Smallpox is caused by variola virus a member of Orthopoxvirus genus. It is the first disease to be eradicated from the history of mankind. In 1977, the last case of endemic smallpox was reported from Somalia and in 1978 one laboratory acquired case was reported. In 1980, WHO declared the world as free from smallpox. However, the virus is now important for its potential threat as a biological weapon and in such scenario if the virus is released it will cause massive outbreak with expected high mortality as the major population of the world is susceptible. It is thus important to know the virus and be familiar with its clinical features.

Pathogenesis: The virus enters through respiratory tract from where it goes to the lymph nodes. Replication at these sites leads to primary viremia. During this period, virus is seeded in reticuloendothelial system and replicates at these sites leading to secondary viremia. This marks the onset of symptoms with prodromal symptoms. During this period, two different events occur.

1. Virus infects the mucosa of mouth and pharynx causing oropharyngeal lesions which appear before the skin rash. High concentration of virus is released in respiratory shedding. The infectivity is maximum during this period. Virus is also found in urine and several visceral organs such as spleen, kidney, liver, and bone marrow.

 2. During the secondary viremia, the infected macrophage migrates to and infects epidermis, and then the virus invades the dermal layer of the skin, which leads to the formation of vesicular lesion. Virus is also found in the lesions.

The histopathological feature of infected cells of all orthopoxviruses including smallpox shows typical cytoplasmic inclusions. Type A inclusions which are intracytoplasmic inclusion bodies containing the clusters of virions. The second one is type B inclusions, also called “Guarneri bodies” which are perinuclear intracytoplasmic inclusion bodies containing viroplasm and maturing virions. Table 1 describes the unique properties of poxviruses.

Table1. Unique properties of poxviruses

Clinical features: Incubation period ranges from 7–17 days. Symptoms start with the prodromal symptoms followed by lesions on oral and pharyngeal mucosa (enanthem) and on skin (exanthem).

Prodromal symptoms start with abrupt onset of high fever and severe constitutional symptoms. Most of the patients are severely ill during this period. It lasts for 2–3 days. This follows the appearance of lesions on oral mucosa and one day later skin lesions. The lesions on the skin are macules to start with and progresses to papules, vesicles and pustules by 7–10 days and formation of scab occurs by 2–3 weeks. The size of lesion also increases with the lesion progression from 2–3 mm to 7–10 mm in diameter. Lesions start from face and are more condensed on face and limbs than trunk (centrifugal distribution) in contrast to chickenpox where the lesions are more on trunk with centripetal distribution. Also, in contrast to chickenpox, all lesions are in same stage. Hemorrhagic lesions are rare and associated with higher fatality.

WHO has classified the clinical features of smallpox into five types:

a. Ordinary smallpox: Most common (90%) with 30% case fatality rate.

 b. Flat type smallpox: Seen in around 7% cases with high mortality of 97%.

 c. Hemorrhagic smallpox: Seen in only 3% but mortality almost 100%.

 d. Modified smallpox: Seen in only 2%, much less severe and rarely fatal. e. Variola sine eruption: Asymptomatic and do not transmit the infection.

Differential diagnosis: Diagnosis of smallpox is based on its classical clinical presentation. However, it may be required to be differentiated from other diseases causing macular rash or papular or vesicular lesions. Table 2 gives the list of common causes of differential diagnosis of smallpox.

Table2. Differential diagnosis of smallpox

Vaccination

Variolation: The first preventive measure for smallpox was attempted by “variolation”. This is a process in which material from smallpox lesion was directly introduced to healthy host with an aim to produce immunity against the virus by producing milder form of disease.

Two methods were practiced:

a. Inhalation of dried scab material.

b. Introduction of pus from active lesion by causing scratch.

In 1796, Sir Edward Jenner showed that intradermal introduction of human cowpox material to a healthy person provided protection against smallpox. This concept of Jenner created world’s first vaccine.

Smallpox Vaccine used during Eradication

First generation smallpox vaccines were used during eradication. These were multiple strains of live vaccinia virus that were propagated on the skin of live animals. These vaccines had the chance of contamination with microorganisms, animal proteins and adventitious tissue materials. Lister-Elstree and New York City Health Board strains of vaccinia virus were the recommended strains by WHO during the eradication program.

Vaccine was given using a bifurcated needle with multiple punctures to introduce through abrasion as vaccinia virus does not grow on intact skin. The efficacy of first generation vaccine was 75%. After correct vaccination, a papule develops at the local site around 4th day and progresses to vesicle and pustule by 7th day.

Second generation smallpox vaccines were prepared from single clone of vaccinia virus grown in tissue culture. This was made to reduce the reactogenicity keeping the immunogenicity intact.

Third generation smallpox vaccines are based on replication competent attenuated vaccinia strains. Attenuation is based either on serial passage in non-human tissues or genetic modification. LC 16m8 and Modified Vaccinia Ankara (MVA) are among the preferred vaccine strains. These vaccines are safer than previous generation vaccine, however, immunogenicity is probably less.

Eradication of Smallpox

 The intensified smallpox eradication program began in 1967. Smallpox was declared to be eradicated from the globe in 1980.

The last case of naturally acquired smallpox by variola major was reported in 1975 in a 3 years old girl named Rahima Banu from Bangladesh. The last case of naturally acquired smallpox due to variola minor was reported in 1977 in Somalia. In 1978, the last case of smallpox was reported which was a lab acquired case in England.

The factors which played a role in smallpox eradication are:

• Presence of effective vaccine and intensive vaccination program

 • No animal reservoir

 • Easily identifiable characteristic clinical features

 • No subclinical infection.

Smallpox as Bioweapon

Currently, the stocks of variola virus is officially present only in two labs under direct supervision of WHO, Center for Disease Control and Prevention (CDC) Atlanta, and State Research Center for Virology and Biotechnology (VECTOR), Koltsovo, Russia. However, it is apprehended that the virus may be present unofficially in many more places and many groups are working on it to use it as a bioterrorism agent.

Smallpox is a suitable bioterrorism agent due to its following characteristics:

• Virus is easy to grow.

 • Can be lyophilized.

 • Survive in the aerosolized form and can be used for mass infection.

• Majority of the current population are susceptible.

 • Disease has a long incubation period hence, may go unnoticed before it spreads.

• Clinicians of current generation are not familiar with the clinical presentation which may delay the diagnosis.

• Genetically modified virus can lead to atypical presentation leading to misdiagnosis and may evade vaccine-induced immunity.

 • Limited number of stockpiles of vaccines.

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مواضيع ذات صلة

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Human Monkeypox

Papovaviridae: Subfamily Polyomavirinae

Effects of viral infection on the host cell

Assembly and release of progeny viruses

Clinical Syndromes of Adenovirus

JCPyV and progressive multifocal leukoencephalopathy (PML)

Polyomavirus-associated nephropathy (PVAN)

Mechanisms of RNA virus genome replication

Epidemiology Human Papillomavirus

Pathogenesis of Human Papillomavirus

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