Reasonable Rascal
12-27-01, 14:50
RICIN
SUMMARY
Signs and Symptoms: Weakness, fever, cough and pulmonary edema occur 18-24 hours after inhalation exposure, followed by severe respiratory distress and death from hypoxemia in 36-72 hours.
Diagnosis: Signs and symptoms noted above in large numbers of geographically clustered patients could suggest an exposure to aerosolized ricin. The rapid time course to severe symptoms and death would be unusual for infectious agents. Laboratory findings are nonspecific but similar to other pulmonary irritants which cause pulmonary edema. Specific serum ELISA is available. Acute and convalescent sera should be collected.
Treatment: Management is supportive and should include treatment for pulmonary edema. Gastric decontamination measures should be used if ingested.
Prophylaxis: There is currently no vaccine or prophylactic antitoxin available for human use, although immunization appears promising in animal models. Use of the protective mask is currently the best protection against inhalation.
Isolation and Decontamination: Standard Precautions for healthcare workers. Secondary aerosols should generally not be a danger to health care providers. Weak hypochlorite solutions (0.1% sodium hypochlorite) and/or soap and water can decontaminate skin surfaces.
OVERVIEW
Ricin is a potent protein toxin derived from the beans of the castor plant (Ricinus communis). Castor beans are ubiquitous worldwide, and the toxin is fairly easily produced. Ricin is therefore a potentially widely available toxin. When inhaled as a small particle aerosol, this toxin may produce pathologic changes within 8 hours and severe respiratory symptoms followed by acute hypoxic respiratory failure in 36-72 hours. When ingested, ricin causes severe gastrointestinal symptoms followed by vascular collapse and death. This toxin may also cause disseminated intravascular coagulation, microcirculatory failure and multiple organ failure if given intravenously in laboratory animals.
HISTORY AND SIGNIFICANCE
Ricin's significance as a potential biological warfare toxin relates in part to its wide availability. Worldwide, one million tons of castor beans are processed annually in the production of castor oil; the waste mash from this process is five percent ricin by weight. The toxin is also quite stable and extremely toxic by several routes of exposure, including the respiratory route. Ricin is said to have been used in the assassination of Bulgarian exile Georgi Markov in London in 1978. Markov was attacked with a specially engineered weapon disguised as an umbrella which implanted a ricin-containing pellet into his body.
TOXIN CHARACTERISTICS
Ricin is actually made up of two hemagglutinins and two toxins. The toxins, RCL III and RCL IV, are dimers of about 66,000 daltons molecular weight. The toxins are made up of two polypeptide chains, an A chain and a B chain, which are joined by a disulfide bond. Ricin can be produced relatively easily and inexpensively in large quantities in a fairly low technology setting. It is of marginal toxicity in terms of its LED50 in comparison to toxins such as botulinum and SEB (incapacitating dose), so an enemy would have to produce it in larger quantities to cover a significant area on the battlefield. This might limit large-scale use of ricin by an adversary. Ricin can be prepared in liquid or crystalline form, or it can be lyophilized to make it a dry powder. It could be disseminated by an enemy as an aerosol, or it could be used as a sabotage, assassination, or terrorist weapon.
MECHANISM OF TOXICITY
Ricin is very toxic to cells. It acts by inhibiting protein synthesis. The B chain binds to cell surface receptors and the toxin-receptor complex is taken into the cell; the A chain has endonuclease activity and extremely low concentrations will inhibit protein synthesis. In rodents, the histopathology of aerosol exposure is characterized by necrotizing airway lesions causing tracheitis, bronchitis, bronchiolitis, and interstitial pneumonia with perivascular and alveolar edema. There is a latent period of 8 hours post-inhalation exposure before histologic lesions are observed in animal models. In rodents, ricin is more toxic by the aerosol route than by other routes of exposure.
There is little toxicity data in humans. The exact cause of morbidity and mortality would be dependent upon the route of exposure. Aerosol exposure in man would be expected to cause acute lung injury, pulmonary edema secondary to increased capillary permeability, and eventual acute hypoxic respiratory failure.
CLINICAL FEATURES
The clinical picture in intoxicated victims would depend on the route of exposure. After aerosol exposure, signs and symptoms would depend on the dose inhaled. Accidental sublethal aerosol exposures which occurred in humans in the 1940's were characterized by onset of the following symptoms in four to eight hours: fever, chest tightness, cough, dyspnea, nausea, and arthralgias. The onset of profuse sweating some hours later was commonly the sign of termination of most of the symptoms. Although lethal human aerosol
exposures have not been described, the severe pathophysiologic changes seen in the animal respiratory tract, including necrosis and severe alveolar flooding, are probably sufficient to cause death if enough toxin is inhaled. Time to death in experimental animals is dose dependent, occurring 36-72 hours post inhalation exposure. Humans would be expected to develop severe lung inflammation with progressive cough, dyspnea, cyanosis and pulmonary edema.
By other routes of exposure, ricin is not a direct lung irritant; however, intravascular injection can cause minimal pulmonary perivascular edema due to vascular endothelial injury. Ingestion causes gastrointestinal hemorrhage with hepatic, splenic, and renal necrosis. Intramuscular administration causes severe local necrosis of muscle and regional lymph nodes with moderate visceral organ involvement.
DIAGNOSIS
An attack with aerosolized ricin would be, as with many biological warfare agents, primarily diagnosed by the clinical and epidemiological setting. Acute lung injury affecting a large number of cases in a war zone (where a BW attack could occur) should raise suspicion of an attack with a pulmonary irritant such as ricin, although other pulmonary pathogens could present with similar signs and symptoms. Other biological threats, such as SEB, Q fever, tularemia, plague, and some chemical warfare agents like phosgene, need to be included in a differential diagnosis. Ricin intoxication would be expected to progress despite treatment with antibiotics, as opposed to an infectious process. There would be no mediastinitis as seen with inhalation anthrax. SEB would be different in that most patients would not progress to a life-threatening syndrome but would tend to plateau clinically. Phosgene-induced acute lung injury would progress much faster than that caused by ricin.
Additional supportive clinical or diagnostic features after aerosol exposure to ricin may include the following: bilateral infiltrates on chest radiographs, arterial hypoxemia, neutrophilic leukocytosis, and a bronchial aspirate rich in protein compared to plasma which is characteristic of high permeability pulmonary edema. Specific ELISA testing on serum or immunohistochemical techniques for direct tissue analysis may be used where available to confirm the diagnosis. Ricin is an extremely immunogenic toxin, and acute as well as convalescent sera should be obtained from survivors for measurement of antibody response.
MEDICAL MANAGEMENT
Management of ricin-intoxicated patients again depends on the route of exposure. Patients with pulmonary intoxication are managed by appropriate treatment for pulmonary edema and respiratory support as indicated. Gastrointestinal intoxication is best managed by vigorous gastric decontamination with superactivated charcoal, followed by use of cathartics such as magnesium citrate. Volume replacement of GI fluid losses is important. In percutaneous exposures, treatment would be primarily supportive.
PROPHYLAXIS
The protective mask is effective in preventing aerosol exposure. Although a vaccine is not currently available, candidate vaccines are under development which are immunogenic and confer protection against lethal aerosol exposures in animals. Prophylaxis with such a vaccine is the most promising defense against a biological warfare attack with ricin.
SMALLPOX
SUMMARY
Signs and Symptoms: Clinical manifestations begin acutely with malaise, fever, rigors, vomiting, headache, and backache. 2-3 days later lesions appear which quickly progress from macules to papules, and eventually to pustular vesicles. They are more abundant on the extremities and face, and develop synchronously.
Diagnosis: Electron and light microscopy are not capable of discriminating variola from vaccinia, monkeypox or cowpox. The new PCR diagnostic techniques may be more accurate in discriminating between variola and other Orthopoxviruses.
Treatment: At present there is no effective chemotherapy, and treatment of a clinical case remains supportive.
Prophylaxis: Immediate vaccination or revaccination should be undertaken for all personnel exposed. Vaccinia immune globulin (VIG) is of value in post-exposure prophylaxis of smallpox when given within the first week following exposure.
Isolation and Decontamination: Droplet and Airborne Precautions for a minimum of 16-17 days following exposure for all contacts. Patients should be considered infectious until all scabs separate.
OVERVIEW
Variola virus causes smallpox. It is an Orthopox virus and occurs in at least two strains, variola major and the milder disease, variola minor. Despite the global eradication of smallpox and continued availability of a vaccine, the potential weaponization of variola continues to pose a military threat. This threat can be
attributed to the aerosol infectivity of the virus, the relative ease of large-scale production, and an increasingly Orthopoxvirus-naive populace. Although the fully-developed cutaneous eruption of smallpox is unique, earlier stages of the rash could be mistaken for varicella. Secondary spread of infection constitutes a nosocomial hazard from the time of onset of a smallpox patient's exanthem until scabs have separated. Quarantine with respiratory isolation should be applied to secondary contacts for 17 days post-exposure. Vaccinia vaccination and vaccinia immune globulin each possess some efficacy in post-exposure prophylaxis.
HISTORY AND SIGNIFICANCE
Endemic smallpox was declared eradicated in 1980 by the World Health Organization (WHO). Although two WHO-approved repositories of variola virus remain at the Centers for Disease Control and Prevention (CDC) in Atlanta and the Institute for Viral Preparations in Moscow, the extent of clandestine stockpiles in other parts of the world remains unknown. In January 1996, WHO's governing board recommended that all stocks of smallpox be destroyed by 30 June, 1999.
The United States stopped vaccinating its military population in 1989 and civilians in the early 1980s. These populations are now susceptible to variola major, although recruits immunized in 1989 may retain
some degree of immunity. Variola may have been used by the British Army against native Americans by giving them contaminated blankets from the beds of smallpox victims during the eighteenth century. Japan considered the use of smallpox as a BW weapon in World War II and it has been considered as a possible threat agent against US forces for many years.
CLINICAL FEATURES
The incubation period of smallpox averaged 12 days, and contacts were quarantined for a minimum of 16-17 days following exposure. Clinical manifestations began acutely with malaise, fever, rigors, vomiting, headache, and backache; 15% of patients developed delirium. Approximately 10% of light-skinned patients exhibited an erythematous rash during this phase. Two to three days later, an enanthem appeared concomitantly with a discrete rash about the face, hands and forearms.
Following eruptions on the lower extremities, the rash spread centrally to the trunk over the next week. Lesions quickly progressed from macules to papules, and eventually to pustular vesicles. Lesions were more abundant on the extremities and face, and this centrifugal distribution is an important diagnostic feature. In distinct contrast to varicella, lesions on various segments of the body remained generally synchronous in their stage of development. From 8 to 14 days after onset, the pustules formed scabs which leave depressed depigmented scars upon healing. Although variola concentrations in the throat, conjunctiva, and urine diminished with time, virus could readily be recovered from scabs throughout convalescence. Therefore, patients should be isolated and considered infectious until all scabs separate.
For the past century, two distinct types of smallpox were recognized. Variola minor was distinguished by milder systemic toxicity and more diminutive pox lesions, and caused 1% mortality in unvaccinated victims. However, the prototypical disease variola major caused mortality of 3% and 30% in the vaccinated and unvaccinated, respectively. Other clinical forms associated with variola major, flat-type and hemorrhagic-type smallpox, were notable for severe mortality. A naturally occurring relative of variola, monkeypox, occurs in Africa, and is clinically indistinguishable from smallpox with the exception of notable enlargement of cervical and inguinal lymph nodes.
DIAGNOSIS
Smallpox must be distinguished from other vesicular exanthems, such as chickenpox, erythema multiforme with bullae, or allergic contact dermatitis. Particularly problematic to infection control measures would be
the failure to recognize relatively mild cases of smallpox in persons with partial immunity. An additional threat to effective quarantine is the fact that exposed persons may shed virus from the oropharynx without ever manifesting disease. Therefore, quarantine and initiation of medical countermeasures should be promptly followed by an accurate diagnosis so as to avert panic. The usual method of diagnosis is demonstration of characteristic virions on electron microscopy of vesicular scrapings. Under light microscopy, aggregations of variola virus particles, called Guarnieri bodies, are found. Another rapid but relatively insensitive test for Guarnieri bodies in vesicular scrapings is Gispen's modified silver stain, in which cytoplasmic inclusions appear black.
None of the above laboratory tests are capable of discriminating variola from vaccinia, monkeypox or cowpox. This differentiation classically required isolation of the virus and characterization of its growth on chorioallantoic membrane. The development of polymerase chain reaction diagnostic techniques promises a more accurate and less cumbersome method of discriminating between variola and other Orthopoxviruses.
MEDICAL MANAGEMENT
Medical personnel must be prepared to recognize a vesicular exanthem in possible biowarfare theaters as potentially variola, and to initiate appropriate countermeasures. Any confirmed case of smallpox should be considered an international emergency with immediate report made to public health authorities. Droplet and Airborne Precautions for a minimum of 16-17 days following exposure for all persons in direct contact with the index case, especially the unvaccinated. Patients should be considered infectious until all scabs separate. Immediate vaccination or revaccination should also be undertaken for all personnel exposed to either weaponized variola virus or a clinical case of smallpox.
The potential for airborne spread to other than close contacts is controversial. In general, close person-to-person proximity is required for transmission to reliably occur. Nevertheless, variola's potential in low
relative humidity for airborne dissemination was alarming in two hospital outbreaks. Smallpox patients were infectious from the time of onset of their eruptive exanthem, most commonly from days 3-6 after onset of fever. Infectivity was markedly enhanced if the patient manifested a cough. Indirect transmission via contaminated bedding or other fomites was infrequent. Some close contacts harbored virus in their throats without developing disease, and hence might have served as a means of secondary transmission.
Vaccination with a verified clinical "take" (vesicle with scar formation) within the past 3 years is considered to render a person immune to smallpox. However, given the difficulties and uncertainties under
wartime conditions of verifying the adequacy of troops' prior vaccination, routine revaccination of all potentially exposed personnel would seem prudent if there existed a significant prospect of smallpox exposure.
Antivirals for use against smallpox are under investigation. Cidofovir has been shown to have significant in vitro and in vivo activity in experimental animals.
PROPHYLAXIS
Vaccine: Smallpox vaccine (vaccinia virus) is most often administered by intradermal inoculation with a bifurcated needle, a process that became known as scarification because of the permanent scar that resulted. Vaccination after exposure to weaponized smallpox or a case of smallpox is effective in preventing disease if given within 7 days after exposure. A vesicle typically appears at the vaccination site 5-7 days post-inoculation, with surrounding erythema and induration. The lesion forms a scab and gradually heals over the next 1-2 weeks.
Side effects include low-grade fever and axillary lymphadenopathy. The attendant erythema and induration of the vaccination vesicle is frequently misdiagnosed as bacterial superinfection. More severe first-time vaccine reactions include secondary inoculation of the virus to other sites such as the face, eyelid, or other
persons (~ 6/10,000 vaccinations), and generalized vaccinia, which is a systemic spread of the virus to produce mucocutaneous lesions away from the primary vaccination site (~3/10,000 vaccinations).
V accination is contraindicated in the following conditions: immunosuppression, HIV infection, history or evidence of eczema, or current household, sexual, or other close physical contact with person(s) possessing one of these conditions. In addition, vaccination should not be performed during pregnancy. Despite the above caveats, most authorities state that, with the exception of significant impairment of systemic immunity, there are no absolute contraindications to post-exposure vaccination of a person who
experiences bona fide exposure to variola. However, concomitant VIG administration is recommended for pregnant and eczematous persons in such circumstances.
Passive Immunoprophylaxis: Evidence indicates that vaccinia immune globulin is of value in post-exposure prophylaxis of smallpox when given within the first week following exposure, and concurrently with vaccination. Vaccination alone is recommended for those without contraindications to the vaccine, unless greater than one week has elapsed after exposure. At this time, administration of both products, if available, is recommended.
The U.S. Army maintains a supply of VIG. The dose for prophylaxis or treatment is 0.6 ml/kg intramuscularly. VIG should be available when using vaccinia vaccine for treatment of adverse reactions.
SUMMARY
Signs and Symptoms: Weakness, fever, cough and pulmonary edema occur 18-24 hours after inhalation exposure, followed by severe respiratory distress and death from hypoxemia in 36-72 hours.
Diagnosis: Signs and symptoms noted above in large numbers of geographically clustered patients could suggest an exposure to aerosolized ricin. The rapid time course to severe symptoms and death would be unusual for infectious agents. Laboratory findings are nonspecific but similar to other pulmonary irritants which cause pulmonary edema. Specific serum ELISA is available. Acute and convalescent sera should be collected.
Treatment: Management is supportive and should include treatment for pulmonary edema. Gastric decontamination measures should be used if ingested.
Prophylaxis: There is currently no vaccine or prophylactic antitoxin available for human use, although immunization appears promising in animal models. Use of the protective mask is currently the best protection against inhalation.
Isolation and Decontamination: Standard Precautions for healthcare workers. Secondary aerosols should generally not be a danger to health care providers. Weak hypochlorite solutions (0.1% sodium hypochlorite) and/or soap and water can decontaminate skin surfaces.
OVERVIEW
Ricin is a potent protein toxin derived from the beans of the castor plant (Ricinus communis). Castor beans are ubiquitous worldwide, and the toxin is fairly easily produced. Ricin is therefore a potentially widely available toxin. When inhaled as a small particle aerosol, this toxin may produce pathologic changes within 8 hours and severe respiratory symptoms followed by acute hypoxic respiratory failure in 36-72 hours. When ingested, ricin causes severe gastrointestinal symptoms followed by vascular collapse and death. This toxin may also cause disseminated intravascular coagulation, microcirculatory failure and multiple organ failure if given intravenously in laboratory animals.
HISTORY AND SIGNIFICANCE
Ricin's significance as a potential biological warfare toxin relates in part to its wide availability. Worldwide, one million tons of castor beans are processed annually in the production of castor oil; the waste mash from this process is five percent ricin by weight. The toxin is also quite stable and extremely toxic by several routes of exposure, including the respiratory route. Ricin is said to have been used in the assassination of Bulgarian exile Georgi Markov in London in 1978. Markov was attacked with a specially engineered weapon disguised as an umbrella which implanted a ricin-containing pellet into his body.
TOXIN CHARACTERISTICS
Ricin is actually made up of two hemagglutinins and two toxins. The toxins, RCL III and RCL IV, are dimers of about 66,000 daltons molecular weight. The toxins are made up of two polypeptide chains, an A chain and a B chain, which are joined by a disulfide bond. Ricin can be produced relatively easily and inexpensively in large quantities in a fairly low technology setting. It is of marginal toxicity in terms of its LED50 in comparison to toxins such as botulinum and SEB (incapacitating dose), so an enemy would have to produce it in larger quantities to cover a significant area on the battlefield. This might limit large-scale use of ricin by an adversary. Ricin can be prepared in liquid or crystalline form, or it can be lyophilized to make it a dry powder. It could be disseminated by an enemy as an aerosol, or it could be used as a sabotage, assassination, or terrorist weapon.
MECHANISM OF TOXICITY
Ricin is very toxic to cells. It acts by inhibiting protein synthesis. The B chain binds to cell surface receptors and the toxin-receptor complex is taken into the cell; the A chain has endonuclease activity and extremely low concentrations will inhibit protein synthesis. In rodents, the histopathology of aerosol exposure is characterized by necrotizing airway lesions causing tracheitis, bronchitis, bronchiolitis, and interstitial pneumonia with perivascular and alveolar edema. There is a latent period of 8 hours post-inhalation exposure before histologic lesions are observed in animal models. In rodents, ricin is more toxic by the aerosol route than by other routes of exposure.
There is little toxicity data in humans. The exact cause of morbidity and mortality would be dependent upon the route of exposure. Aerosol exposure in man would be expected to cause acute lung injury, pulmonary edema secondary to increased capillary permeability, and eventual acute hypoxic respiratory failure.
CLINICAL FEATURES
The clinical picture in intoxicated victims would depend on the route of exposure. After aerosol exposure, signs and symptoms would depend on the dose inhaled. Accidental sublethal aerosol exposures which occurred in humans in the 1940's were characterized by onset of the following symptoms in four to eight hours: fever, chest tightness, cough, dyspnea, nausea, and arthralgias. The onset of profuse sweating some hours later was commonly the sign of termination of most of the symptoms. Although lethal human aerosol
exposures have not been described, the severe pathophysiologic changes seen in the animal respiratory tract, including necrosis and severe alveolar flooding, are probably sufficient to cause death if enough toxin is inhaled. Time to death in experimental animals is dose dependent, occurring 36-72 hours post inhalation exposure. Humans would be expected to develop severe lung inflammation with progressive cough, dyspnea, cyanosis and pulmonary edema.
By other routes of exposure, ricin is not a direct lung irritant; however, intravascular injection can cause minimal pulmonary perivascular edema due to vascular endothelial injury. Ingestion causes gastrointestinal hemorrhage with hepatic, splenic, and renal necrosis. Intramuscular administration causes severe local necrosis of muscle and regional lymph nodes with moderate visceral organ involvement.
DIAGNOSIS
An attack with aerosolized ricin would be, as with many biological warfare agents, primarily diagnosed by the clinical and epidemiological setting. Acute lung injury affecting a large number of cases in a war zone (where a BW attack could occur) should raise suspicion of an attack with a pulmonary irritant such as ricin, although other pulmonary pathogens could present with similar signs and symptoms. Other biological threats, such as SEB, Q fever, tularemia, plague, and some chemical warfare agents like phosgene, need to be included in a differential diagnosis. Ricin intoxication would be expected to progress despite treatment with antibiotics, as opposed to an infectious process. There would be no mediastinitis as seen with inhalation anthrax. SEB would be different in that most patients would not progress to a life-threatening syndrome but would tend to plateau clinically. Phosgene-induced acute lung injury would progress much faster than that caused by ricin.
Additional supportive clinical or diagnostic features after aerosol exposure to ricin may include the following: bilateral infiltrates on chest radiographs, arterial hypoxemia, neutrophilic leukocytosis, and a bronchial aspirate rich in protein compared to plasma which is characteristic of high permeability pulmonary edema. Specific ELISA testing on serum or immunohistochemical techniques for direct tissue analysis may be used where available to confirm the diagnosis. Ricin is an extremely immunogenic toxin, and acute as well as convalescent sera should be obtained from survivors for measurement of antibody response.
MEDICAL MANAGEMENT
Management of ricin-intoxicated patients again depends on the route of exposure. Patients with pulmonary intoxication are managed by appropriate treatment for pulmonary edema and respiratory support as indicated. Gastrointestinal intoxication is best managed by vigorous gastric decontamination with superactivated charcoal, followed by use of cathartics such as magnesium citrate. Volume replacement of GI fluid losses is important. In percutaneous exposures, treatment would be primarily supportive.
PROPHYLAXIS
The protective mask is effective in preventing aerosol exposure. Although a vaccine is not currently available, candidate vaccines are under development which are immunogenic and confer protection against lethal aerosol exposures in animals. Prophylaxis with such a vaccine is the most promising defense against a biological warfare attack with ricin.
SMALLPOX
SUMMARY
Signs and Symptoms: Clinical manifestations begin acutely with malaise, fever, rigors, vomiting, headache, and backache. 2-3 days later lesions appear which quickly progress from macules to papules, and eventually to pustular vesicles. They are more abundant on the extremities and face, and develop synchronously.
Diagnosis: Electron and light microscopy are not capable of discriminating variola from vaccinia, monkeypox or cowpox. The new PCR diagnostic techniques may be more accurate in discriminating between variola and other Orthopoxviruses.
Treatment: At present there is no effective chemotherapy, and treatment of a clinical case remains supportive.
Prophylaxis: Immediate vaccination or revaccination should be undertaken for all personnel exposed. Vaccinia immune globulin (VIG) is of value in post-exposure prophylaxis of smallpox when given within the first week following exposure.
Isolation and Decontamination: Droplet and Airborne Precautions for a minimum of 16-17 days following exposure for all contacts. Patients should be considered infectious until all scabs separate.
OVERVIEW
Variola virus causes smallpox. It is an Orthopox virus and occurs in at least two strains, variola major and the milder disease, variola minor. Despite the global eradication of smallpox and continued availability of a vaccine, the potential weaponization of variola continues to pose a military threat. This threat can be
attributed to the aerosol infectivity of the virus, the relative ease of large-scale production, and an increasingly Orthopoxvirus-naive populace. Although the fully-developed cutaneous eruption of smallpox is unique, earlier stages of the rash could be mistaken for varicella. Secondary spread of infection constitutes a nosocomial hazard from the time of onset of a smallpox patient's exanthem until scabs have separated. Quarantine with respiratory isolation should be applied to secondary contacts for 17 days post-exposure. Vaccinia vaccination and vaccinia immune globulin each possess some efficacy in post-exposure prophylaxis.
HISTORY AND SIGNIFICANCE
Endemic smallpox was declared eradicated in 1980 by the World Health Organization (WHO). Although two WHO-approved repositories of variola virus remain at the Centers for Disease Control and Prevention (CDC) in Atlanta and the Institute for Viral Preparations in Moscow, the extent of clandestine stockpiles in other parts of the world remains unknown. In January 1996, WHO's governing board recommended that all stocks of smallpox be destroyed by 30 June, 1999.
The United States stopped vaccinating its military population in 1989 and civilians in the early 1980s. These populations are now susceptible to variola major, although recruits immunized in 1989 may retain
some degree of immunity. Variola may have been used by the British Army against native Americans by giving them contaminated blankets from the beds of smallpox victims during the eighteenth century. Japan considered the use of smallpox as a BW weapon in World War II and it has been considered as a possible threat agent against US forces for many years.
CLINICAL FEATURES
The incubation period of smallpox averaged 12 days, and contacts were quarantined for a minimum of 16-17 days following exposure. Clinical manifestations began acutely with malaise, fever, rigors, vomiting, headache, and backache; 15% of patients developed delirium. Approximately 10% of light-skinned patients exhibited an erythematous rash during this phase. Two to three days later, an enanthem appeared concomitantly with a discrete rash about the face, hands and forearms.
Following eruptions on the lower extremities, the rash spread centrally to the trunk over the next week. Lesions quickly progressed from macules to papules, and eventually to pustular vesicles. Lesions were more abundant on the extremities and face, and this centrifugal distribution is an important diagnostic feature. In distinct contrast to varicella, lesions on various segments of the body remained generally synchronous in their stage of development. From 8 to 14 days after onset, the pustules formed scabs which leave depressed depigmented scars upon healing. Although variola concentrations in the throat, conjunctiva, and urine diminished with time, virus could readily be recovered from scabs throughout convalescence. Therefore, patients should be isolated and considered infectious until all scabs separate.
For the past century, two distinct types of smallpox were recognized. Variola minor was distinguished by milder systemic toxicity and more diminutive pox lesions, and caused 1% mortality in unvaccinated victims. However, the prototypical disease variola major caused mortality of 3% and 30% in the vaccinated and unvaccinated, respectively. Other clinical forms associated with variola major, flat-type and hemorrhagic-type smallpox, were notable for severe mortality. A naturally occurring relative of variola, monkeypox, occurs in Africa, and is clinically indistinguishable from smallpox with the exception of notable enlargement of cervical and inguinal lymph nodes.
DIAGNOSIS
Smallpox must be distinguished from other vesicular exanthems, such as chickenpox, erythema multiforme with bullae, or allergic contact dermatitis. Particularly problematic to infection control measures would be
the failure to recognize relatively mild cases of smallpox in persons with partial immunity. An additional threat to effective quarantine is the fact that exposed persons may shed virus from the oropharynx without ever manifesting disease. Therefore, quarantine and initiation of medical countermeasures should be promptly followed by an accurate diagnosis so as to avert panic. The usual method of diagnosis is demonstration of characteristic virions on electron microscopy of vesicular scrapings. Under light microscopy, aggregations of variola virus particles, called Guarnieri bodies, are found. Another rapid but relatively insensitive test for Guarnieri bodies in vesicular scrapings is Gispen's modified silver stain, in which cytoplasmic inclusions appear black.
None of the above laboratory tests are capable of discriminating variola from vaccinia, monkeypox or cowpox. This differentiation classically required isolation of the virus and characterization of its growth on chorioallantoic membrane. The development of polymerase chain reaction diagnostic techniques promises a more accurate and less cumbersome method of discriminating between variola and other Orthopoxviruses.
MEDICAL MANAGEMENT
Medical personnel must be prepared to recognize a vesicular exanthem in possible biowarfare theaters as potentially variola, and to initiate appropriate countermeasures. Any confirmed case of smallpox should be considered an international emergency with immediate report made to public health authorities. Droplet and Airborne Precautions for a minimum of 16-17 days following exposure for all persons in direct contact with the index case, especially the unvaccinated. Patients should be considered infectious until all scabs separate. Immediate vaccination or revaccination should also be undertaken for all personnel exposed to either weaponized variola virus or a clinical case of smallpox.
The potential for airborne spread to other than close contacts is controversial. In general, close person-to-person proximity is required for transmission to reliably occur. Nevertheless, variola's potential in low
relative humidity for airborne dissemination was alarming in two hospital outbreaks. Smallpox patients were infectious from the time of onset of their eruptive exanthem, most commonly from days 3-6 after onset of fever. Infectivity was markedly enhanced if the patient manifested a cough. Indirect transmission via contaminated bedding or other fomites was infrequent. Some close contacts harbored virus in their throats without developing disease, and hence might have served as a means of secondary transmission.
Vaccination with a verified clinical "take" (vesicle with scar formation) within the past 3 years is considered to render a person immune to smallpox. However, given the difficulties and uncertainties under
wartime conditions of verifying the adequacy of troops' prior vaccination, routine revaccination of all potentially exposed personnel would seem prudent if there existed a significant prospect of smallpox exposure.
Antivirals for use against smallpox are under investigation. Cidofovir has been shown to have significant in vitro and in vivo activity in experimental animals.
PROPHYLAXIS
Vaccine: Smallpox vaccine (vaccinia virus) is most often administered by intradermal inoculation with a bifurcated needle, a process that became known as scarification because of the permanent scar that resulted. Vaccination after exposure to weaponized smallpox or a case of smallpox is effective in preventing disease if given within 7 days after exposure. A vesicle typically appears at the vaccination site 5-7 days post-inoculation, with surrounding erythema and induration. The lesion forms a scab and gradually heals over the next 1-2 weeks.
Side effects include low-grade fever and axillary lymphadenopathy. The attendant erythema and induration of the vaccination vesicle is frequently misdiagnosed as bacterial superinfection. More severe first-time vaccine reactions include secondary inoculation of the virus to other sites such as the face, eyelid, or other
persons (~ 6/10,000 vaccinations), and generalized vaccinia, which is a systemic spread of the virus to produce mucocutaneous lesions away from the primary vaccination site (~3/10,000 vaccinations).
V accination is contraindicated in the following conditions: immunosuppression, HIV infection, history or evidence of eczema, or current household, sexual, or other close physical contact with person(s) possessing one of these conditions. In addition, vaccination should not be performed during pregnancy. Despite the above caveats, most authorities state that, with the exception of significant impairment of systemic immunity, there are no absolute contraindications to post-exposure vaccination of a person who
experiences bona fide exposure to variola. However, concomitant VIG administration is recommended for pregnant and eczematous persons in such circumstances.
Passive Immunoprophylaxis: Evidence indicates that vaccinia immune globulin is of value in post-exposure prophylaxis of smallpox when given within the first week following exposure, and concurrently with vaccination. Vaccination alone is recommended for those without contraindications to the vaccine, unless greater than one week has elapsed after exposure. At this time, administration of both products, if available, is recommended.
The U.S. Army maintains a supply of VIG. The dose for prophylaxis or treatment is 0.6 ml/kg intramuscularly. VIG should be available when using vaccinia vaccine for treatment of adverse reactions.