- 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).
-
- Vaccination 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.
-
- VENEZUELAN EQUINE ENCEPHALITIS
-
- SUMMARY
-
- Signs and Symptoms: Sudden onset of illness
with generalized malaise, spiking fevers, rigors, severe headache, photophobia,
and myalgias. Nausea, vomiting, cough, sore throat, and diarrhea may follow.
Full recovery takes 1-2 weeks.
-
- Diagnosis: Clinical diagnosis. Physical
findings are usually non-specific. The white blood cell count often shows
a striking leukopenia and lymphopenia. Virus isolation may be made from
serum, and in some cases throat swab specimens. Both neutralizing or IgG
antibody in paired sera or VEE specific IgM present in a single serum sample
indicate recent infection.
-
- Treatment: Supportive only.
-
- Prophylaxis: A live, attenuated vaccine
is available as an investigational new drug. A second, formalin-inactivated,
killed vaccine is available for boosting antibody titers in those initially
receiving the live vaccine.
-
- Isolation and Decontamination: Standard
Precautions for healthcare workers. Human cases are infectious for mosquitoes
for at least 72 hours. The virus can be destroyed by heat (80 degrees centigrade
for 30 minutes) and standard disinfectants.
-
- OVERVIEW
-
- Venezuelan equine encephalitis (VEE)
virus is an arthropod-borne alphavirus that is endemic in northern South
America, Trinidad, Central America, Mexico, and Florida. Eight serologically
distinct viruses belonging to the VEE complex have been associated with
human disease; the two most important of these pathogens are designated
subtype I, variants A/B, and C. These agents also cause severe disease
in horses, mules, burros and donkeys (Equidae). Natural infections are
acquired by the bites of a wide variety of mosquitoes. Equidae serve as
amplifying hosts and source of mosquito infection. In natural human epidemics,
severe and often fatal encephalitis in Equidae always precedes disease
in humans. The virus is rather easily killed by heat and disinfectants.
-
- HISTORY AND SIGNIFICANCE
-
- VEE was weaponized by the United States
in the 1950's and 1960's before the U.S. offensive biowarfare program was
terminated, and other countries have been or are suspected to have weaponized
this agent. This virus could theoretically be produced in either a wet
or dried form and potentially stabilized for weaponization. This agent
could then theoretically be delivered against friendly forces in a manner
similar to the other agents already discussed.
-
- As mentioned above, in natural human
epidemics, disease in Equidae always precedes that in humans. A biological
warfare attack with virus disseminated as an aerosol would almost certainly
cause human disease as a primary event. If Equidae were present, disease
in these animals would occur simultaneously with human disease. However,
during natural epidemics, illness or death in wild or free ranging Equidae
may not be recognized before the onset of human disease, thus a natural
epidemic could be confused with a BW event, and data on onset of disease
should be considered with caution. A more reliable method for determining
the likelihood of a BW event would be the presence of VEE outside of its
natural geographic range. Secondary spread by person-to-person contact
has not been conclusively shown to occur; however, observations during
a recent outbreak in Columbia suggest that it may occur often enough to
sustain epidemics in the absence of Equidae. A BW attack in a region populated
by Equidae and appropriate mosquito vectors could initiate an epizootic/epidemic.
-
- CLINICAL FEATURES
-
- VEE is characterized by inflammation
of the meninges of the brain and of the brain itself, thus accounting for
the predominance of CNS symptoms in the small percentage of infections
that develop encephalitis. The disease is usually acute, prostrating and
of short duration. The case fatality rate is less than 1 percent, although
is somewhat higher in the very young or aged. Nearly 100 percent of those
infected suffer an overt illness. Recovery from an infection results in
excellent short-term and long-term immunity.
-
- DIAGNOSIS
-
- After an incubation period varying from
1 to 5 days, onset is usually sudden. It is manifested by generalized malaise,
spiking fever, rigors, severe headache, photophobia, and myalgias in the
legs and lumbosacral area. Nausea, vomiting, cough, sore throat, and diarrhea
may follow. This acute phase lasts 24-72 hours. A prolonged period of asthenia
and lethargy may follow, with full health and activity regained after 1-2
weeks. Approximately 4 percent of children during natural epidemics develop
signs of central nervous system infection, with meningismus, convulsions,
coma, and paralysis. Adults rarely develop neurologic complications. In
children manifesting severe encephalitis, the fatality rate may reach 20
percent. Permanent neurologic sequelae are reported in survivors. Experimental
aerosol challenges in animals suggest that the incidence of CNS disease
and associated morbidity and mortality would be high after a BW attack,
as the VEE virus would infect the olfactory nerve and spread directly to
the CNS. A VEE infection during pregnancy may cause encephalitis in the
fetus, placental damage, abortion, or severe congenital neuroanatomical
anomalies.
-
- The white blood cell count shows a striking
leukopenia and lymphopenia. In cases with encephalitis, the cerebrospinal
fluid may be under increased pressure and contain up to 1,000 white cells/mm3
(predominantly mononuclear cells) and a mildly elevated protein concentration.
Viremia during the acute phase of the illness (but not during encephalitis)
is generally high enough to allow detection by antigen-capture enzyme immunoassay.
Virus isolation may be made from serum, and in some cases throat swab specimens,
by inoculation of cell cultures or suckling mice. A variety of serological
tests are applicable, including the IgM ELISA indirect FA, hemagglutination
inhibition, complement-fixation, and neutralization. For persons without
prior exposure to VEE complex viruses, a presumptive diagnosis may be made
by finding IgM antibody in a single serum sample taken 5 to 7 days after
onset of illness.
-
- MEDICAL MANAGEMENT
-
- Standard Precautions are recommended
for healthcare workers. Person-to-person transmission may theoretically
occur by means of respiratory droplet infection. There is no specific therapy.
Patients with uncomplicated VEE infection may be treated with analgesics
to relieve headache and myalgia. Patients who develop encephalitis may
require anticonvulsants and intensive supportive care to maintain fluid
and electrolyte balance, ensure adequate ventilation, and avoid complicating
secondary bacterial infections. Patients should be treated in a screened
room or in quarters treated with a residual insecticide for at least 5
days after onset, or until afebrile, as human cases may be infectious for
mosquitoes for at least 72 hours. The virus can be destroyed by heat and
disinfectants.
-
- PROPHYLAXIS
-
- Vaccine: An investigational vaccine,
designated TC-83, is a live, attenuated cell-culture-propagated vaccine
which has been used in several thousand persons to prevent laboratory infections.
The vaccine is given as a single 0.5 ml subcutaneous dose. Febrile reactions
occur in up to 18 percent of persons vaccinated, and may be moderate to
severe in 5 percent, with fever, myalgias, headache, and prostration. Approximately
18 percent of vaccinees fail to develop detectable neutralizing antibodies,
but it is unknown whether they are susceptible to clinical infection if
challenged. Contraindications for use include an intercurrent viral infection
or pregnancy. TC-83 is a licensed vaccine for Equidae.
-
- A second investigational product that
has been tested in humans is the C-84 vaccine, prepared by formalin-inactivation
of the TC-83 strain. The vaccine is not used for primary immunization,
but is currently used to boost nonresponders to TC-83 (0.5 ml subcutaneously
at 2-4 week intervals for up to 3 inoculations or until an antibody response
is measured), and probably affords complete protection against aerosol
infection from homologous strains in these individuals. As with all vaccines,
the degree of protection depends upon the magnitude of the challenge dose;
vaccine-induced protection could be overwhelmed by extremely high doses.
-
- Antiviral Drugs: In experimental animals,
alpha-interferon and the interferon-inducer poly-ICLC have proven highly
effective for post-exposure prophylaxis of VEE. There are no clinical data
on which to assess efficacy in humans.
-
- VIRAL HEMORRHAGIC FEVERS
-
- SUMMARY
-
- Signs and Symptoms: VHFs are febrile
illnesses which can be complicated by easy bleeding, petechiae, hypotension
and even shock, flushing of the face and chest, and edema. Constitutional
symptoms such as malaise, myalgias, headache, vomiting, and diarrhea may
occur in any of the hemorrhagic fevers.
-
- Diagnosis: Definitive diagnosis rests
on specific virologic techniques. Significant numbers of military personnel
with a hemorrhagic fever syndrome should suggest the diagnosis of a viral
hemorrhagic fever.
-
- Treatment: Intensive supportive care
may be required. Antiviral therapy with ribavirin may be useful in several
of these infections. Convalescent plasma may be effective in Argentine
hemorrhagic fever.
-
- Prophylaxis: The only licensed VHF vaccine
is yellow fever vaccine. Prophylactic ribavirin may be effective for Lassa
fever, Rift Valley fever, CCHF, and possibly HFRS.
-
- Isolation and Decontamination: Contact
Precautions for healthcare workers. Decontamination is accomplished with
hypochlorite or phenolic disinfectants. Isolation measures and barrier
nursing procedures are indicated.
-
- OVERVIEW
-
- The viral hemorrhagic fevers are a diverse
group of human illnesses that are due to RNA viruses from several different
viral families: the Filoviridae, which consists of Ebola and Marburg viruses;
the Arenaviridae, including Lassa fever, Argentine and Bolivian hemorrhagic
fever viruses; the Bunyaviridae, including various members from the Hantavirus
genus, Congo-Crimean hemorrhagic fever virus from the Nairovirus genus,
and Rift Valley fever from the Phlebovirus genus; and Flaviviridae, such
as Yellow fever virus, Dengue hemorrhagic fever virus, and others. The
viruses may be spread in a variety of ways, and for some there is a possibility
that humans could be infected through a respiratory portal of entry. Although
evidence for weaponization does not exist for many of these viruses, many
are included in this handbook because of their potential for aerosol dissemination
or weaponization, or likelihood for confusion with similar agents which
might be weaponized.
-
- HISTORY AND SIGNIFICANCE
-
- Because these viruses are so diverse
and occur in different geographic locations endemically, their full history
is beyond the scope of this handbook. However, there are some significant
events for each of them that may provide insight into their possible importance
as biological threat agents.
-
- Ebola virus disease was first recognized
in the western equatorial province of the Sudan and the nearby region of
Zaire in 1976; a second outbreak occurred in Sudan in 1979, and in 1995
a large outbreak (316 cases) developed in Kikwit, Zaire from a single index
case. Subsequent epidemics have occurred in Gabon and the Ivory Coast.
A related virus was isolated from a group of infected cynomolgus monkeys
imported into the United States from the Philippines in 1989. As of yet,
this Ebola Reston strain has not been determined as a cause of human disease.
The African strains have caused severe disease and death, and it is not
known why this disease only appears infrequently or why the most recent
strain appears to be less pathogenic in humans. Marburg disease has been
identified on four occasions as causing disease in man: three times in
Africa, and once in Germany, where the virus got its name. The first recognized
outbreak of Marburg disease involved 31 infected persons in Germany and
Yugoslavia who were exposed to African green monkeys, with 7 fatalities.
It is unclear how easily these filoviruses can be spread from human to
human, but spread definitely occurs by direct contact with infected blood,
secretions, organs, or semen. The reservoir in nature for these viruses
is unknown.
-
- Argentine hemorrhagic fever (AHF), caused
by the Junin virus, was first described in 1955 in corn harvesters. It
is spread in nature through contact with infected rodent excreta. From
300 to 600 cases per year occur in areas of the Argentine pampas. Bolivian
hemorrhagic fever, caused by the related Machupo virus, was described subsequent
to AHF in northeastern Bolivia. These viruses have caused laboratory infections,
and airborne transmission via dusts contaminated with rodent excreta may
occur. A related African arenavirus, Lassa virus, causes disease which
is widely distributed over West Africa.
-
- Congo-Crimean hemorrhagic fever (CCHF)
is a tick-borne disease which occurs in the Crimea and in parts of Africa,
Europe and Asia. It can also be spread by contact with infected animals
or nosocomially in healthcare settings. Rift Valley fever occurs only in
Africa, and can occasionally cause explosive disease outbreaks. Hantavirus
disease was described prior to WW II in Manchuria along the Amur River,
later among United Nations troops during the Korean conflict, and since
that time in Korea, Japan, and China. Hemorrhagic disease due to hantaviruses
also occurs in Europe (usually in a milder form) and a non-hemorrhagic
Hantavirus Pulmonary Syndrome occurs in the Americas and probably worldwide.
-
- Yellow fever and dengue fever are two
mosquito-borne fevers which can cause a hemorrhagic fever syndrome and
have great historic importance in the history of military campaigns and
military medicine.
-
- All of these viruses (except for dengue
virus) are infectious by aerosol or fomites. Since most patients are viremic,
there is a potential for nosocomial transmission to patients, medical staff,
and particularly laboratory personnel. Hantavirus infections are an exception,
as at the time of presentation, viremia is waning and circulating antibody
is present.
-
- The age and sex distributions of each
disease as it occurs endemically generally reflect the opportunities for
zoonotic exposure to the disease reservoir. The way in which the filoviruses
are transmitted to humans is not well understood.
-
- CLINICAL FEATURES
-
- The clinical syndrome which these viruses
may cause in humans is generally referred to as viral hemorrhagic fever
or VHF. Not all infected patients develop VHF; there is both divergence
and uncertainty about which host factors and virus strain differences might
be responsible for clinically manifesting hemorrhagic disease. For instance,
an immunopathogenic mechanism has been identified for dengue hemorrhagic
fever, which is seen only in patients previously infected with a heterologous
dengue serotype. The target organ in the VHF syndrome is the vascular bed;
correspondingly, the dominant clinical features are usually a consequence
of microvascular damage and changes in vascular permeability. Common presenting
complaints are fever, myalgia, and prostration; clinical examination may
reveal only conjunctival injection, mild hypotension, flushing, and petechial
hemorrhages. Full-blown VHF typically evolves to shock and generalized
mucous membrane hemorrhage and often is accompanied by evidence of neurologic,
hematopoietic, or pulmonary involvement. Apart from epidemiologic and intelligence
information, some distinctive clinical features may suggest a specific
etiologic agent: high AST elevation correlates with severity of illness
from Lassa fever, and jaundice is a poor prognostic sign in yellow fever.
Hepatic involvement is common among the VHFs, but a clinical picture dominated
by jaundice and other evidence of hepatic failure is only seen in some
cases of Rift Valley fever, Congo-Crimean HF, Marburg HF, Ebola HF, and
yellow fever. Neurologic symptoms and thrombocytopenia are common in Argentine
and Bolivian hemorrhagic fever. Kyanasur Forest disease and Omsk hemorrhagic
fever are notable for a concomitant pulmonary involvement, and a biphasic
illness with subsequent CNS manifestations. With regard to the Bunyaviruses,
copious hemorrhage and nosocomial transmission are typical for Congo-Crimean
HF, and retinitis is commonly seen in Rift Valley fever. Renal insufficiency
is proportional to cardiovascular compromise, except in hemorrhagic fever
with renal syndrome (HFRS) due to hantaviruses, where renal azotemia is
an integral part of the disease process. Mortality may be substantial,
ranging from 5 to 20 percent or higher in recognized cases. Ebola outbreaks
in Africa have been notable for the extreme prostration and toxicity of
the victims, as well as frighteningly high case fatality rates ranging
from 50 to 90 percent. This particularly virulent virus could conceivably
be chosen by an adversary as a biological warfare agent due to its probable
aerosol infectivity and high mortality.
-
- DIAGNOSIS
-
- A detailed travel history and a high
index of suspicion are essential in making the diagnosis of VHF. Patients
with arenaviral or hantaviral infections often recall having seen rodents
during the presumed incubation period, but, since the viruses are spread
to man by aerosolized excreta or environmental contamination, actual contact
with the reservoir is not necessary. Large mosquito populations are common
during Rift Valley fever or flaviviral transmission, but a history of mosquito
bite is sufficiently common to be of little assistance, whereas tick bites
or nosocomial exposure are of some significance in suspecting Congo-Crimean
hemorrhagic fever. Large numbers of military personnel presenting with
VHF manifestations in the same geographic area over a short time period
should lead treating medical care providers to suspect either a natural
outbreak if in an endemic setting, or possibly a biowarfare attack, particularly
if this type of disease does not occur naturally in the local area where
troops are deployed.
-
- VHF should be suspected in any patient
presenting with a severe febrile illness and evidence of vascular involvement
(subnormal blood pressure, postural hypotension, petechiae, easy bleeding,
flushing of face and chest, non-dependent edema) who has traveled to an
area where the virus is known to occur, or where intelligence information
suggests a biological warfare threat. Signs and symptoms suggesting additional
organ system involvement are common (headache, photophobia, pharyngitis,
cough, nausea or vomiting, diarrhea, constipation, abdominal pain, hyperesthesia,
dizziness, confusion, tremor), but usually do not dominate the picture
with the exceptions listed above under "Clinical Features."
-
- For much of the world, the major differential
diagnosis is malaria. It must be borne in mind that parasitemia in patients
partially immune to malaria does not prove that symptoms are due to malaria.
Typhoid fever, rickettsial, and leptospiral diseases are major confounding
infections, with nontyphoidal salmonellosis, shigellosis, relapsing fever,
fulminant hepatitis, and meningococcemia being some of the other important
diagnoses to exclude. Any condition leading to disseminated intravascular
coagulation could present in a confusing fashion, as well as diseases such
as acute leukemia, lupus erythematosus, idiopathic or thrombotic thrombocytopenic
purpura, and hemolytic uremic syndrome.
-
- Because of recent recognition of their
worldwide occurrence, additional consideration should be given to infection
with hantavirus. Classic HFRS (also referred to as Korean hemorrhagic fever
or epidemic hemorrhagic fever) has a severe course which progresses sequentially
from fever through hemorrhage, shock, renal failure, and polyuria. This
clinical form of HFRS is widely distributed in China, the Korean peninsula,
and the Far Eastern USSR. Severe disease also is found in some Balkan states,
including Bosnia/Serbia and Greece. However, the Scandinavian and most
European virus strains carried by bank voles usually produce a milder disease
(referred to as nephropathia epidemica) with prominent fever, myalgia,
abdominal pain, and oliguria, but without shock or severe hemorrhagic manifestations.
Hantavirus Pulmonary Syndrome, recently recognized in the Americas and
probably worldwide, lacks hemorrhagic manifestations, but nevertheless
carries a very high mortality due to its rapidly progressive and severe
pulmonary capillary leak which presents as ARDS.
-
- The clinical laboratory can be very helpful.
Thrombocytopenia (exception: Lassa) and leukopenia (exception: Lassa, Hantaan,
and some severe CCHF cases) are the rule. Proteinuria and/or hematuria
are common, and their presence is the rule for Argentine HF, Bolivian HF,
and HFRS. A positive tourniquet test has been particularly useful in Dengue
hemorrhagic fever, but should be sought in other hemorrhagic fevers as
well.
-
- Definitive diagnosis in an individual
case rests on specific virologic diagnosis. Most patients have readily
detectable viremia at presentation (exception: hantaviral infections).
Rapid enzyme immunoassays can detect viral antigens in acute sera from
patients with Lassa, Argentine HF, Rift Valley fever, Congo-Crimean HF,
yellow fever and specific IgM antibodies in early convalescence. Lassa-
and Hantaan-specific IgM often are detectable during the acute illness.
Diagnosis by virus cultivation and identification will require 3 to 10
days or longer. With the exception of dengue, specialized microbiologic
containment is required for safe handling of these viruses. Appropriate
precautions should be observed in collection, handling, shipping, and processing
of diagnostic samples. Both the Centers for Disease Control and Prevention
(CDC, Atlanta, Georgia) and the U.S. Army Medical Research Institute of
Infectious Diseases (USAMRIID, Frederick, Maryland) have diagnostic laboratories
functioning at the highest (BL-4 or P-4) containment level.
-
- MEDICAL MANAGEMENT
-
- Contact Precautions required for healthcare
workers. General principles of supportive care apply to hemodynamic, hematologic,
pulmonary, and neurologic manifestations of VHF, regardless of the specific
etiologic agent concerned. Patients generally are either moribund or recovering
by the second week of illness, but only intensive care will save the most
severely ill patients. Health care providers employing vigorous fluid resuscitation
of patients with hemodynamic compromise must be mindful of the propensity
of some VHF cases (e.g., hantaviral) for pulmonary capillary leak. Pressor
agents are frequently required. Invasive hemodynamic monitoring should
be used where normal indications warrant, but extra caution should be exercised
with regard to sharp objects and their potential for nosocomial transmission
of a viral agent (see below). Intramuscular injections, aspirin and other
anticoagulant drugs should be avoided. Restlessness, confusion, myalgia,
and hyperesthesia should be managed by conservative measures and judicious
use of sedative, pain-relieving, and amnestic medications. Secondary infections
may occur as with any patient undergoing intensive care and invasive procedures,
such as intravenous lines and indwelling catheters.
-
- The management of clinical bleeding should
follow the same principles as for any patient with a systemic coagulopathy,
assisted by coagulation studies. DIC has been implicated specifically in
Rift Valley fever and Marburg/Ebola infections, but in most VHF the etiology
of the coagulopathy is multifactorial (e.g., hepatic damage, consumptive
coagulopathy, and primary marrow injury to megakaryocytes). Dengue HF is
a notable case where antibody-mediated enhancement of dengue virus infection
of monocytes and cytotoxic T-cell responses to these presented viral antigens
precipitates vascular injury and permeability, complement activation, and
a systemic coagulopathy.
-
- The investigational antiviral drug ribavirin
is available via compassionate use protocols for therapy of Lassa fever,
hemorrhagic fever with renal syndrome (HFRS), Congo-Crimean hemorrhagic
fever, and Rift Valley fever. Separate Phase III efficacy trials have indicated
that parenteral ribavirin reduces morbidity in both HFRS and Lassa fever,
in addition to lowering mortality in the latter disease. In the human field
trial with HFRS, treatment was effective if begun within the first 4 days
of fever, and was continued for 7 days total. For Lassa fever patients,
a compassionate use protocol utilizing intravenous ribavirin as a treatment
is sponsored by the CDC. Dosages used were slightly different, and continued
for 10 days total; treatment is most effective if begun within 7 days of
onset. The only significant side effect of ribavirin is a modest anemia
related to reversible block in erythropoiesis and mild hemolysis. Although
ribavirin has demonstrated teratogenicity in animal studies, its use in
a pregnant woman with grave illness from one of these VHFs must be weighed
against potential benefit. Safety in infants and children has not been
established. A similar dose of ribavirin begun within 4 days of disease
may be effective in HFRS patients. It is important to note that ribavirin
has poor in vitro and in vivo activity against either the filoviruses (Marburg
and Ebola) or the flaviviruses (Dengue, Yellow Fever, Omsk HF and Kyanasur
Forest Disease).
-
- Argentine HF responds to therapy with
2 or more units of convalescent plasma containing adequate amounts of neutralizing
antibody and given within 8 days of onset.
-
- PROPHYLAXIS
-
- The only established and licensed virus-specific
vaccine available for any of the hemorrhagic fever viruses is Yellow Fever
vaccine, which is mandatory for travelers to endemic areas of Africa and
South America. Argentine hemorrhagic fever (AHF) vaccine is a live, attenuated,
investigational vaccine developed at USAMRIID, which has proved efficacious
both in an animal model and in a field trial in South America, and seems
to protect against Bolivian hemorrhagic fever (BHF) as well. Both inactivated
and live-attenuated Rift Valley fever vaccines are currently under investigation.
There is no currently available vaccine for either the filoviruses or for
dengue.
-
- Persons with percutaneous or mucocutaneous
exposure to blood, body fluids, secretions, or excretions from a patient
with suspected VHF should immediately wash the affected skin surface(s)
with soap and water. Mucous membranes should be irrigated with copious
amounts of water or saline.
-
- Close personal contacts or medical personnel
extensively exposed to blood or secretions from VHF patients (particularly
Lassa fever, CCHF, and filoviral diseases) should be monitored for fever
and other disease manifestations during a time equal to the established
incubation period. A DoD compassionate use protocol exists for prophylactic
administration of oral ribavirin to high risk contacts (direct exposure
to body fluids) of Congo-Crimean HF patients. A similar post-exposure prophylaxis
strategy has been suggested for high contacts of Lassa fever patients.
Most patients will tolerate this drug dose well, but patients should be
under surveillance for breakthrough disease (especially after drug cessation)
or adverse drug effects (principally anemia).
-
- ISOLATION AND CONTAINMENT
-
- It should be noted that strict adherence
to Contact Precautions has halted secondary transmission in the vast majority
of circumstances. With the exception of dengue (virus present, but no secondary
infection hazard) and hantaviruses (infectious virus not present in blood
or excreta at the time of diagnosis), VHF patients generally have significant
quantities of virus in blood and often other secretions. Special caution
must be exercised in handling sharps, needles, and other potential sources
of parenteral exposure. Clinical laboratory personnel are also at risk
for exposure, and should employ a biosafety cabinet (if available) and
barrier precautions when handling specimens.
-
- Caution should be exercised in evaluating
and treating the patient with a suspected VHF. Over-reaction on the part
of health care providers is inappropriate and detrimental to both patient
and staff, but it is prudent to provide as rigorous isolation measures
as feasible. These should include: isolation of the patient; stringent
adherence to barrier nursing practices; mask, gown, glove, and needle precautions;
decontamination of the outside of double-bagged specimens proceeding from
the patient’s room; autoclaving or liberal application of hypochlorite
or phenolic disinfectants to excreta and other contaminated materials;
and biosafety cabinet containment of laboratory specimens undergoing analysis.
-
- Experience has shown that Marburg, Ebola,
Lassa, and Congo-Crimean HF viruses may be particularly prone to aerosol
nosocomial spread. Well-documented secondary infections among contacts
and medical personnel who were not parenterally exposed have occurred.
Sometimes this occurred when the acute hemorrhagic disease (as seen in
CCHF) mimicked a surgical emergency such as a bleeding gastric ulcer, with
subsequent exposure and secondary spread among emergency and operating
room personnel. Therefore, when a significant suspicion of one of these
diseases exists, additional management measures should include: an anteroom
adjoining the patient’s isolation room to facilitate putting
on and removing protective barriers and storage of supplies; use of a negative
pressure room for patient care if available; minimal handling of the body
should the patient die, with sealing of the corpse in leak-proof material
for prompt burial or cremation.
-
- No carrier state has ever been observed
with any VHF, but excretion of virus in urine (e.g., hantaviruses) or semen
(e.g., Argentine hemorrhagic fever) may occur in convalescence.
-
- BIOLOGICAL TOXINS
-
- Toxins are defined as any toxic substance
of natural origin produced by an animal, plant, or microbe. They are different
from chemical agents such as VX, cyanide, or mustard in that they are not
man-made. They are non-volatile, are usually not dermally active (mycotoxins
are an exception), and tend to be more toxic per weight than many chemical
agents. Their lack of volatility also distinguishes them from many of the
chemical threat agents, and is very important in that they would not be
either a persistent battlefield threat or be likely to produce secondary
or person to person exposures. Many of the toxins, such as low molecular
weight toxins and some peptides, are quite stable, as where the stability
of the larger protein bacterial toxins is more variable. The bacterial
toxins, such as botulinum toxins or shiga toxin, tend to be the most toxic
in terms of dose required for lethality (Appendix C), whereas the mycotoxins
tend to be among the least toxic compounds, thousands of times less toxic
than the botulinum toxins. Some toxins are more toxic by the aerosol route
than when delivered orally or parenterally (ricin, saxitoxin, and T2 mycotoxins
are examples), whereas botulinum toxins have lower toxicity when delivered
by the aerosol route than when ingested. However, botulinum is so toxic
inherently that this characteristic does not limit its potential as a biological
warfare agent. The utility of many toxins as military weapons is potentially
limited by their inherent low toxicity (too much toxin would be required),
or by the fact that some, such as saxitoxin, can only feasibly be produced
in minute quantities. The relationship between aerosol toxicity and the
quantity of toxin required to provide an effective open-air exposure is
shown in Appendix D. The lower the lethal dose for fifty percent of those
exposed (LD50), in micrograms per kilogram, the less agent would be required
to cover a large battlefield sized area. The converse is also true, and
means that for some agents such as ricin, very large quantities (tons)
would be needed for an effective open-air attack.
-
- Where toxins are concerned, incapacitation
as well as lethality must be considered. Several toxins cause significant
illness at levels much lower than the level required for lethality, and
are thus militarily significant in their ability to incapacitate soldiers.
-
- This manual will cover four toxins considered
to be among the most likely toxins which could be used against U.S. forces:
botulinum toxins, staphylococcal enterotoxin B (SEB), ricin, and T-2 mycotoxins.
-
- BOTULINUM TOXINS
-
- SUMMARY
-
- Signs and Symptoms: Ptosis, generalized
weakness, dizziness, dry mouth and throat, blurred vision and diplopia,
dysarthria, dysphonia, and dysphagia followed by symmetrical descending
flaccid paralysis and development of respiratory failure. Symptoms begin
as early as 24-36 hours but may take several days after inhalation of toxin.
-
- Diagnosis: Clinical diagnosis. No routine
laboratory findings. Biowarfare attack should be suspected if multiple
casualties simultaneously present with progressive descending bulbar, muscular,
and respiratory weakness.
-
- Treatment: Intubation and ventilatory
assistance for respiratory failure. Tracheostomy may be required. Administration
of heptavalent botulinum antitoxin (IND product) may prevent or decrease
progression to respiratory failure and hasten recovery.
-
- Prophylaxis: Pentavalent toxoid vaccine
(types A, B, C, D, and E) is available as an IND product for those at high
risk of exposure.
-
- Isolation and Decontamination: Standard
Precautions for healthcare workers. Toxin is not dermally active and secondary
aerosols are not a hazard from patients. Hypochlorite (0.5% for 10-15 minutes)
and/or soap and water.
-
- OVERVIEW
-
- The botulinum toxins are a group of seven
related neurotoxins produced by the bacillus Clostridium botulinum. These
toxins, types A through G, could be delivered by aerosol over concentrations
of troops. When inhaled, these toxins produce a clinical picture very similar
to foodborne intoxication, although the time to onset of paralytic symptoms
may actually be longer than for foodborne cases, and may vary by type and
dose of toxin. The clinical syndrome produced by one or more of these toxins
is known as "botulism".
-
- HISTORY AND SIGNIFICANCE
-
- Botulinum toxins have caused numerous
cases of botulism when ingested in improperly prepared or canned foods.
Many deaths have occurred secondary to such incidents. It is feasible to
deliver botulinum toxins as a biological weapon, and other countries have
weaponized or are suspected to have weaponized one or more of this group
of toxins. Iraq admitted to a United Nations inspection team in August
of 1991 that it had done research on the offensive use of botulinum toxins
prior to the Persian Gulf War, which occurred in January and February of
that year. Further information given in 1995 revealed that Iraq had not
only researched the use of this toxin as a weapon, but had filled and deployed
over 100 munitions with botulinum toxin.
-
- TOXIN CHARACTERISTICS
-
- Botulinum toxins are proteins of approximately
150,000 kD molecular weight which can be produced from the anaerobic bacterium
Clostridium botulinum. As noted above, there are seven distinct but related
neurotoxins, A through G, produced by different strains of the clostridial
bacillus. All seven types act by similar mechanisms. The toxins produce
similar effects when inhaled or ingested, although the time course may
vary depending on the route of exposure and the dose received. Although
an aerosol attack is by far the most likely scenario for the use of botulinum
toxins, theoretically the agent could be used to sabotage food supplies;
enemy special forces or terrorists might use this method in certain scenarios
to produce foodborne botulism in those so targeted.
-
- MECHANISM OF TOXICITY
-
- The botulinum toxins as a group are among
the most toxic compounds known to man. Appendix C shows the comparative
lethality of selected toxins and chemical agents in laboratory mice. Botulinum
toxin is the most toxic compound per weight of agent, requiring only 0.001
microgram per kilogram of body weight to kill 50 percent of the animals
studied. As a group, bacterial toxins such as botulinum tend to be the
most lethal of all toxins. Note that botulinum toxin type A is 15,000 times
more toxic than VX and 100,000 times more toxic than Sarin, two of the
well known organophosphate nerve agents.
-
- Botulinum toxins act by binding to the
presynaptic nerve terminal at the neuromuscular junction and at cholinergic
autonomic sites. These toxins then act to prevent the release of acetylcholine
presynaptically, and thus block neurotransmission. This interruption of
neurotransmission causes both bulbar palsies and the skeletal muscle weakness
seen in clinical botulism.
-
- Unlike the situation with nerve agent
intoxication, where there is too much acetylcholine due to inhibition of
acetylcholinesterase, the problem in botulism is lack of the neurotransmitter
in the synapse. Thus, pharmacologic measures such as atropine are not indicated
in botulism and would likely exacerbate symptoms.
-
- CLINICAL FEATURES
-
- The onset of symptoms of inhalation botulism
may vary from 24 to 36 hours, to several days following exposure. Recent
primate studies indicate that the signs and symptoms may in fact not appear
for several days when a low dose of the toxin is inhaled versus a shorter
time period following ingestion of toxin or inhalation of higher doses.
Bulbar palsies are prominent early, with eye symptoms such as blurred vision
due to mydriasis, diplopia, ptosis, and photophobia, in addition to other
bulbar signs such as dysarthria, dysphonia, and dysphagia. Skeletal muscle
paralysis follows, with a symmetrical, descending, and progressive weakness
which may culminate abruptly in respiratory failure. Progression from onset
of symptoms to respiratory failure has occurred in as little as 24 hours
in cases of foodborne botulism.
-
- Physical examination usually reveals
an alert and oriented patient without fever. Postural hypotension may be
present. Mucous membranes may be dry and crusted and the patient may complain
of dry mouth or even sore throat. There may be difficulty with speaking
and with swallowing. Gag reflex may be absent. Pupils may be dilated and
even fixed. Ptosis and extraocular muscle palsies may also be observed.
Variable degrees of skeletal muscle weakness may be observed depending
on the degree of progression in an individual patient. Deep tendon reflexes
may be present or absent. With severe respiratory muscle paralysis, the
patient may become cyanotic or exhibit narcosis from CO2 retention.
-
- DIAGNOSIS
-
- The occurrence of an epidemic of cases
of a descending and progressive bulbar and skeletal paralysis in afebrile
patients points to the diagnosis of botulinum intoxication. Foodborne outbreaks
tend to occur in small clusters and have never occurred in soldiers on
military rations such as MRE’s (Meals, Ready to Eat). Higher
numbers of cases in a theater of operations should raise at least the consideration
of a biological warfare attack with aerosolized botulinum toxin. Foodborne
outbreaks are theoretically possible in troops on normal "A"
rations.
-
- Individual cases might be confused clinically
with other neuromuscular disorders such as Guillain-Barre syndrome, myasthenia
gravis, or tick paralysis. The edrophonium or Tensilon® test may be
transiently positive in botulism, so it may not distinguish botulinum intoxication
from myasthenia. The cerebrospinal fluid in botulism is normal and the
paralysis is generally symmetrical, which distinguishes it from enteroviral
myelitis. Mental status changes generally seen in viral encephalitis should
not occur with botulinum intoxication.
-
- It may become necessary to distinguish
nerve agent and/or atropine poisoning from botulinum intoxication. Nerve
agent poisoning produces copious respiratory secretions and miotic pupils,
whereas there is if anything a decrease in secretions in botulinum intoxication.
Atropine overdose is distinguished from botulism by its central nervous
system excitation (hallucinations and delirium) even though the mucous
membranes are dry and mydriasis is present. The clinical differences between
botulinum intoxication and nerve agent poisoning are depicted in Appendix
E.
-
- Laboratory testing is generally not helpful
in the diagnosis of botulism. Survivors do not usually develop an antibody
response due to the very small amount of toxin necessary to produce clinical
symptoms. Detection of toxin in serum or gastric contents is possible,
and mouse neutralization (bioassay) remains the most sensitive test. Other
assays include gel hydralization or ELISA. Serum specimens should be drawn
from suspected cases and held for testing at such a facility.
-
- MEDICAL MANAGEMENT
-
- Respiratory failure secondary to paralysis
of respiratory muscles is the most serious complication and, generally,
the cause of death. Reported cases of botulism prior to 1950 had a mortality
of 60%. With tracheostomy or endotracheal intubation and ventilatory assistance,
fatalities should be less than five percent. Intensive and prolonged nursing
care may be required for recovery which may take several weeks or even
months.
-
- Antitoxin: In isolated cases of food-borne
botulism, circulating toxin is present, perhaps due to continued absorption
through the gut wall. Botulinum antitoxin (equine origin) has been used
in those circumstances, and is thought to be helpful. Animal experiments
show that after aerosol exposure, botulinum antitoxin can be very effective
if given before the onset of clinical signs. Administration of antitoxin
is reasonable if disease has not progressed to a stable state.
-
- A trivalent equine antitoxin has been
available from the Centers for Disease Control and Prevention for cases
of foodborne botulism. This product has all the disadvantages of a horse
serum product, including the risks of anaphylaxis and serum sickness. A
"despeciated" equine heptavalent antitoxin against types A, B,
C, D, E, F, and G has been prepared by cleaving the Fc fragments from horse
IgG molecules, leaving F(ab) 2 fragments. This product is under advanced
development, and is currently available under IND status. Its efficacy
is inferred from its performance in animal studies. Disadvantages include
a reduced, but theoretical risk of serum sickness.
-
- Use of the antitoxin requires skin testing
for horse serum sensitivity prior to administration. Skin testing is performed
by injecting 0.1 ml of a 1:10 dilution (in sterile physiological saline)
of antitoxin intradermally in the patient’s forearm with a 26
or 27 gauge needle. Monitor the injection site and observe the patient
for allergic reaction for 20 minutes. The skin test is positive if any
of these allergic reactions occur: hyperemic areola at the site of the
injection 0.5 cm; fever or chills; hypotension with decrease of blood pressure
20 mm Hg for systolic and diastolic pressures; skin rash; respiratory difficulty;
nausea or vomiting; generalized itching. Do NOT administer Botulinum F(ab’)2
Antitoxin, Heptavalent (equine derived) if the skin test is positive. If
no allergic symptoms are observed, the antitoxin is administered intravenously
in a normal saline solution, 10 mls over 20 minutes.
-
- With a positive skin test, desensitization
is carried out by administering 0.01 - 0.1 ml of antitoxin subcutaneously,
doubling the previous dose every 20 minutes until 1.0 - 2.0 ml can be sustained
without any marked reaction.
-
- PROPHYLAXIS
-
- Vaccine: A pentavalent toxoid of Clostridium
botulinum toxin types A, B, C, D, and E is available under an IND status.
This product has been administered to several thousand volunteers and occupationally
at-risk workers, and induces serum antitoxin levels that correspond to
protective levels in experimental animal systems. The currently recommended
primary series of 0, 2, and 12 weeks, then a 1 year booster induces protective
antibody levels in greater than 90 percent of vaccinees after one year.
Adequate antibody levels are transiently induced after three injections,
but decline prior to the one year booster.
-
- Contraindications to the vaccine include
sensitivities to alum, formaldehyde, and thimerosal, or hypersensitivity
to a previous dose. Reactogenicity is mild, with two to four percent of
vaccinees reporting erythema, edema, or induration at the local site of
injection which peaks at 24 to 48 hours, then dissipates. The frequency
of such local reactions increases with each subsequent inoculation; after
the second and third doses, seven to ten percent will have local reactions,
with higher incidence (up to twenty percent or so) after boosters. Severe
local reactions are rare, consisting of more extensive edema or induration.
Systemic reactions are reported in up to three percent, consisting of fever,
malaise, headache, and myalgia. Incapacitating reactions (local or systemic)
are uncommon. The vaccine should be stored at refrigerator temperatures
(not frozen).
-
- Three or more vaccine doses at 0, 2,
and 12 weeks, then at 1 year if possible, all by deep subcutaneous injection
are recommended for selected individuals or groups judged at high risk
for exposure to botulinum toxin aerosols. There is no indication at present
for use of botulinum antitoxin as a prophylactic modality except under
extremely specialized circumstances.
-
- STAPHYLOCOCCAL ENTEROTOXIN
B
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