Smallpox

Synonyms:

Variola, alastrim, amaas

Etiology:

Infection with variola poxvirus

Associations:

Since eradication in 1979, confirmed presence should

prompt consideration of biowarfare/terrorism

Clinical:

Influenza-like prodrome ~ 3 days prior to erythematous

macular rash into vesiculating papules to umbilicated

pustules and finally scars

Histology:

Intraepidermal and subepidermal vesiculation with

neutrophils predominating, epithelium with eosinophilic

(Guarnieri) inclusions

IHC repertoire:

N/A

Staging:

None

Prognosis:

Overall ~30% mortality

Adverse factors:

Confluent eruption, thrombocytopenia/DIC

Treatment:

Prevented with vaccination, cidofovir efficacious in animal

studies

Smallpox, otherwise known as variola, was first described in ancient Chinese texts dating from the eleventh century b.c. The Chinese were the first to discover that purposeful inoculation of lesional material into the nose of the uninfected was preventative of disease in the sixth century b.c. (1). Although the disease was officially eradicated in 1979, known stocks of the material have been maintained in biolabs located in Russia and the United States, where they pose a potential source of public health concern if subverted as biowarfare agents (2-5). Smallpox belongs to the Poxvirus group of double-stranded DNA containing viruses that includes vaccinia, molluscum contagiosum, and cowpox. The poxviruses are among the largest of all human viruses, attaining a maximum diameter of 300 nm, and possess characteristic rectangular or cylindrical outer capsids and a central DNA core (6).

Natural infection follows contact with an infectious human most commonly via respiratory droplets but may also occur with skin inoculation or fomite spread. The virus is hearty and resistant to dessication. Scales and desquamated epithelium harbor viable virus for long periods. Following exposure, there is an asymptomatic 10- to 14-day period in which viral replication occurs within infected respiratory mucosa and associated draining lymphatic tissues. This phase of infection (primary viremia) coincides with generalized involvement of the reticuloendothelial organs including the liver, spleen, and lymph organs. Secondary viremia then follows in which systemic spread of the virus through the bloodstream occurs, heralding the onset of an influenza-like prodromal syndrome. Prodromal symptoms include high fever, severe headache, back pain, and vomiting. During this prodromal phase a characteristic and fleeting maculo-papular rash involving the waist and proximal lower extremities may occur. The patient remains noninfectious during the prodromal phase, becoming infectious only when the exanthem appears. Laboratory testing during this period often yields abnormal coagulation parameters including thrombocytopenia and altered clotting times that may be associated with the development of the disseminated intravascular coagulation (DIC) syndrome. Abnormal bleeding is an ominous sign ascribed to the hemorrhagic form of the disease (purpura variolosa) with a generally fatal outcome. With secondary viremia, there is viral spread to the mucosa and skin epithelium, initiating the characteristic exanthematous rash of the disorder approximately 3 days after prodromal symptoms begin.

Although the morphology and course of individual rash lesions are similar, their number can vary (6). Mild forms of the disease (alastrim, variola minor) are charac

HematopoiesisMultiple Pustules Erythematous Base
Figure 27.1. Multiple ulcerating pustules with erythematous bases seen in smallpox.

terized by a sparse number of lesions, whereas more severe forms may present with a confluent eruption. Lesions tend to be peripherally distributed with the greatest number located over the extremities and face (Figure 27.1). The earliest lesion consists of an erythematous macule that proceeds to a deep-seated papule with a cloudy appearing surmounted vesicle. The vesicle is multiloculated and resilient. The lesions mature generally within 7 days into pustules with characteristic central umbilication. Within 10 days, the surface forms a crusted scab, healing as a depressed scar. Occasionally, the lesions may present as crusted plaques or pass through the various stages without vesicle or pustule formation. Mucosal involvement often noted at the time of the exanthem includes ocular, genital, or oropharyngeal disease including upper airway obstruction with laryngeal and tracheal involvement. Visceral disease may take the form of pneumonitis, encephalitis, osteomyelitis, orchitis, or hepatitis. Pneumonia and encephalitis constitute serious complications that may eventuate in death.

The histologic features seen in variola are suggestive of the disorder (7). Early lesions show dermal edema with neutrophilic capillaritis. Developed lesions of smallpox show, in addition to the dermal edema, pronounced intrapidermal vesiculation with exocytosis of neutrophils (Figures 27.2 and 27.3). The blister cavity may contain or be surrounded by epithelial cells that possess characteristic eosinophilic granular inclusions known as Guarnieri bodies (Figure 27.4). Elementary or Paschen viral bodies may be demonstrated with Geimsa staining scrapped from or expressed from lesional material. Multinucle-ation, nuclear molding, and/or nucleus inclusions typical of the Herpesvirus infections are not identified.

Diagnosis of suspected cases of smallpox has obvious global implications and public health ramifications. Once presumptively diagnosed on the basis of the clinical presentation, the disease should now be confirmed by ancillary diagnostic techniques and in conjunction with public health agencies. Genomic-based technologies, including PCR techniques and fluorescent antibody testing of infectious material, provide fairly rapid and, presumptive results but the gold standard for identification involves tissue culturing and anti-serum neutralization. The diagnosis can also be achieved serologically through retrospective analysis of paired acute and convalescent sera.

The most important disorder to distinguish from smallpox is chickenpox. The latter typically produces little if any prodromal symptoms, and is associated with successive crops of lesions, thus showing lesions in various stages of development. There is a tendency of the lesions of smallpox to be peripherally distributed, larger, more often deep-seated, to possess central umbilication, and to become confluent compared to chickenpox.

There is no effective treatment for established cases. Ongoing trials with the antiviral agent cidofovir have been promising in animal models. Treatment with immune globulin, anti-vaccinia serum, and thiosemicarbazone has been attempted in the past with questionable efficacy. Supportive measures aimed at reducing secondary bacterial infection and monitoring fluid and electrolyte levels are important. Prevention remains the most important means of deterring smallpox. The Jennerian vaccination consists of the purposeful inoculation of vaccinia virus (a laboratory-altered form of smallpox) into the skin (8). Following inoculation, a crusted papule should develop at the site

Figure 27.2. Low power photomicrograph showing epidermal blister with subepidermal necrosis.

Figure 27.2. Low power photomicrograph showing epidermal blister with subepidermal necrosis.

Photomicrograph

within 10 days of administration. Failure to develop an inoculation site lesion is an indication of ineffective immunization or loss of vaccine potency and the immunization should be repeated. Vaccination is contraindi-cated in the immunosuppressed, infants, or individuals with atopy or other undisclosed dermatitis that may predispose them to dissemination of the virus. Vaccination against smallpox ended in 1972, leaving approximately 65% of the current U.S. population who have never received vaccination and, of those vaccinated, all have a questionable ability to mount an effective immune response. For these reasons, interest in vaccination, particularly among health care workers and those who might respond to its use as a bioterrorism agent, has emerged.

Guarneri Bodies SmallpoxGuarnieri Bodies
Figure 27.4. High power detail of blister cavity. Note central rounded eosinophilic bodies (Guarneri) associated with smallpox cytopathic effect.

Widespread immunization of the public engenders important practical and medical concerns. Vaccine production has only recently been reinstituted after a long hiatus and thus limited stocks are available. Important complications of the vaccine itself include hypersensitivity reaction, sys-temization or progressive cutaneous spread of the virus, encephalitis, and bacterial superinfection (8-10). An increased incidence of myocardial infarction among recipients of the vaccine has also been recently reported (11).

The overall mortality rate of smallpox is 30%. Individuals who develop disseminated or confluent lesions, DIC, encephalitis, or pneumonitis are at greater risk.

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