However, because plague, unlike smallpox, is spread by large respiratory
droplets, close contact is required for transmission.
Clinical Manifestations. Bubonic plague is characterized by the classic bubo, a
tender, enlarged, fluctuant lymph node in the distribution of the infected flea bite.
Fever and malaise are usually present. Bubonic plague may progress to
septicemia as bacteria gain access to the circulation; 80% of bubonic plague
victims have positive blood cultures. Petechiae, purpura, and overwhelming
disseminated intravascular coagulation (DIC) may develop.
Pneumonic plague may arise secondarily after blood-borne seeding of the lungs
or may be seen primarily after aerosol exposure. Symptoms include high fever,
chills, malaise, fatigue, headache, and cough. Chest radiographs may reveal a
patchy or consolidated bronchopneumonia, and the classic clinical finding is one
of blood-streaked sputum; DIC and an overwhelming sepsis may develop as the
disease progresses. Meningitis develops in 6% of cases. Untreated pneumonic
plague has a mortality rate approaching 100%.
A presumptive diagnosis of plague can be made by observing the classic
bipolar-staining “safety pin”—like rods in Gram or Wayson stains of sputum,
aspirated lymph node material, or cerebrospinal fluid. Confirmation is obtained
via blood, sputum, or aspirate culture.
Management. Droplet precautions should be employed in cases of suspected
pneumonic plague. Such precautions should be continued in confirmed cases until
sputum cultures are negative. Standard precautions are adequate in managing
bubonic plague victims. Given the incubation period, decontamination would not
be necessary in a clinical setting. See Table 132.3B for detailed treatment
recommendations for children.
Smallpox
CLINICAL PEARLS AND PITFALLS


Smallpox is contagious 1 day prior to the onset of rash.
In contrast to chickenpox, the rash of smallpox starts on the face and

extremities and spreads centrally.
The smallpox rash develops synchronously such that lesions are all in
the same stage.
Strict airborne, droplet, and contact precautions should be instituted
immediately for smallpox victims and should continue until all scabs
have separated.
Smallpox is associated with a high mortality and there is no specific
therapy available.
Background. The global eradication of smallpox represents one of the great
success stories of public health, with the last endemic case occurring in Somalia
in 1977. Since then, research stockpiles of variola virus have been consolidated
into two World Health Organization (WHO)–approved stores at the CDC in
Atlanta and at a Russian institute in Koltsovo. This achievement would seem to
make terrorist use of this virus impossible; however, several factors give cause for
concern. First is the fear that other stockpiles already exist in the hands of
belligerent nations unbeknownst to WHO. Astonishingly, in 2014, vials
containing the smallpox virus were discovered in a storage room of an FDA
laboratory in Bethesda, Maryland. Second, the entire viral genomic sequence is
known and published; therefore, it is likely only a matter of time before
technology permits reconstruction of the virus (the related horsepox virus has
already been synthesized de novo). Finally, although the virulence factors of
variola virus are poorly understood, it may be possible for someone to manipulate
related orthopoxviruses such as monkeypox to enhance their virulence in humans
and create a disease similar to smallpox. In light of these considerations, the CDC
in 2003 recommended a strategy of reintroducing vaccination in the United States
after a nearly 30-year hiatus, with the initial goal of vaccinating up to 10,000,000
front-line EMS and healthcare providers. This program has subsequently proven
controversial and has been suspended; probably fewer than 50,000 civilians were
vaccinated. The U.S. military, however, has vaccinated several hundred thousand
service members and serious adverse events have been rare.

Several factors might make smallpox an attractive weapon to potential
belligerents. First, the duration of immunity after vaccination is a matter of
controversy, with some studies suggesting a duration of only 3 to 5 years, while
other studies suggest the possibility of lifelong immunity. Second, following


cessation of universal vaccination within the United States in 1972, vaccine had
been out of production until the 2007 licensing of a new product (ACAM2000,
Acambis Corporation); although the CDC now controls enough ACAM2000 to
vaccinate every American, susceptibility to the disease is nearly universal. Also,
effective therapy is lacking and healthcare providers are unfamiliar with the
disease. Finally, the potential for rapid spread potentially permits a terrorist to
cause widespread disease and panic with a minimum of infectious material.
Pathophysiology. Although infectivity is highest when the smallpox rash first
appears, the disease may be spread by exposed persons about 24 hours before the
exanthem manifests. During the 7- to 17-day long incubation period, the virus
replicates in upper respiratory tract mucosa, giving rise to a primary viremia. The
liver and spleen are then seeded, further amplification of the virus occurs, and a
secondary viremia ultimately develops. The skin is seeded with this secondary
viremia, and the classic exanthem of smallpox develops.
Clinical Manifestations. Clinical illness has an abrupt onset during the phase of
secondary viremia and is characterized by fever, malaise, rigors, vomiting,
headache, and backache. The classic exanthem typically begins 2 to 4 days later
as macules on the face and extremities. These lesions progress in synchronous
fashion to papules, vesicles, and then to pustules, which finally form scabs. As
scabs separate, survivors are left with disfiguring depigmented scars. The rash
spreads centrally to the trunk but remains more abundant at the periphery. This
centrifugal distribution and synchrony distinguish smallpox from chickenpox,
which has a centripetal distribution of lesions in varying stages of development.
An enanthem usually accompanies the characteristic exanthem, and internal

organs become viral targets as well. Death historically occurred in approximately
30% of variola major (the predominant form of smallpox in the past) patients and
typically resulted from hypotension and immune complex–associated toxemia.
Eye involvement led to blindness in a small number of victims. Uncommon
variants with lesser (variola minor) or greater (hemorrhagic and flat-type variants)
mortality also existed. Ominously, a 1971 smallpox outbreak in Aralsk, in the
former Kazakh Soviet Republic, is thought by some to have originated from a
bioweapons accident. All three fatalities in this small outbreak involved
unvaccinated individuals who contracted rare and universally fatal hemorrhagic
disease, raising the specter of genomic manipulation for increased virulence.
Management. The diagnosis of smallpox should be suspected on clinical
grounds. Laboratory confirmation (e.g., electron microscopy, PCR) is best


effected in a biosafety level 4 laboratory by emergent notification and specimen
transport to the CDC.
Based on past experience, vaccination (with vaccinia, an orthopoxvirus closely
related to variola) of smallpox-exposed persons within the first 4 days after
exposure may prevent the development of overt disease. Although the vaccine has
been used safely and successfully in even young infants, it has a relatively high
rate of serious complications in certain patients. Notably, fetal vaccinia and
resultant fetal demise can occur when pregnant women are vaccinated. Vaccinia
gangrenosa, a frequently fatal complication, occurred when immunocompromised
persons were inadvertently vaccinated. Eczema vaccinatum may occur in those
with pre-existing skin conditions and can be serious. Myocarditis and pericarditis
may occur. A severe postvaccinal encephalitis was well known, albeit relatively
rare, during the era of widespread vaccination, because this complication occurs
only after primary vaccination, it would disproportionately affect pediatric
patients. Autoinoculation can occur when virus from the primary lesion arising at
the site of vaccination is transferred by scratching or rubbing to other areas of the

skin or to the eye. To manage these complications, vaccinia immune globulin
(VIG) should be available when undertaking a vaccination campaign. VIG (0.6
mg/kg intramuscular [IM]) may be given to vaccine recipients who experience
severe complications or to significantly immunocompromised individuals
exposed to smallpox in whom vaccination would be unsafe. Today, stocks of
vaccine and VIG are controlled by the CDC. There is also a nonreplicating
smallpox vaccine (IMVAMUNE) for immune-compromised patients that is not
yet FDA approved but is stocked by the CDC for emergency use.
Even a single case of smallpox occurring anywhere in the world today would
represent a grave public health emergency. A suspected case should thus prompt
immediate notification and consultation with health authorities. Strict airborne,
droplet, and contact precautions should be instituted immediately for victims and
should continue until all scabs have separated. Decontamination of symptomatic
patients is unnecessary. Contacts must be observed closely for 17 days following
their last potential exposure. The development of fever during this period would
be a cause for isolation. Multiple victims would ideally be managed as a cohort at
dedicated sites removed from conventional hospital facilities.
Botulism
Background. Botulism occurs as a result of exposure to one of eight botulinum
neurotoxins (A through H). Only types A, B, E, and, rarely, F appear to cause
human botulism in nature. Botulinum toxin was included in the U.S. biologic