Smallpox pathophysiology

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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]

Transmission

Smallpox virus is transmitted by:

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

Pathogenesis

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

Once in the respiratory mucosa, the infection commonly progresses as:

• 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 scabs. Other organs with high viral loads include:

• 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.

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

• 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:

• Hypotension

• Coagulopathy

• Multiorgan failure

• Bacterial infections

Gross Pathology

Depending on the status of the patient's immune system, there may be identified 3 forms of smallpox:

Ordinary Smallpox

Characterized by the following progression of lesions:

• Initial hypopigmented macules
• 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, whose immune system is able to inhibit viral replication.

Flat-type Smallpox

Characterized by the following progression of lesions:

• 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

Characterized by the following progression of lesions:

• Skin petechiae
• Mucous membrane and conjunctival bleeding
• Early death, usually before appearance of maculae.

Microscopic Pathology

The typical skin vesicles observed in smallpox occur following:

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

On the other hand, in the infected mucosal 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 through the oropharynx.