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SMALLPOX

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Smallpox, or variola virus, is part of the group of orthopoxviruses which also includes vaccinia, monkeypox, rabbitpox, cowpox, camelpox, buffalopox, and ectromelia. Variola is a general term for any of the pox viruses (e.g., cowpox, horsepox, fowlpox) but is usually used to refer to human smallpox. Variola is a double-stranded DNA virus. With the site of entry being respiratory and an incubation period of about 12 days, the disease is characterized by an initial febrile period followed by a macular rash which quickly becomes papular, then vesicular, then pustular. Subsequent scarring or pitting develops.

Specific Substances

    1) Cowpox
    2) Monkeypox
    3) Orthopoxvirus
    4) Smallpox
    5) Smallpox vaccine
    6) Vaccinia
    7) Variola virus
    8) VACCINA
    9) VARIOLA

Available Forms Sources

    A) FORMS
    1) Variola virus is one of a group of orthopoxviruses, which are the largest viruses so far recognized (Henderson, 1994). Also included in this group are vaccinia, monkeypox, cowpox, rabbitpox, fowlpox, horsepox, camelpox, buffalopox, and ectromelia.
    B) SOURCES
    1) Variola virus is known to exist in at least two laboratories as of 1994 and possibly in other laboratories. It is kept under high security conditions (Henderson, 1994).
    2) Archeological recovery teams have had concerns about exhuming bodies of former smallpox victims. Environmental conditions necessary for survival of the virus after a hundred years or more, outside the laboratory, include extreme upper and lower reaches of the two temperate zones, or well-sealed coffins that are interred in very cool and dry regions. Even in these cases, the victim must exhibit scabs and there would need to be direct contact with the live human researcher. Thus, there appears to be little chance for contact infection or reintroduction of smallpox. Permafrost is most likely the ultimate preservation tool for smallpox (Kennedy, 1994).
    C) USES
    1) BIOLOGIC WARFARE: A risk exists for use as a biologic warfare agent against military forces in combat or as a tool of terrorists against civilians. Hidden stockpiles of smallpox virus may exist in a number of laboratories, which could be used as a biological agent in an attack. Within a laboratory, the virus can be produced in large quantities and freeze-dried for future use. The virus is stable in aerosol form and remains stable outside its host for prolonged periods of time, producing a potentially high mortality rate, particularly now since there is little or no immunity to this disease (Ball, 1998; Sattar & Ijaz, 1987). The virus travels surprisingly far in the air and infects at very low doses (Henderson, 1999). Following aerosolization, the virus is likely to retain its infectivity for at least several hours if not exposed to sunlight or ultraviolet light (Anon, 2001). High civilian fatality rates are possible because case fatality rates of 30% were observed in epidemics among unvaccinated individuals (Henderson et al, 1999a). A potential for significant ongoing transmission due to secondary spread also contributes to the significance of this agent as a bioterrorist agent ((Anon, 2000)). In the previous Soviet biowarfare program, the Indian strain of smallpox virus that was developed could cause a mortality of about 30% in unvaccinated people (Whitby et al, 2002).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH POISONING/EXPOSURE
    1) Smallpox is identified by its characteristic skin lesions. Following an abrupt onset with a febrile period (2 to 5 days) (flu-like prodrome), vomiting, malaise, headache and severe backache, and a macular rash develops. The rash quickly becomes papular. The papules evolve into vesicles within 2 days, then progress to pustules, with pain associated with pustule growth. Crusting begins on the eighth or ninth day of illness, with scabs separating over the next 2 to 3 weeks. A pigment-free skin is then exposed. Scarring and pitting develops.
    a) Infected persons are able to transmit infection only from the time of first appearance of the rash until the last scabs have separated.
    b) Approximately two-thirds of recovered patients may have characteristic residual facial scars.
    c) Smallpox may be confused with chickenpox; however, chickenpox lesions are much more superficial and develop in crops. Smallpox lesions develop at the same pace and appear identical on any part of the body. The rash in chickenpox is more dense over the trunk (the reverse of smallpox), and chickenpox lesions are almost never found on the palms or soles.
    d) A more rapidly progressive, malignant disease develops in 5% to 10% of smallpox patients, which is almost always fatal within 5 to 7 days. In these patients, the lesions are so densely confluent that the skin resembles crepe rubber. In some of these patients bleeding into the skin and intestinal tract occurs. These cases are exceedingly infectious.
    2) COMPLICATIONS - Encephalitis, pneumonitis, secondary cutaneous infection, arthritis, conjunctivitis, keratitis, corneal ulceration, and blindness.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Chills and high fever are likely to occur at the pre-eruptive stage.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Marked exhaustion and malaise occurs during the first 2 to 5 days of illness. Encephalitis is a complication of smallpox .
    0.2.20) REPRODUCTIVE
    A) Smallpox vaccine is classified as FDA pregnancy category D. Smallpox vaccine can cause fetal harm when used during pregnancy. Fetal vaccinia, early delivery of a stillborn infant, or a high risk of perinatal death has been reported when smallpox vaccinations are administered during pregnancy. Although lactation studies have not been conducted, live vaccinia virus can be inadvertently transmitted from a lactating mother to her infant. This could lead to serious complications in the infant.

Laboratory Monitoring

    A) Diagnosis may be quickly established by electron microscopic identification of virus particles in vesicular or pustular fluid or scabs. Suspected cases of smallpox in recent years were actually cases of varicella.
    B) Monitor vital signs, including temperature and blood pressure.

Treatment Overview

    0.4.3) INHALATION EXPOSURE
    A) Treatment for smallpox infections is SYMPTOMATIC and SUPPORTIVE.
    B) Although international certificates of vaccination are no longer required, some military personnel and laboratory workers may still receive vaccinia vaccination. Health care providers may be vaccinated.
    C) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    0.4.4) EYE EXPOSURE
    A) Mucocutaneous exposures to blood, body fluids, secretions, or excretions from patients with suspected smallpox infections should be immediately rinsed with copious amounts of water or eyewash solution.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Dermal sites, particularly where breaks in skin integrity occur, exposed to blood, body fluids, secretions, or excretions from patients with suspected smallpox should be immediately washed with soap and water.

Range Of Toxicity

    A) The World Health Assembly officially declared smallpox eradicated in 1980. The last known naturally occurring case was in Somalia in 1977. However, at least two laboratories have known stores of the smallpox virus. Monkeypox, another orthopox virus, is still a threat in some areas, such as Africa; however, the transmission potential of monkeypox virus in humans is appreciably less than that of classical smallpox.
    B) Smallpox virus (variola) is an airborne infectious agent. Release of an aerosol will be the most likely route of transmission during an act of bioterrorism.
    C) Prior to eradication, humans were the only known natural reservoir for the smallpox virus.
    D) The most common modes of transmission were person-to-person via deposition of droplets on nasal, oral, pharyngeal mucosa or by direct viral inhalation from close contact with an infectious person. Indirect spread via fine particle aerosols or viral fomites occurred less frequently.
    E) Biological weapon use of the smallpox virus is of great concern. High civilian fatality rates in unvaccinated individuals are estimated. Smallpox infection treatment is symptomatic and supportive. There is no specific treatment currently available.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) Smallpox is identified by its characteristic skin lesions. Following an abrupt onset with a febrile period (2 to 5 days) (flu-like prodrome), vomiting, malaise, headache and severe backache, and a macular rash develops. The rash quickly becomes papular. The papules evolve into vesicles within 2 days, then progress to pustules, with pain associated with pustule growth. Crusting begins on the eighth or ninth day of illness, with scabs separating over the next 2 to 3 weeks. A pigment-free skin is then exposed. Scarring and pitting develops.
    a) Infected persons are able to transmit infection only from the time of first appearance of the rash until the last scabs have separated.
    b) Approximately two-thirds of recovered patients may have characteristic residual facial scars.
    c) Smallpox may be confused with chickenpox; however, chickenpox lesions are much more superficial and develop in crops. Smallpox lesions develop at the same pace and appear identical on any part of the body. The rash in chickenpox is more dense over the trunk (the reverse of smallpox), and chickenpox lesions are almost never found on the palms or soles.
    d) A more rapidly progressive, malignant disease develops in 5% to 10% of smallpox patients, which is almost always fatal within 5 to 7 days. In these patients, the lesions are so densely confluent that the skin resembles crepe rubber. In some of these patients bleeding into the skin and intestinal tract occurs. These cases are exceedingly infectious.
    2) COMPLICATIONS - Encephalitis, pneumonitis, secondary cutaneous infection, arthritis, conjunctivitis, keratitis, corneal ulceration, and blindness.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Chills and high fever are likely to occur at the pre-eruptive stage.
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) Chills and high fever, lasting 2 to 5 days, generally occur at the beginning of illness (i.e., the pre-eruptive stage) (Hu et al, 2004; Albert et al, 2002; Henderson, 1996; Henderson et al, 1999a) Anon, 1994; (Wien et al, 1988). Temperature exceeds 40 degrees C, then drops (but generally not to normal), then spikes again (Dworetzky, 2002).

Heent

    3.4.3) EYES
    A) Smallpox survivors may develop keratitis, conjunctivitis and corneal ulcers which may progress to blindness in about 1% of cases (Albert et al, 2002; (Anon, 2000); Henderson et al, 1999a; Henderson, 1996).
    B) OCULAR VACCINIA CASE REPORT - Following contact with a military smallpox vaccine recipient, a 26-year-old female developed right eye preseptal cellulitis and blepharoconjunctivitis (visual acuity 20/40 right eye, 20/20 left eye) . Ophthalmologic examination revealed marked periorbital edema and erythema of right eye, a small cutaneous vesicle on the right lower eyelid, diffuse, severe conjunctival injection and chemosis that obscured the peripheral cornea, and a white plaque-like membrane involving the nasal lower fornix and canthus of the right eye. She also experienced sore throat, fever, regional lymphadenopathy and headache. Conjunctival infection with vaccinia virus was confirmed. There was marked improvement following treatment with antibiotics, topical trifluridine and a single dose of intravenous vaccinia immune globulin. Follow-up examination at 2 and 4 months revealed a normal right eye (Hu et al, 2004).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) Following a 2 to 5 day course of high fever, lesions begin to dot the tongue and roof of the mouth, gradually spreading over the face and arms and legs (Henderson, 1996). Typically the virus is spread to 3 or 4 other persons in close contact, often from the victim coughing (Henderson et al, 1999a).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Severe cases result in hypotension with progression to cardiovascular collapse from secondary infection (Henderson, 1996).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PNEUMONITIS
    1) WITH POISONING/EXPOSURE
    a) Smallpox handler's lung is a pneumonic illness characterized by a flu-like illness and first described in 1963 in nurses and others following close contact with smallpox patients(Albert et al, 2002; Foster, 1994).
    1) CASE REPORT - During an acute illness, chest x-ray revealed nodular opacities bilaterally in the upper zones, with calcified lesions at the apices in one nurse. Approximately 12 years later, the same nurse was noted to have multiple calcified lesions bilaterally in her lung fields on chest x-ray (Foster, 1994). The occurrence of multiple widespread calcified pulmonary lesions may represent a modified smallpox pneumonia.
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Acute lung injury (pulmonary edema) is a common complication of hemorrhagic and flat-type smallpox ((Anon, 2000)).
    C) BRONCHITIS
    1) WITH POISONING/EXPOSURE
    a) Cough and bronchitis may be a prominent symptom during the course of illness. Pneumonia is not commonly seen ((Anon, 2000)).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Marked exhaustion and malaise occurs during the first 2 to 5 days of illness. Encephalitis is a complication of smallpox .
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH POISONING/EXPOSURE
    a) Marked exhaustion, headache, backache, and malaise typically occur during the first 2 to 5 days of illness, accompanied by high fever (Hu et al, 2004; Henderson, 1996; Henderson et al, 1999a).
    B) ENCEPHALITIS
    1) WITH POISONING/EXPOSURE
    a) Encephalitis is a complication of smallpox (Albert et al, 2002).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) PUSTULE
    1) WITH POISONING/EXPOSURE
    a) On about the fifth day of illness, a macular rash develops, which quickly becomes papular. The papules develop into vesicles within 2 days, then progress to pustules. Crusting begins on the eighth or ninth day of the rash. Over the next 2 to 3 weeks, scabs separate, leaving pigment-free skin and subsequent scarring or pitting. The rash process is more severe on the face and distal parts of the arms and legs, with less severe rash formation over the trunk and abdomen. Sores may often be found on the palms of the hands and soles of the feet, unlike chickenpox. Sores may become bloody, sometimes with the entire rash becoming bloody, resulting in a substantial amount of blood loss (Albert et al, 2002; (Anon, 2000); Henderson, 1996; Wien et al, 1988; Gurvich et al, 1986).
    b) Smallpox lesions progress synchronously, from stage to stage (macules to papules to vesicles to pustules to crusty scabs) ((Anon, 2000)).
    c) Variola (smallpox) lesions are firm and deep-seated with a characteristic uniformity in stage of appearance; later in the course, the vesicles mature into pustules that often coalesce (Henderson et al, 1999a). Giant cells are NOT seen in lesion scrapings, unlike herpes simplex.
    d) Pustular lesions are common. In fatal cases, however, confluent subcutaneous hemorrhages which rapidly spread to the entire body, with a similar enanthema involving mucous membranes of the oral cavity, respiratory mucosa, and entire gastrointestinal tract are consistently seen. Pain associated with these lesions is intense (Dworetzky, 2002).
    e) SMALLPOX VARIATIONS -
    1) FLAT-TYPE/"MALIGNANT" SMALLPOX - Approximately 2% to 5% of cases will develop severe systemic toxicity and slow evolution of flat, soft, focal skin lesions. This is due to a lack of adequate cell-mediate immune response. Pustular lesions do not develop. Papule lesions coalesce. A fine-grained reddish color is noted on the skin, which resembles crepe rubber. Mortality approaches 95% among unvaccinated persons ((Anon, 2000); Anon, 2001; Henderson et al, 1999a).
    2) HEMORRHAGIC-TYPE SMALLPOX - Extensive petechia, mucosal hemorrhage and intense toxemia (high fevers) occurs in <3% of cases, and is seen more commonly in pregnant women. Death usually occurs before development of typical pox lesions ((Anon, 2000); Anon, 2001; Henderson et al, 1999a).
    B) ERYTHEMA
    1) WITH POISONING/EXPOSURE
    a) Secondary smallpox infections due to smallpox vaccinations may result in nonspecific rashes, including erythema nodosum and erythema multiforme (Grabenstein & Winkenwerder, 2003; Albert et al, 2002); Anon, 1994).
    C) INJECTION SITE REACTION
    1) WITH POISONING/EXPOSURE
    a) On the fourth day following an accidental injection of recombinant vaccinia virus into the forefinger of a laboratory technician, the inoculation site became itchy, then red and papular. A serous fluid was discharged from the site on day 5 and 6, and the lesion reached a diameter of about 1 cm. No systemic effects occurred, and the lesion healed spontaneously while kept under an occlusive dressing. The technician had been vaccinated with standard smallpox vaccine within 2 years of the accident (Openshaw et al, 1991).
    D) ECZEMA
    1) WITH POISONING/EXPOSURE
    a) Eczema vaccinatum is a localized or systemic dissemination of vaccinia virus in patients with a history of eczema and other chronic or exfoliative skin disorder. It is generally mild and self-limiting, but in some cases may be severe and occasionally fatal. Serious cases have developed among primary vaccinees. Severe cases have been reported following contact infection, such as from contacts of vaccinees (Wien et al, 1988; CDC, 1991; CDC, 2001).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH POISONING/EXPOSURE
    a) General aching, myalgia, and malaise may develop initially during illness and persist for up to 2 weeks before resolving. Backache may be severely painful ((Anon, 2000); Henderson, 1996; Foster, 1994) Anon, 1994).
    B) ARTHRITIS
    1) WITH POISONING/EXPOSURE
    a) Arthritis and osteomyelitis are complications of smallpox, occurring late in the course of illness in 1% to 2% of cases, predominantly in children. Bilateral elbow joint involvement is most commonly seen (Albert et al, 2002; (Anon, 2000)).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) LYMPHADENOPATHY
    1) WITH THERAPEUTIC USE
    a) Painful and enlarged regional lymph nodes have been reported following a secondary infection due to a smallpox vaccination (Anon, 1994), and in a woman who developed ocular vaccinia after contact with a recently vaccinated person (Hu et al, 2004); ).
    B) INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) Persons with compromised immune systems, such as those with HIV infection, neoplasms, or drug-induced immunocompromise, may acquire disseminated vaccinia when vaccinated for smallpox (Redfield et al, 1987; Gurvich et al, 1986).
    b) Smallpox vaccination risk to individuals with HIV infection is unknown (CDC, 2001). There is no current data that smallpox vaccination accelerates the progression of HIV-related disease or what degree of HIV infection places the individual at increased risk for adverse vaccine reactions. Until additional information is available, the CDC advises withholding smallpox vaccination in nonemergency situations from HIV infected persons (CDC, 2001).

Reproductive

    3.20.1) SUMMARY
    A) Smallpox vaccine is classified as FDA pregnancy category D. Smallpox vaccine can cause fetal harm when used during pregnancy. Fetal vaccinia, early delivery of a stillborn infant, or a high risk of perinatal death has been reported when smallpox vaccinations are administered during pregnancy. Although lactation studies have not been conducted, live vaccinia virus can be inadvertently transmitted from a lactating mother to her infant. This could lead to serious complications in the infant.
    3.20.2) TERATOGENICITY
    A) FETAL VACCINIA VIRUS
    1) Smallpox vaccine can cause fetal harm when used during pregnancy. Fetal vaccinia, early delivery of a stillborn infant, or a high risk of perinatal death has been reported (Prod Info ACAM2000(TM) percutaneous injection, 2007; Anon, 2000). Exposure to the smallpox vaccine, whether through inadvertent vaccination or to a vaccinee, can result in fetal vaccinia, but should not be a reason to consider pregnancy termination. This is a rare condition, with approximately 50 cases reported worldwide between 1932 and 1972. Of these, one pregnancy was carried through to full-term. Three of the children born to these mothers survived. Although congenital infection occurs mainly during the first trimester, vaccinia can occur irrespective of trimester (Centers for Disease Control and Prevention (CDC), 2003; Wharton et al, 2003).
    B) LACK OF EFFECT
    1) In controlled studies of large case series, there was no significant increase in the rate of congenital malformations occurring in mothers receiving vaccination during pregnancy (Greenberg, 1949; Jablonski, 1967).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified smallpox vaccine as FDA pregnancy category D (Prod Info ACAM2000(TM) percutaneous injection, 2007).
    B) STILLBIRTH
    1) In one study, the incidence of stillbirth was 16 of 67 whose mothers had been vaccinated in the first trimester, 3 of 69 vaccinated in the second trimester, and 2 of 67 vaccinated in the third trimester (McArthur, 1952).
    C) LACK OF EFFECT
    1) In controlled studies of large case series, there was no significant increase in the rate of premature or stillbirths occurring in mothers receiving vaccination during pregnancy (Greenberg, 1949; Jablonski, 1967).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known whether smallpox vaccine virus or antibodies are excreted into human breast milk. However, live vaccinia can be inadvertently transmitted from a lactating mother to her infant. Live vaccinia smallpox vaccination can lead to serious complications in infants (Prod Info ACAM2000(TM) percutaneous injection, 2007).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info ACAM2000(TM) percutaneous injection, 2007).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Diagnosis may be quickly established by electron microscopic identification of virus particles in vesicular or pustular fluid or scabs. Suspected cases of smallpox in recent years were actually cases of varicella.
    B) Monitor vital signs, including temperature and blood pressure.
    4.1.2) SERUM/BLOOD
    A) OTHER
    1) DIFFERENTIAL DIAGNOSIS -
    a) Sores may often be found on the palms of the hands and soles of the feet, unlike chickenpox. Sores may become bloody, sometimes with the entire rash becoming bloody, resulting in a substantial amount of blood loss (Henderson, 1996; Wien et al, 1988; Gurvich et al, 1986).
    b) Variola (smallpox) lesions are firm and deep-seated with a characteristic uniformity in stage of appearance; later in the course, the vesicles mature into pustules that often coalesce (Henderson et al, 1999a). Giant cells are NOT seen in lesion scrapings, unlike herpes simplex.

Methods

    A) IMMUNOASSAY
    1) Openshaw et al (1991) described an ELISA-binding antibody response technique to determine the effects of an accidental injection of recombinant vaccinia virus in a laboratory technician. Evidence of T-cell recognition of the 22K protein was shown in this case.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) Any patient suspected of having smallpox should be admitted to the hospital and placed under strict isolation (Henderson et al, 1999a; Henderson, 1996). Since smallpox has been officially eradicated, the occurrence of a single case has profound implications. Immediate notification of local, state, and national health officials is important.
    6.3.3.3) CONSULT CRITERIA/INHALATION
    A) Smallpox is a national notifiable disease and reported to the CDC via state health departments. If appropriate, the local health department will refer the physician to the CDC, where a physician is available to take patient history and data.
    6.3.3.4) PATIENT TRANSFER/INHALATION
    A) All emergency department patients must be screened, stabilized, and transferred in accordance with the COBRA (antidumping) law. Immediate transfer of a patient with suspected smallpox to a strict isolation unit is essential.
    6.3.4) DISPOSITION/EYE EXPOSURE
    6.3.4.3) CONSULT CRITERIA/EYE
    A) Persons with conjunctiva exposure to blood, body fluids, secretions, or excretions from a patient with suspected smallpox infection should receive medical evaluation and follow-up management.

Monitoring

    A) Diagnosis may be quickly established by electron microscopic identification of virus particles in vesicular or pustular fluid or scabs. Suspected cases of smallpox in recent years were actually cases of varicella.
    B) Monitor vital signs, including temperature and blood pressure.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) DECONTAMINATION
    1) Oral decontamination measures following exposure to variola or vaccinia viruses have not been proven to be effective and are NOT recommended.
    2) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    3) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Inhalation Exposure

    6.7.2) TREATMENT
    A) SUPPORT
    1) There is no specific treatment for smallpox (variola virus). Treatment is symptomatic and supportive. Vaccinia virus is classified by the Advisory Committee on Dangerous Pathogens (ACDP) as Hazard Group 2.
    B) ACTIVE IMMUNIZATION
    1) International certificates of vaccination are no longer required. Military personnel in some countries, including the United States, may continue to be vaccinated as well as investigators working with poxviruses in laboratories. Vaccinia virus vaccine induces a mild infection and provides protection against all orthopoxviruses known to infect humans (monkeypox, variola, and cowpox). Following vaccination, protection is complete for 5 years, then wanes over time (Whitby et al, 2002; Henderson, 1996). Immunity can persist at some level for ten years or more (Anon, 2001; CDC, 2001). When immunity has waned, vaccinated persons tend to shed less virus and are less likely to transmit smallpox; if symptoms appear, they are milder and mortality is less (Anon, 2001). Smallpox vaccination within the first 4 days after initial smallpox virus exposure can reduce symptoms or prevent smallpox disease (Bicknell, 2002; CDC, 2001).
    a) "RING VACCINATION" - In the event of a bioterrorism smallpox event, the CDC currently recommends post-exposure "ring vaccination". This approach requires rapid identification and quarantine of exposed victims, with vaccination of their contacts and the contacts' contacts. Ring vaccination is effective for small, localized outbreaks in a population with widespread immunity. The CDC does not recommend mass vaccination campaigns in response to documented smallpox cases or in anticipation of a potential outbreak. This approach minimizes the potential for vaccine-related adverse events that may be seen following mass vaccination (Fauci, 2002; Bicknell, 2002).
    b) Smallpox vaccine is no longer administered to civilians. CDC will provide vaccinia vaccine to protect laboratory and other health-care personnel with occupational exposure risk to vaccinia and other closely related Orthopoxviruses, including vaccinia recombinants. Vaccine should be administered under physician supervision. Vaccine will be shipped to the designated physician (CDC, 2001; CDC, 1991) CDC, 1985; Pers Comm, 1994).
    2) VACCINE AVAILABILITY
    a) ACAM2000
    1) The US FDA has licensed a second-generation smallpox vaccine (ACAM2000, a live vaccinia virus) that uses a pox virus called vaccinia which has been derived from the previous smallpox vaccine licensed by the FDA, Dryvax. This earlier vaccine was approved in 1931 and is now in limited supply because it is no longer manufactured (Acambis, 2007; Prod Info ACAM2000(TM) percutaneous injection, 2007).
    2) INDICATIONS: For active immunization of individuals at high risk for smallpox infection (Prod Info ACAM2000(TM) percutaneous injection, 2007)
    3) DOSING: Special training is required by the FDA to ensure safe and effective administration of the vaccine. The vaccine is reconstituted by adding 0.3 mL of diluent (provided) to lyophilized vaccine and given by the percutaneous route only. Each reconstituted vial contains about 100 doses of 0.0025 mL of vaccinia virus (live) containing 2.5-12.5x10(5) plaque forming units/dose. INJECTION SITE: Upper arm over the insertion of the deltoid muscle (Prod Info ACAM2000(TM) percutaneous injection, 2007).
    4) METHOD: Using a bifurcated needle pick up a drop of vaccine and deposit it on a clean, dry site of skin. With the same needle (using multiple pressure or multiple puncture technique) vaccinate through the drop of vaccine. Rapidly make 15 jabs of the needle to the skin through the droplet to puncture the skin. Cover the site loosely with a gauze bandage and secure with first aid adhesive tape to provide a barrier to protect against the spread of the vaccinia virus. After completion of vaccination, blot off any vaccine remaining on the skin. The vaccination site should be checked 6 to 8 days after vaccination for a response (Prod Info ACAM2000(TM) percutaneous injection, 2007; Frey et al, 2002a).
    5) BOOSTER SCHEDULE: The smallpox vaccine should be repeated every 3 years for individuals at continued high risk for exposure (eg, research laboratory workers handling variola virus) (Prod Info ACAM2000(TM) percutaneous injection, 2007).
    a) Individuals with high risk of occupational exposure to nonhighly attenuated vaccinia viruses, recombinant viruses developed from nonhighly attenuated vaccinia viruses, or other nonvariola Orthopoxviruses should be revaccinated at least every 10 years. Revaccination every 3 years can be considered for individuals working with virulent nonvariola Orthopoxviruses (e.g., monkeypox) (CDC, 2001).
    6) INTERPRETING VACCINATION RESPONSE (Prod Info ACAM2000(TM) percutaneous injection, 2007):
    1) PRIMARY VACCINEES (first time vaccination): Expected response is a major cutaneous reaction (presence of a pustule) at the site of inoculation which occurs over 2 to 5 days with the maximum size reached at 8 to 10 days. The area will scab and leave a pitted scar. A cutaneous reaction by day 6 to 8 is considered successful and will provide immunity to the individual.
    2) PREVIOUSLY VACCINATED (revaccination): As with a primary vaccinee, a cutaneous reaction by day 6 to 8 is considered successful. However, previously vaccinated individuals may not develop a cutaneous reaction, which does indicate vaccine failure or a need to revaccinate the individual.
    3) VACCINATION FAILURES: Individuals who are not successfully vaccinated may be revaccinated using vaccine from another lot and using the same administration techniques.
    7) SPECIAL POPULATIONS - ACAM2000 has not been studied in infants or children (from birth to age 16). It has also not been studied in pregnant women. Fetal harm may potentially occur following the administration of live vaccinia virus vaccines. Currently, it is not known if the vaccine virus or antibodies are excreted in human milk (Prod Info ACAM2000(TM) percutaneous injection, 2007).
    8) SIDE EFFECTS: In clinical trials, myocarditis and pericarditis, with suspected cases observed at a rate of 5.7 per 1000 primary vaccinees (95% CI: 1.9 to 13.3) were reported in individuals that were primary vaccinees. Other events included: encephalitis, encephalomyelitis, encephalopathy, progressive vaccina, generalized vaccina, severe vaccinial skin infections, erythema multiforme major (including Stevens-Johnson Syndrome), eczema vaccinatum that either resulted in permanent sequelae or death. Based on data gathered by the US military, the incidence of myo/pericarditis (86/730,580 (117.7 incidence/million) and 21/40,422 (519.52 incidence/million)) has been higher as compared to data collected during the 1960's likely due to better screening and reporting methods. Other events such as eczema vaccinatum, contact transmission, and auto-inoculation were notably lower in individuals receiving vaccines today (Prod Info ACAM2000(TM) percutaneous injection, 2007).
    a) The potential risk of serious events (ie, severe disability, permanent neurological sequelae) or death can be increased when the following conditions are present (Prod Info ACAM2000(TM) percutaneous injection, 2007):
    1) Cardiac disease or a history of cardiac disease
    2) Eye disease(s) treated with steroids
    3) Acquired or congenital immune deficiency; including use of immunosuppressive therapy
    4) Eczema or history of eczema, or history of exfoliative skin diseases
    5) Infants less than 12 months
    6) Pregnancy
    b) NOTE: Any possible or suspected ADVERSE REACTIONS should be reported to: Acambis, Inc, at 617 866 4500 or 866 440 9440 (toll-free within the US) or VAERS at 800 822 7967.
    3) GENERAL COMPLICATIONS RELATED TO SMALLPOX VACCINATION
    a) The CDC can assist physicians in the diagnosis and management of patients with suspected complications of vaccinia vaccination. Vaccinia Immune Globulin (VIG) is indicated for certain complications and can be obtained by contacting the CDC at (day (404) 639-3670 Monday through Friday 8 am to 4:30 pm EST; at other times call (404) 639-2888) (Prod Info ACAM2000(TM) percutaneous injection, 2007). SEE Vaccinia Immune Globulin below for further detail.
    b) SURVEILLANCE - In a review of adverse events reported to the Vaccine Adverse Event Reporting System of 665,000 persons vaccinated against smallpox (590,400 by Department of Defense; 64,600 by Health and Human Services) between 2002 and 2004, 214 neurologic adverse events were reported. Most adverse events (54%) occurred within the first week of vaccination and just over half of the events reported occurred among primary (ie, first time) vaccinees. The most common events reported were headache (n=95), nonserious limb paresthesia (n=17), pain (n=13), and dizziness or vertigo (n=13). Serious events developed most often in primary vaccinees (27/39 patients (69%)) within the first 2 weeks of vaccination. Of the events reported, there were 13 cases each of possible meningitis and suspected encephalitis or myelitis, 11 cases of Bell's palsy, 8 with seizures (including one death) and 3 cases of Guilian-Barre syndrome (Sejvar et al, 2005).
    1) NEUROLOGICAL - The estimated reporting rate of postvaccinial encephalomyelitis (PVE) was 5 cases per million vaccines which was consistent with prior rates found in the United States. The estimated rate for Bell's palsy were determined to be 1.7 per 100,000 vaccinations, and for Guillain Barre Syndrome the estimated rate was 0.5 per 100,000 vaccinations, which was similar to the expected rate of 0.4 to 4.0 cases per 100,000 per year in the general population (Sejvar et al, 2005).
    2) OTHER FINDINGS - Complications of vaccinations have included: Generalized vaccinia (212 per million), post-vaccine encephalitis (4 per million), eczema vaccinatum (30 per million), and mortality from vaccination (1.1 per million) (Williams & Cooper, 1993).
    c) ECZEMA VACCINATUM (EV) is a localized or systemic dissemination of vaccinia virus in patients with a history of atopic dermatitis (previously known as eczema) and other chronic or exfoliative skin disorder. EV can occur through immunization or through contact with immunized or infected individuals whose disease is quiescent. A review article reported that approximately three fourths of the cases of children with secondary vaccinia infection have occurred in patients with a dermatologic disorder, usually atopic dermatitis. It is generally mild and self-limiting, but in some cases may be severe and occasionally fatal. Serious cases have developed among primary vaccinees. Patients with EV may have diffuse dermatitis with open vesicles, fever, regional or generalized adenopathy, and rarely encephalitis (Gruchalla & Jones, 2003; Sepkowitz, 2003; Wien et al, 1988; CDC, 1991).
    d) PROGRESSIVE VACCINIA (PV; also known as vaccinia necrosum or vaccinia gangrenosa) occurs in patients with altered humoral and cellular immune responses. Patients with PV experience non-healing primary vaccination site with painless progression of central necrosis. It is difficult to treat patients with PV since this condition mainly occurs in markedly immunodeficient individuals (Gruchalla & Jones, 2003; Sepkowitz, 2003).
    e) GENERALIZED VACCINIA (GV) - In patients with GV, virus usually spreads hematogenously and a maculopapular or vesicular skin eruption develops 6 to 9 days after vaccination; in immunocompetent patients, the course is usually self-limited (Gruchalla & Jones, 2003).
    1) CASE REPORT - A 25-year-old active duty serviceman developed pruritic papules 12 days after receiving vaccinia vaccine on his left upper arm. On post-vaccination day 17, several lesions (simple nodules on an erythematous base or vesicles, pustules, and pustules with central eschar) appeared on his arms, elbows, hands, chest, legs, and feet. On post-vaccination day 19, oral and palmar lesions were observed. Cleavage of the eschar developed on post-vaccination day 26 (Gibson & Langsten, 2004).
    f) During the US military smallpox vaccination program (n=450,293; 70.5% primary vaccinees; 29.5% revaccinees), very low rates of serious adverse events (1 encephalitis and 37 acute myopericarditis) were reported. All patients recovered and returned to duty. Less than 3% of vaccine recipients required short-term sick leave (mean 1.5 days) (Grabenstein & Winkenwerder, 2003).
    1) MYOPERICARDITIS - Halsell et al (2003) reported 18 cases of probable myopericarditis, occurring 7 to 19 days after smallpox vaccination of vaccinia-naive (primary vaccinees) members of US military (n=230,734). Myopericarditis did not occur following smallpox vaccination of 95,622 revaccinees (Halsell et al, 2003).
    2) FOLLICULITIS - Following smallpox vaccination among vaccinia-naive recipients (n=148), focal and generalized folliculitis occurred in 11 and 4 patients, respectively (Talbot et al, 2003).
    4) EFFICACY FOLLOWING POSTEXPOSURE SMALLPOX VACCINATION
    a) One report attempted to estimate the effectiveness of postexposure smallpox vaccination in preventing or modifying disease in naive and previously vaccinated adults, using a formal Delphi analysis. By using a screening questionnaire, this analysis provided a quantitative evaluation of postexposure vaccination effectiveness from a group of smallpox experts who were involved in the eradication campaign. The following results were obtained(Massoudi et al, 2003):
    b) INDIVIDUALS NOT VACCINATED
    1) The median effectiveness in preventing disease with vaccination at 0 to 6 hours, 6 to 24 hours, and 1 to 3 days after exposure was estimated as 93%, 90%, and 80%, respectively(Massoudi et al, 2003).
    2) The effectiveness in modifying disease among those who develop illness was estimated as 80%, 80%, and 75%, respectively(Massoudi et al, 2003).
    c) VACCINATED INDIVIDUALS (LONGER THAN 30 YEARS PRIOR)
    1) The median effectiveness in preventing disease with vaccination at 0 to 6 hours, 6 to 24 hours, and 1 to 3 days after exposure as estimated as 95%, 95%, 90%, respectively(Massoudi et al, 2003).
    2) The effectiveness in modifying disease among those who develop illness was estimated as 95%, 90%, 80%, respectively(Massoudi et al, 2003).
    d) MULTIPLE DOSE
    1) Vaccination is reported to last 30 years (el-Ad et al, 1990). Routine revaccination beyond the primary injection and two revaccinations is not needed. However, persons at high risk are recommended to receive revaccination regardless of vaccination status.
    5) HISTORICAL EVIDENCE
    a) Albert et al (2002) studied the records of patients during Boston's last major epidemic of 1901 to 1903. Patients were divided into the following groups: successful vaccination (vaccinated more than 3 weeks before admission and evidence of a scar), unsuccessful vaccination (vaccination with no scar), recent primary vaccination (no history of successful vaccination and were vaccinated within 3 weeks of admission) or none (no history of vaccination). It was found that vaccinated patients had mild varioloid form of disease and had a higher probability of survival compared with patients who were not vaccinated. Although these patients had incomplete immunity and were susceptible to infection, vaccination could protect them by modifying disease severity. Patients with recent primary vaccination had an increased probability of survival compared with patients who had never been vaccinated. Since vaccinia inoculated into the arm has a shorter incubation period (6 to 8 days) than variola virus acquired through respiratory inhalation (7 to 17 days), vaccination, given soon after exposure, can alleviate or even abort smallpox. The authors concluded that younger patients (younger than 5 years of age) or older patients (45 years of age or older) had a lower probability of survival than those in the middle age group (5 years of age or older and younger than 45 years of age) (Albert et al, 2002).
    6) ALTERNATE ADMINISTRATION METHODS
    a) Dilutions of vaccinia virus vaccine produced in 1982 or earlier were tested for clinical effects, humoral responses and virus-specific activity of cytotoxic T cells and interferon-gamma-producing T cells. Three groups of previously unvaccinated patients, 20 in each group, were inoculated intradermally by bifurcated needle with undiluted vaccine, a 1:10 dilution, or a 1:100 dilution. Vesicles resulted in 19/20 of patients inoculated with undiluted vaccine, 14/20 of patients inoculated with 1:10 dilution, and 3/20 of patients inoculated with 1:100 dilution. In 94% of patients with vesicles, vigorous cytotoxic T-cell and interferon-y responses resulted. Diluting the vaccine resulted in a reduced rate of successful vaccination (Frey et al, 2002a). In a follow-up study, it was determined that use of a 1:10 dilution in persons never before vaccinated, followed by a second vaccination in those with no response after 7 days, could potentially protect up to 10 times as many people as the use of undiluted vaccine (Frey et al, 2002).
    b) One study evaluated the use of undiluted or a reduced dose (dilution of 1:3.2, 1:10, or 1:32) vaccinia virus in vaccination of previously vaccinated (non-naive) subjects. Undiluted or diluted doses were given to 80 non-naive subjects and undiluted vaccines were given to 10 vaccinia-naive subjects. Major reactions (vesicular or pustular lesion or area of palpable induration surrounding a central lesion) were observed in 64 of 80 non-naive subjects (95% in undiluted group, 90% in 1:3.2 dilution group, 81% in the 1:10 dilution group). Major reactions were observed in all of the vaccinia-naive subjects. Non-naive subjects had significantly smaller skin lesions and significantly less incidence of fever. Seventy-six of 80 non-naive subjects had preexisting antibody. Virus shedding was 2 to 6 days longer for vaccinia-naive subjects. The authors concluded that non-naive subjects can be successfully revaccinated with dilute (less or equal to 1:10) smallpox vaccine. Overall non-naive subjects had fewer adverse reactions when compared with events in vaccinia-naive subjects (Frey et al, 2003).
    C) VACCINIA IMMUNE GLOBULIN, HUMAN
    1) In February 2005, the US Food and Drug Administration approved the Vaccinia Immune Globulin Intravenous (VIGIV). It is used to treat certain rare complications of smallpox vaccination (Prod Info Vaccinia Immune Globulin Intravenous (Human) (VIGIV), 2005).
    2) The CDC can assist physicians in the diagnosis and management of patients with suspected complications of vaccinia vaccination. Vaccinia Immune Globulin (VIG) is indicated for certain complications and can be obtained by contacting the CDC at (day (404) 639-3670 Monday through Friday 8 am to 4:30 pm EST; at other times call (404) 639-2888) (Prod Info ACAM2000(TM) percutaneous injection, 2007).
    3) AVAILABILITY: Requests for Vaccinia Immune Globulin (VIG), including the reason for the request, should be referred to: 
    Centers for Disease Control and Prevention
   Drug Services, National Center for
     Infectious Diseases
   Mailstop D-09
   Atlanta, GA 30333
   Telephone: (404) 639-3670
   Facsimile: (404) 639-3717

    a) VIGIV is indicated to treat and/or modify the following conditions (Prod Info Vaccinia Immune Globulin Intravenous (Human) (VIGIV), 2005):
    1) Aberrant infections caused by vaccinia virus that include its accidental implantation in eyes (except in cases of isolated keratitis), mouth, or other areas where vaccinia infection would constitute a special hazard.
    2) Eczema vaccinatum
    3) Progressive vaccinia
    4) Severe generalized vaccinia, and
    5) Vaccinia infections in individuals who have skin conditions such as burns, impetigo, varicella-zoster, or poison ivy; or in individuals who have eczematous skin lesions because of either the activity or extensiveness of such lesions.
    b) VIGIV is made from pooled human plasma obtained from donors who received booster immunizations with the Dryvax(R) smallpox vaccine (Prod Info Vaccinia Immune Globulin Intravenous (Human) (VIGIV), 2005).
    c) AVAILABLE FORMS - VIGIV is available as a sterile vial; each vial has 50 mL of solution with VIGIV at a level of 50 mg/mL (2,500 mg immunoglobulin per vial) (Prod Info Vaccinia Immune Globulin Intravenous (Human) (VIGIV), 2005).
    d) DOSE - Initially 2 mL/kg (100 mg/kg) intravenous infusion, a rate of 1 mL/kg/hour for the first 30 minutes, increased to 2 mL/kg/hour for the next 30 minutes and then to 3 mL/kg/hour for the remainder of the infusion, as tolerated. This dose may be repeated depending on the severity of the illness. Higher doses (200 mg/kg or 500 mg/kg) may be given if the patient does not respond to the initial dose. Slow the rate of infusion or temporarily interrupt the infusion if a minor adverse reaction (eg; flushing) is observed. Discontinue the infusion if a serious adverse reaction (eg; anaphylaxis or severe hypotension) is observed. To treat fluid overload during administration, a loop diuretic should be available. The following infusion rate-related adverse effects have been reported: flushing, chills, muscle cramps, back pain, fever, nausea, vomiting, arthralgia, and wheezing (Prod Info Vaccinia Immune Globulin Intravenous (Human) (VIGIV), 2005).
    e) PRECAUTION - One animal study reported increased corneal scarring with intramuscular VIG administration; therefore, VIGIV should be used with caution in patients with ocular complications due to vaccinia virus. VIGIV should not be used in patients with isolated vaccinia keratitis. In addition, VIGIV should be used with caution in patients with renal insufficiency or in patients at increased risk of developing renal insufficiency (including, but not limited to those with diabetes mellitus, age greater than 65 years, volume depletion, paraproteinemia, sepsis, and patients receiving known nephrotoxic drugs). (Prod Info Vaccinia Immune Globulin Intravenous (Human) (VIGIV), 2005).
    f) ADVERSE EFFECTS - In studies, the most common adverse effect was headache. Other adverse effects were urticaria, upper respiratory infection, back pain, nausea, injection site reaction, and dizziness (Prod Info Vaccinia Immune Globulin Intravenous (Human) (VIGIV), 2005).
    g) PREGNANCY - No data are available on the risk of VIGIV to the fetus. VIGIV should only be used during pregnancy if the potential benefit justifies the potential risk to fetus (Prod Info Vaccinia Immune Globulin Intravenous (Human) (VIGIV), 2005).
    h) Redfield et al (1987) reported administering VIG (50 mL intramuscularly weekly for 12 weeks) to a military recruit with HIV infection who sustained disseminated vaccinia following vaccination with vaccinia. VIG is reported to have no benefit in patients with clinical smallpox (Breman & Henderson, 2002).
    D) ISOLATION PROCEDURE
    1) Respiratory isolation is required for at least 17 days after symptoms appear (Barbera et al, 2001; Ball, 1998). Widespread use of disposable masks, with instructions, and short-term voluntary home curfew and restrictions on assembly of groups may be advisable for infected persons and contacts (Barbera et al, 2001).
    E) EXPERIMENTAL THERAPY
    1) ANTIVIRAL DRUGS are not currently approved or have proven efficacy in human cases of smallpox. However, adefovir, dipivoxil, cidofovir and ribavirin have been shown to have significant in-vitro antiviral activity against poxviruses. Their efficacy as therapy for human smallpox is uncertain. Cidofovir has shown the most promising results in animal models and in-vitro studies; however, it must be administered within 1 or 2 days after exposure in order to prevent disease (Albert et al, 2002; Kern et al, 2002; Breman & Henderson, 2002; (Anon, 2000); Henderson et al, 1999a).
    a) CIDOFOVIR - has been used investigationally and shown effective in laboratory animal experiments and in in-vitro studies for smallpox infections (Ball, 1998). Dosage used for CMV retinitis in patients with AIDS is 5 milligrams/kilogram weekly intravenously for 2 weeks. Major drawbacks of cidofovir are its nephrotoxicity and lack of oral bioavailability. The efficacy in humans has not been demonstrated and this drug is not FDA approved for use in smallpox (Smee et al, 2004; Kern et al, 2002).
    1) ANIMAL STUDY - Topical cidofovir (1% cream; twice daily for 7 days) was more effective than parenteral cidofovir (100 mg/kg/day, administered every 3 days) in inhibiting the size of primary cutaneous lesions and reducing the number of satellite lesions in immunocompromised hairless mice. Overall, virus titers in skin lesions were significantly reduced (1000-fold) by topical cidofovir but were reduced less than 10-fold by parenteral cidofovir. When topical cidofovir was started 9 days after infection, death was delayed by 10 days. The authors suggested that combining topical and parenteral cidofovir treatments can provide the greatest reduction in lesion severity and prolongation of life (Smee et al, 2004).
    F) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    6.8.2) TREATMENT
    A) GENERAL TREATMENT
    1) CORNEAL LESIONS - Although efficacy for smallpox is unproven, consider the antiviral topical idoxuridine (0.1% ophthalmic solution) for treatment of corneal lesions (Breman & Henderson, 1999a). The usual adult dose for herpetic keratitis is 1 drop into each eye Q1H during the day and Q2H at night.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION
    1) INTACT SKIN - should be washed with soap and water under running water.
    2) CUTS - should be encouraged to bleed, then placed under running water.
    3) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    B) CLOTHING
    1) Bag soiled clothing or dressings in clearly labeled leak-proof polyethylene bags until autoclaved or incinerated.
    6.9.2) TREATMENT
    A) SAFETY PRECAUTIONS
    1) Due to drainage from smallpox lesions, barrier precautions should be used since drainage material is potentially highly infectious.
    B) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.

Abstracts

Case Reports

    A) PEDIATRIC
    1) An 18-month-old boy, with intermittent eczema controlled by topical steroid treatments, developed eczema vaccinatum following contact with his father's recent open and weeping smallpox vaccine inoculation site. The boy developed a fever of 102.4 degrees F and came to the ED with what initially was felt to be a chickenpox-like rash. The next day a diagnosis of eczema vaccinatum with secondary skin infection was made and the patient was hospitalized (Wien et al, 1988).
    a) Confluent lesions were present on a large area of his body, with crusting of isolated lesions, suggesting secondary infection. The boy was placed in isolation and treatment with Aveeno baths, hydroxyzine for pruritus, cephalexin for secondary skin infection, and triamcinolone cream was started. Blood cultures were positive for Streptococcus faecalis and ampicillin and gentamicin were then given for 7 days. Silver sulfadiazine cream was used to treat denuded skin (Wien et al, 1988).
    b) Vaccinia immune globulin (VIG) 4 mL IM (0.36 mL/kg) was given on the first and third hospital day. An ELISA test was positive for herpes simplex virus (HSV). The authors felt concurrent infections with vaccinia and HSV were evident, and they postulated that vaccinia reactivated a latent herpes infection. The patient was discharged on the fourteenth hospital day (Wien et al, 1988).

Range Of Toxicity

Summary

    A) The World Health Assembly officially declared smallpox eradicated in 1980. The last known naturally occurring case was in Somalia in 1977. However, at least two laboratories have known stores of the smallpox virus. Monkeypox, another orthopox virus, is still a threat in some areas, such as Africa; however, the transmission potential of monkeypox virus in humans is appreciably less than that of classical smallpox.
    B) Smallpox virus (variola) is an airborne infectious agent. Release of an aerosol will be the most likely route of transmission during an act of bioterrorism.
    C) Prior to eradication, humans were the only known natural reservoir for the smallpox virus.
    D) The most common modes of transmission were person-to-person via deposition of droplets on nasal, oral, pharyngeal mucosa or by direct viral inhalation from close contact with an infectious person. Indirect spread via fine particle aerosols or viral fomites occurred less frequently.
    E) Biological weapon use of the smallpox virus is of great concern. High civilian fatality rates in unvaccinated individuals are estimated. Smallpox infection treatment is symptomatic and supportive. There is no specific treatment currently available.

Minimum Lethal Exposure

    A) ROUTE OF EXPOSURE
    1) Release of an aerosol will be the most likely route of transmission during an act of bioterrorism. The virus is stable in aerosol form and remains stable outside its host for prolonged periods of time, producing a potentially high mortality rate, particularly now since there is little or no immunity to this disease. The infectious dose is thought to as low as a few virions ((Anon, 2000); Ball, 1998; Sattar & Ijaz, 1987).
    2) Smallpox fatalities are usually attributed to toxemia, associated with immune complexes, and severe hypotension (Breman & Henderson, 2002).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) Fine et al (1988) reports secondary attack rates among unvaccinated household contacts for monkeypox and smallpox:
    INFECTION POPULATION# OF CONTACTS# OF CASESSECONDARY ATTACK RATE
    MonkeypoxZaire 1980-19842362611.0%
    SmallpoxIndia1033836.9%
    Nigeria392564.1%
    Dahomey431643.2%
    Bangladesh21942.9%
    Pakistan272696.3%

    B) ROUTE OF EXPOSURE
    1) Experimental work with smallpox virus (variola), vaccinia, and other orthopox viruses has shown that relative humidity appears to have little effect on their airborne survival. Biological decay rates of the viruses were not affected by relative humidity (Sattar & Ijaz, 1987). Contamination of bed linen could potentially resuspend the virus in the air during housekeeping procedures.
    2) Viability of vaccinia virus, which is presumed similar to variola, in aerosols has been demonstrated to be higher at lower temperatures and lower humidity after spraying. Vaccinia virus is almost completely destroyed within 6 hours if released as an aerosol in an atmosphere of high temperature (31-33 degrees C) and humidity (80%). It survives for as long as 24 hours in cooler temperatures (10-11 degrees C) and lower humidity (20%) ((Anon, 2000); Anon, 2001; Henderson et al, 1999a).
    3) Transmission of smallpox (variola) to unvaccinated contacts has occurred at rates of 60% to 90%. Generalized vaccinia as a result of smallpox vaccination (vaccinia) is very rare, but may occur in immunocompromised patients (Herron, 1996).
    4) Following a clandestine aerosol release of smallpox, rapid spread in susceptible individuals would occur by a factor of 10 to 20 times or more with each generation of cases. After the initial release of smallpox, an interval of up to 2 weeks or more may occur before diagnosis of smallpox (Henderson et al, 1999a).

Pharmacology Toxicology

Toxicologic Mechanism

    A) Following exposure via the respiratory tract there is a 12 day incubation period (range, 7 to 17 days) during which the virus multiplies in the regional lymphoid tissues. Viremia, which begins at the onset of fever, continues during the first 2 to 3 days of the pre-eruptive phase. The virus is localized in the mucous membranes, skin, and internal tissues during this time. Pustulation is caused by virus multiplication in the epithelial cells of the skin and mucous membranes. As early as the fourth day of disease, antibodies may appear (Albert et al, 2002; Henderson et al, 1999a)Henderson, 1994.

References

General Bibliography

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    2) Albert MR, Ostheimer KG, Liewehr DJ, et al: Smallpox manifestations and survival during the Boston epidemic of 1901 to 1903. Ann Intern Med 2002; 137:993-1000.
    3) Anon: Medical treatment and response to suspected smallpox: Information for health care providers during biologic emergencies. New York City Department of Health. New York, NY. 2000. Available from URL: http://www.ci.nyc.ny.us/html/doh/html/cd/smallmd.html. As accessed 10/6/00.
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    44) Product Information: ACAM2000(TM) percutaneous injection, lyophilized preparation smallpox (vaccinia) vaccine, live percutaneous injection. Acambis,Inc, Cambridge, MA, 2007.
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    46) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    47) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
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