Smallpox

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Smallpox is a contagious disease unique to humans.^[1] Smallpox is caused by either of two virus variants named Variola major and Variola minor. The deadlier form, V. major, has a mortality rate of 30–35%, while V. minor causes a milder form of disease called alastrim and kills ~1% of its victims.^[2][1] Long-term side-effects for survivors include the characteristic skin scars. Occasional side effects include blindness due to corneal ulcerations and infertility in male survivors.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Smallpox virus may be transmitted from contaminated surfaces or aerosolized particles. It is capable of inducing harm by evading the host’s immune system and replicating inside host’s cells. The virus may cause 3 forms of the disease: 1) ordinary; 2) flat-type; or 3) hemorrhagic smallpox. It infects different cells of the body, being known by it’s propensity to cause characteristic pock like lesions on the skin.

Smallpox virus is transmitted by:^[1]

• Physical contact
• Contact with infected body fluids
• Contact with infected objects
• Air through aerosolized particles

Smallpox pathogenicity is due to its ability to evade the host’s immune system. Most proteins responsible for the pathogenesis of the virus are located at the terminal DNA regions of the virus.

Genetic comparisons of the smallpox virus with the vaccinia virus allowed to observe certain genetic changes that may be responsible for the virulence of the smallpox virus. However, without studying the gene transcripts, it is not possible to draw objective conclusions.^[2]

The smallpox virus commonly enters the body through the upper respiratory tract, invading the oropharyngeal and respiratory mucosa.^[3] Other possible ports of entry include: skin, conjunctiva as well as through the placenta.^[4] Although the viral scabs may contain life viruses, they are commonly contained within thickened material, which limits transmission.

Once in the respiratory mucosa, the infection commonly progresses as:^[5][4][6]

• Asymptomatic respiratory mucosa infection
• Viral replication within respiratory epithelium
• Transient primary asymptomatic viraemia
• Virus enters macrophages and spreads to lymph nodes and reticuloendothelial system, where it replicates during 4 – 14 days
• Exuberant secondary viraemia, leading to symptom onset

During secondary viraemia the virus infects mucous cells of the pharynx and mouth, and endothelium of the capillaries of the dermis, causing skin lesions. Other organs with high viral loads include:^[6]

• Spleen

• Liver

• Bone marrow

• Kidneys

Before development of the rash, the first lesions appear on the oropharyngeal mucosa, at which time the virus is released through the mucosal secretions, making that patient infectious.

Skin lesions develop due to migration of macrophages to the infected areas of the dermis, leading to edema and necrosis. With the influx of more polymorphonuclear cells, skin pustules will develop.^[5]

The immune system responds to the viremia with activation of lymphocytes T and B and concomitant production of:^[6]

• Neutralizing antibodies, during first week of disease, remaining for many years

• Hemagglutination-inhibition antibodies, by the 16th day of infection, beginning to decrease after 1 year

• Complement-fixation antibodies, by the 18th day of infection, beginning to decrease after 1 year

• Memory T cells, remaining for 50 years

Death by smallpox was commonly due to toxemia, following:^[5]

• Hypotension

• Coagulopathy

• Multiorgan failure

• Bacterial infections

Depending on the status of the patient’s immune system, there are 3 forms of smallpox:^[7]

Ordinary smallpox is characterized by the following progression of lesions:^[8]

• Initial hypopigmented macules, which appear first in the mouth
• Macules progress into papules and subsequently to vesicles
• Vesicles become pustules
• At the 14th day, pustules loose liquid content and become crusted
• At the 3rd week, most crusts will separate (palms and soles last)

This form of smallpox is typical of an immunocompetent patient, in whom the immune system is able to inhibit viral replication.

Flat-type smallpox is characterized by the following progression of lesions:^[9]

• Delayed appearance of macules
• Slow progression of the lesions, usually with flat and soft appearance
• Possible slough of skin sections

Most cases are fatal with presence of severe toxemia. This form of smallpox is typical of patients with weak cellular immune response to the virus.

Hemorrhagic-type smallpox is characterized by the following progression of lesions:^[10]

• Skin petechiae
• Mucous membrane and conjunctival bleeding
• Subcutaneous hemorrhage gives skin and conjunctivae deep red appearance
• Organ bleeding
• Early death by multi organ failure, usually before appearance of maculae.

This rare form of smallpox is typical of patients with severely compromised immune response, in which there is intense viral replication in the bone marrow and spleen. It is also associated with intense toxemia.

The typical skin vesicles observed in smallpox occur following:^[11]

• Viral infection of the epidermal cell
• Cells in malpighian layer entering balloon degeneration, from formation of vacuoles
• Cytoplasmic enlargement leading to loss of nuclear material
• Destruction of upper and middle layers of stratum spinosum
• Formation of vesicles, with high viral index

On the other hand, in the infected mucous surfaces, the viral proliferation and absence of the stratum corneum, lead to the formation of ulcers. These ultimately lead to the release of greater loads of virus into the oropharynx.^[12]

Poxviruses are characterized by cytoplasmic inclusions, however, these do not identify specifically the smallpox virus on a biopsy. There are 2 types of inclusion bodies:^[13]

Typical of some viruses of the:

• Genus Orthopoxvirus:

• Cowpox virus
• Ectromelia virus

• Genus Avipoxvirus

• In areas of active viral replication
• Present in infections by all poxviruses
• Appear as basophilic bodies near the nucleus on hematoxylin and eosin-stained samples
• Evident at epithelial cells underlying vesicles and pustules

• 
  Hematoxylin and eosin (H&E)-stained tissue sample, reveals some of the histopathologic changes found in a human skin tissue sample from the site of a smallpox lesion. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[14]
• 
  hematoxylin and eosin (H&E)-stained tissue sample, reveals some of the histopathologic changes found in a human skin tissue sample from the site of a smallpox lesion. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[14]
• 
  This is a chickenpox scab (left), and smallpox scab (right) viewed in profile as a demonstration in comparative morphology. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[14]
• 
  This image depicts three mounted chickenpox scabs seen from the side revealing the superficiality of these scabs when morphologically compared to a smallpox scab.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[14]
• 
  Viewed from above, this image depicts a smallpox scab (left), and chickenpox scab (right) as a demonstration in comparative morphology. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[14]
• 
  Cytoarchitectural pathologic changes found in a sample of skin tissue from a eczema vaccinatum lesion, which had manifested itself after this patient had received a smallpox vaccination.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[14]
• 
  Cytoarchitectural pathologic changes found in a sample of skin tissue from a eczema vaccinatum lesion, which had manifested itself after this patient had received a smallpox vaccination.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.^[14]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Smallpox is caused by the variola virus, a dsDNA virus of the Poxviridae family. There are two forms of this virus with different virulences, as evidenced by their respective death rates. The virus survives in the cold and aerosoled environments, which explains its oral transmission among humans. Humans are the viruses only host which likely facilitated its eradication. Unlike other DNA viruses, smallpox replicates within the cytoplasm, to which it shows tropism.

Viruses; dsDNA; Poxviridae; Chordopoxvirinae; Orthopoxvirus; Variola vera

Variola virus, also known as smallpox virus, is an orthopoxvirus, from the family Poxviridae, the largest viruses to infect humans. It is a 200-400 nm dsDNA virus, lacking icosahedral symmetry. The other viruses of the family Poxviridae include:^[1]

• Vaccinia virus
• Molluscum contagiosum virus
• Cowpox virus
• Monkeypox virus

The viral structure includes:^[2][3][4]

• 1 Outer membrane
• 2 lateral bodies
• 1 dsDNA molecule in its core, containing 186,999 base pairs

Variola virus genes are similar to the ones of vaccinia virus. Since there is cross-protection between poxviruses, it was possible to use the second as a vaccine for smallpox virus.^[5]

There are 2 forms of variola virus:

• Variola major
• Variola minor

Both strains of the virus share a large amount of genome, yet they differ clinically. This leads to the assumption that the difference in virulence resides in alternate gene expression.^[1][6]

Poxviruses survive in cold and dry environments being able to survive in the aerosoled form, and are killed by hospital disinfectants and UV light.^[1][6][7][8]

Unlike other DNA viruses, poxviruses replicate within the cytoplasm of the host cell. In order to replicate, poxviruses produce a variety of specialized proteins, not produced by other DNA viruses, the most important of which is a viral-associated DNA-dependent RNA polymerase.

The date of the origin of the smallpox virus is not settled. It most likely evolved from a rodent virus between 68,000 and 16,000 years ago.^[9][10] This broad range of dates is due to the different records used to calibrate the molecular clock. It appears that the smallpox virus derived from a remote zoonosis from another animal host, that is today extinct.^[11]

Little is known about the mechanism responsible for host species tropism of smallpox virus. The virus is known to bind mammalian cells unspecifically. There appears to be no particular extracellular receptors involved in viral internalization and initial transcription. However, intracellular availability of trans-acting factors and viral capacity to block host cells antiviral response, such as the interferon pathway, are though to be important intracellular factors, determining viral tropism. The overall immune response by the host towards the virus, will be the key determinant of the infection’s outcome and potential transmission to other hosts.^[11]

Humans are the only known natural reservoir of the smallpox virus.^[12]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Prior to its eradication, smallpox would need to be differentiated from other diseases that cause a vesicular rash and a fever including chickenpox (which was often mistaken for smallpox), herpes zoster and erythema multiforme.^[1]

Different rash-like conditions may be misdiagnosed with smallpox, particularly during the initial maculopapular phase, including:^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Smallpox was declared eradicated in 1980 by the WHO. The true incidence of smallpox before its eradication is difficult to estimate due to poor reporting from endemic regions, which may have reported only 1-2% of the cases. Children and young adults were the most often affected, especially in regions with low levels of immunity. There is no evidence of gender or race differences in the incidence of the disease. Developing countries had a higher incidence of the disease.^[1]

The number of new cases, reported to the international health authorities, was often inaccurate. The data obtained from non-endemic countries, with good health services, was probably the most accurate. Yet, according to the Intensified Smallpox Eradication Programme, the reported incidence amounted only to 1-2% of the actual number of cases, which made it impossible to obtain an accurate estimate of the incidence.^[1]

In endemic regions there were periods called epidemic years in which the incidence was much higher. In order to try to justify this discrepancy, several possibilities were evoked, such as:^[1]

• Viability of the virus
• Changes in susceptibility of the host
• Social factors, such as dispersion of the population
• Seasonal variation in incidence in relation to eradication

The age adjusted incidence of the disease may vary depending upon the level of acquired immunity in the population. When populations were exposed to the disease for the first time, all ages would be affected. In endemic regions, where there was some previous level of immunity, children and young adults were the most severely affected.^[2][1][3]

Smallpox affected males and females equally.^[1][3]

The incidence of smallpox did not differ according to the race.^[1][3]

Developed countries, due to a better and established health system, had lower incidence of smallpox and better reports of new cases to international organizations.^[1]

In developing countries where healthcare facilities are sometimes not trusted by the population, cases were sometimes not reported to public health authorities. Also, vaccination was not sanctioned by some religious beliefs. Taken together, these factors might explain at least in part the higher incidence of smallpox in developing countries.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

People who work in laboratories with the virus are at risk of contracting smallpox. Before its eradication, risk factors for developing smallpox included: physical contact with a patient with the disease, contact with contaminated body fluids, and exposure to contaminated aerosolized particles.^[1]

• Physical contact with someone with smallpox

• Direct contact with infected bodily fluids

• Direct contact with contaminated surfaces

• Exposure to aerosolized particles from someone with smallpox

• Laboratory work with the virus

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

The natural history and outcome of smallpox depend on the form of disease. The common progress will start with flu-like symptoms followed by a skin rash that generally progresses in a typical fashion, leading to the formation of scabs that will fall off, leaving a scar. The complications may include respiratory conditions, from bronchitis to pneumonia, but may also involve the joints, bones and/or eyes. The overall fatality rate for the variola major form was about 30%.

Smallpox, considered eradicated since 1980 by the WHO, affected mainly children, young adults and family members of infected patients. Symptoms depended on the form of the disease. For the most common form, the ordinary smallpox, symptoms usually developed according to the following sequence:^[1]

• Duration approximately 12 – 14 days
• Noncontagious
• Asymptomatic

• Duration approximately 2 – 4 days
• Sometimes contagious
• Fever
• Malaise
• Muscle pain and headache
• Vomiting

• Duration approximately 4 days
• Most contagious stage
• Rash as small red spots in the mouth
• Rash turns into sores releasing the virus
• Rash appears on the skin, starting on the face, moving towards arms and hands, eventually spreading to the rest of the body within 24 hours
• At this time, fever usually falls and the person feels better
• At the 3rd day of rash, it turns into raised bumps
• At the 4th day of rash, bumps are filled with fluid, with a central depression
• Fever will then raise again, until scabs are formed

• Duration approximately 5 days
• Contagious
• Bumps turn into pustules

• Duration approximately 5 days
• Contagious
• Pustules first form a crust and than a scab

• Duration approximately 6 days
• Scabs start to fall leaving scars not the skin
• Contagious, until all scabs have fallen
• Most scabs will have fallen 3 weeks after start of rash

• All scabs have fallen off
• Person is no longer contagious

Common complications of smallpox include:

• Respiratory complications (viral or bacterial):

• Bronchitis
• Fatal pneumonia

• Secondary bacterial skin infection
• Encephalitis – 1 in 500 patients, commonly in adults
• Permanent pitted scars
• Eye problems – 2% of all cases; pustules can form on the eyelid, conjunctiva, and cornea, leading to:

• Conjunctivitis
• Keratitis
• Corneal ulcer
• Iritis
• Iridocylcitis
• Optic atrophy
• Blindness – occurs in 35% to 40% of eyes affected with keratitis and corneal ulcer
• Subconjunctival and retinal hemorrhages.

• Osteomyelitis – lesions are symmetrical, most common in the elbows, tibia, and fibula
• Arthritis may lead to limb deformities
• Ankylosis

The prognosis of smallpox depends on the form of the disease:

• Fatality rate about 10% for patients with discrete lesions and 60% for those with confluent lesions^[2]
• In fatal cases, death usually occurs between the 10th and 16th days of illness
• Unclear cause of death
• Infection often affected multiple organs
• Possible contributors include:

• Circulating immune complexes
• Severe viremia
• Uncontrolled immune response

• Fatality rate about 90%
• Cause of death commonly included: loss of fluids, electrolytes and protein, as well as severe sepsis

• Fatality rate near 100%, usually between 6th and 7th day after the beginning of fever
• Cause of death was often heart failure, or in late cases intense viremia, with severe platelet loss and weak immune response

• Fatality rate about ≤1%

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