disable the blocking mechanism for smallpox as there are no drugs that effectively combat smallpox

Interferon-gamma (IFN-γ) binding protein

Recent research has revealed the reason that the poxvirues and the variola virus in particular are so efficient at infecting the patient with very few particles of virus and why it is able to resist immune response in the early stages of infection. Research at Saint Louis University has revealed that mousepox, a type of poxvirus, contains a protein that binds to the IFN-γ molecule that is produced by natural killer cells and natural killer T cells. Its main role is to prevent virus replication directly by altering the genome of affected cells and activating natural killer responses. The protein binds to the IFN-γ molecule and neutralizes it, rendering one of the first levels of immune system useless. This gives the virus time to reproduce with little restriction and spread until a secondary immune response is activated.

Types

There are two types of the variola virus, variola major and variola minor. Variola major is the deadlier version of the virus with a general fatality rate of 30%, whereas variola minor has a fatality rate of less than 1%. Variola major has three different presentations in victims.

Type of infection	Occurrence	Fatality rate	Principal Factors	Symptoms	Summary
Classic	High	30% (variola major)	Infection with variola major	Prodrome Symptoms (lasting 3-4 days)- organized by rate of occurrence in large case series Fever, 100% Headache, 90% Backache, 90% Vomiting, 50% Chills, 60% Pharyngitis, 15% Abdominal pain, 13% Diarrhea, 10%	The most common reaction to the smallpox virus
Hemorrhagic	Very Low	Extremely high, about 96% : Usually death occurs in less than a week after incubation period (same as classic)	Thought to be caused by abnormal immune system response or lack thereof, not a variant of the variola virus	Early-onset form (Sudden onset, hemorrhagic symptoms occur within 2 days of onset) Prodrome stage high fever severe headache and backache Rash generalized dusky erythema petechiae ecchymoses Late-onset form (typical prodrome lasting 3-4 days) Prodrome stage (see classic smallpox symptoms) Rash (similar to classic smallpox, except for indicated) Lesion development is accelerated Bleeding occurs at base of lesions General Hemorrhagic Symptoms Bleeding from mucosal surfaces including the gums Hemoptysis Subconjunctival hemorrhage Hematuria Epistaxis	One of the more severe reactions to the smallpox virus, it is the second deadliest
Flat (malignant)	Very Low	Extremely high; approaches 100%	Unknown	Prodrome (Same symptoms of classic smallpox except as noted, lasting 2-4 days) Severe toxemia Rash Lesions develop much slower Rarely develop into pustules; remain flattened Lesions "velvety" by 4th or 5th day Normally confluent Heals without scarring	The most severe reaction to smallpox

Timeline of Infection

Timeline of the classic presentation of the disease and a description as reported by the CDC's Emergency Response and Preparedness page on Smallpox

Stage	Duration	Contagious	Desription
Incubation Period	7 to 17 days	Not contagious	Exposure to the virus is followed by an incubation period during which people do not have any symptoms and may feel fine. This incubation period averages about 12 to 14 days but can range from 7 to 17 days. During this time, people are not contagious.
Initial Symptoms (Prodrome)	2 to 4 days	Sometimes contagious*	The first symptoms of smallpox include fever, malaise, head and body aches, and sometimes vomiting. The fever is usually high, in the range of 101 to 104 degrees Fahrenheit. At this time, people are usually too sick to carry on their normal activities. This is called the prodrome phase and may last for 2 to 4 days.
Early Rash	About 4 Days	Most Contagious	A rash emerges first as small red spots on the tongue and in the mouth. These spots develop into sores that break open and spread large amounts of the virus into the mouth and throat. At this time, the person becomes most contagious. Around the time the sores in the mouth break down, a rash appears on the skin, starting on the face and spreading to the arms and legs and then to the hands and feet. Usually the rash spreads to all parts of the body within 24 hours. As the rash appears, the fever usually falls and the person may start to feel better. By the third day of the rash, the rash becomes raised bumps. By the fourth day, the bumps fill with a thick, opaque fluid and often have a depression in the center that looks like a bellybutton. (This is a major distinguishing characteristic of smallpox.) Fever often will rise again at this time and remain high until scabs form over the bumps.
Pustular Rash	About 5 Days	Contagious	The bumps become pustules—sharply raised, usually round and firm to the touch as if there’s a small round object under the skin. People often say the bumps feel like BB pellets embedded in the skin.
Pustules and Scabs	About 5 Days	Contagious	The pustules begin to form a crust and then scab. By the end of the second week after the rash appears, most of the sores have scabbed over.
Resolving Scabs	About 6 Days	Contagious	The scabs begin to fall off, leaving marks on the skin that eventually become pitted scars. Most scabs will have fallen off three weeks after the rash appears. The person is contagious to others until all of the scabs have fallen off.
Scabs resolved	n/a	Not Contagious	Scabs have fallen off. Person is no longer contagious.

• Smallpox may be contagious during the prodrome phase, but is most infectious during the first 7 to 10 days following rash onset.

Definitions of Medical Terms

Natural Killer - Bone marrow-derived lymphocytes that possess cytotoxic properties, classically directed against transformed and virus-infected cells. Unlike T-CELLS and B-CELLS, NK cells are not antigen specific. The cytotoxicity of natural killer cells is determined by the collective signaling of an array of inhibitory and stimulatory CELL SURFACE RECEPTORS. A subset of T-LYMPHOCYTES referred to as NATURAL KILLER T CELLS shares some of the properties of this cell type.