**Medical Management of Smallpox Patients and**

**Vaccination Complications**

**Public health officials should be immediately notified of any
suspected smallpox patient.** Currently, there is [no]{.underline}
proven treatment for clinical smallpox (variola). Clinical trials
conducted during the smallpox era that evaluated several antiviral
compounds, including N-methylisatin β-thiosemicarbazone (Maboran),
adenide arabinoside, cytosine arabinoside, and idoxiuridine, failed to
demonstrate clinical efficacy for these compounds.

Evaluation of modern day antiviral compounds at CDC is ongoing. One
current antiviral, Cidofovir, has shown some in vitro and in vivo
(animal studies) activity against orthopoxviruses. However, its
effectiveness for treating clinical smallpox or vaccine adverse events
is not known. This medication is labeled for the treatment of CMV
retinitis and has been associated with renal failure. Were an outbreak
of smallpox to occur, this medication would be made available through
the CDC or NIH under an Investigational New Drug (IND) protocol for
potential treatment of smallpox or vaccine adverse events.

Medical management of a patient with smallpox is mainly
[supportive]{.underline} and consists of: 1) isolation of the patient to
prevent transmission of the smallpox (variola) virus to non-immune
persons, 2) monitoring and maintaining fluid and electrolyte balance, 3)
skin care, and 4) monitoring for and treatment of complications. In
addition, unless the diagnosis of smallpox is laboratory confirmed, the
patient should also receive smallpox vaccination if they will be
isolated with other confirmed or suspected smallpox cases. Vaccination
of suspected cases of smallpox is done to prevent the accidental
transmission of smallpox virus to any suspected smallpox patients who
have been misdiagnosed as smallpox cases.

**[Isolation]{.underline}**

In a smallpox outbreak, isolation of confirmed or suspected smallpox
patient(s) may be accomplished by several different methods depending
upon certain circumstances (number of patients, severity of illness,
availability of resources, etc.). Ultimately, the goal of isolation is
to prevent transmission of smallpox from an infectious patient (from the
time the rash appears until all of the scabs have separated, about 3 to
4 weeks) to nonimmune individuals while maintaining an appropriate care
and comfort level for the patient. All potential methods of isolation
must be considered with these goals in mind. Several potential methods
for patient isolation are outlined below. **Medical personnel should
consult with public health officials to determine the most appropriate
method for isolation of a smallpox patient(s).**

**Hospital isolation** - [If]{.underline} a confirmed or suspected
smallpox patient(s) [requires]{.underline} hospital care, the following
steps must be taken while the patient(s) is hospitalized:

1\. Place the patient(s) under strict respiratory and contact isolation
in a room with negative air pressure (and individual HEPA-filtered
ventilation exhaust, if available). This room should have private
shower/bathroom facilities and not share ventilation with any other part
of the hospital.

2\. Protective clothing including: gowns, masks (properly fitted N95
respirator masks), gloves, protective eyewear, and surgical booties
should be worn by unvaccinated personnel who enter and leave the
isolation room. Recently successfully vaccinated personnel should
exercise contact precautions (gowns, gloves, etc.) and should wear a
surgical mask and eye protection as indicated for procedures where
contact with body fluids may occur.

3\. Removal and disposal of all protective clothing into biohazard waste
disposal containers should be done before leaving the isolation room and
re-entering other areas of the hospital.

4\. All infectious waste and contaminated protective clothing should be
disposed of or sterilized in an appropriate manner (incineration for
disposable materials, autoclaving, ethylene oxide decontamination, or
laundering in hot water and bleach for reusable equipment or clothing).
**Public health officials should be consulted for specific waste
disposal and decontamination guidelines.**

5\. Personnel entering the isolation room or handling infectious waste
or clinical specimens from the patient(s) should be vaccinated or have
documented successful recent smallpox vaccinations (within 3 years).
**Public health officials should be contacted for vaccination
requests.**

6\. Steps should be taken to confirm or rule out the diagnosis of
smallpox. **Public health officials should be consulted for assistance
with the laboratory diagnosis.**

**Nonhospital isolation** -- **Public health officials should be
consulted before nonhospital isolation is initiated.** Confirmed or
suspected smallpox patients who do not require hospital care may be
isolated in nonhospital facilities that [do not]{.underline} have shared
ventilation systems with other facilities (see Guide C -- Isolation and
Quarantine Guidelines). These facilities should have appropriate climate
control capabilities (heating/air conditioning), running water, and
bathroom facilities. If suspected and confirmed smallpox patients are
isolated together, all patients should receive smallpox vaccination to
prevent accidental transmission because of misdiagnosis. **All persons
entering these facilities must have documented successful recent
smallpox vaccinations (within 3 years).**

**[Fluid and Electrolyte balance]{.underline}**

During the vesicular and pustular stages of smallpox, patients may
experience significant fluid losses and become hypovolemic or develop
shock. Fluid loss can result from: 1) fever, 2) nausea and vomiting, 3)
decreased fluid intake due to swallowing discomfort from pharyngeal
lesions, 4) body fluid shifts from the vascular bed into the
subcutaneous tissue, and 5) massive skin desquamation in patients with
extensive confluent lesions. Electrolyte and protein loss may also occur
in these patients. Fluid and electrolyte balance should be monitored in
hospitalized patients with appropriate oral or intravenous correction of
imbalances. Patients with less severe disease who do not require
hospitalization should be encouraged to maintain good oral intake of
fluids, educated on the signs/symptoms of hypovolemia/dehydration, and
counseled on when to seek medical attention if hypovolemia/dehydration
occurs.

**[Skin Care]{.underline}**

The skin should be kept clean and efforts should be made to avoid
rupturing vesicles or pustules. No salves or ointments should be
applied. In general, scab lesions should be allowed to heal and separate
on their own. All scabs should separate by 3 to 4 weeks, however,
lesions on the palms and soles may persist longer than 3 to 4 weeks
unless artificially removed. Bacterial superinfection of lesions may
occur (see Monitoring and Treatment of Complications) and should be
treated with appropriate antibiotics.

**[Monitoring and Treatment of Complications]{.underline}**

Several complications may occur during the course of a smallpox
infection. These include: 1) hemorrhagic, 2) secondary bacterial
infections, 3) corneal ulceration and/or keratitis, 4) arthritis or
"osteomyelitis variolosa", 5) respiratory, 6) encephalitis, 7)
gastrointestinal, and 8) genitourinary. These complications and their
treatment are described below.

**Hemorrhagic** - Minor hemorrhagic manifestations such as
subconjunctival hemorrhages occur commonly in smallpox patients. If
these subconjuctival hemorrhages are isolated and are not accompanied by
evidence of a consumption coagulopathy or active bleeding (decreasing
hemoglobin, hematocrit or platelets), no specific therapy is needed.
However, if signs of more extensive hemorrhage are present (mucosal
bleeding, bleeding into smallpox lesions, ecchymoses, hematemesis,
hematuria etc.) the patient should be evaluated for disseminated
intravascular coagulation (DIC) and treated appropriately. Hemorrhagic
complications may indicate a more severe form of the disease called
"hemorrhagic smallpox", which has a poor prognosis. Also, because of a
high, sustained viremia coupled with mucosal hemorrhaging during their
course of illness, these patients are highly infectious.

**Secondary bacterial infections** -- Bacterial superinfections can
include abscesses of skin lesions, pneumonia, osteomyelitis, joint
infections, and septicemia. Laboratory diagnostics (gram stain, culture,
antibiotic susceptibility testing etc.) should be performed to help
guide antibiotic therapy.

**Corneal ulceration and/or keratitis --** These complications occurred
more frequently in hemorrhagic-type smallpox but were occasionally seen
in the more typical ordinary-type smallpox. In one case series \[Rao AR,
Smallpox, Bombay, 1972, The Kothari Book Depot\] corneal ulcers occurred
in 1% of nonhemorrhagic type smallpox cases and keratitis occurred in
about 0.25%. Corneal ulcerations can appear around the 2^nd^ week of
illness and begin at the corneal margins. Ulcers can heal rapidly,
leaving a minor opacity, or on occasion, may cause severe corneal
scarring. Keratitis and corneal ulceration was far more common in
malnourished individuals. Topical idoxuridine has been used but its
efficacy is undocumented.

**Arthritis or "Osteomyelitis variolosa"** -- This complication occurred
in approximately 1.7% of the cases in case series reviewed by Rao (see
above). It usually occurred after the 15^th^ day and was accompanied by
a brief recurrence of fever during the scabbing stage. The elbow is the
most commonly affected joint and symmetrical, bilateral involvement was
frequently seen. This complication was most commonly caused by viral
infection of the metaphyses of growing bones. Most cases resolved
without permanent deformity.

**Respiratory** --Viral bronchitis and pneumonitis can be common
complications of severe smallpox and are considered part of the normal
disease syndrome. Treatment is symptomatic with measures to treat
hypoxemia with supplemental oxygen and/or intubation/ventilation as
indicated. Secondary bacterial pneumonia can occur and should be treated
with appropriate antibiotics as guided by laboratory diagnostics (gram
stain, culture, antibiotic susceptibility testing, etc.). Pulmonary
edema is common in the more severe forms of smallpox, hemorrhagic and
flat-type, and should be treated with careful monitoring of oxygenation,
fluid-status, and blood pressure with supplemental oxygen, and diuretics
administered as needed. Patients with cough during the first week of
disease may transmit disease more readily than patients without a cough
as this is the period when oral secretions contain the largest amount of
virus. Patients that developed a cough later in the course of disease
(after day 10), when viral counts in secretions were lower, are not as
infectious as those that develop coughs earlier.

**Encephalitis** -- This complication occurred in about 1 out of every
500 cases of smallpox. It usually appeared between the 6^th^ and 10^th^
day of illness when the rash was still in the papular or vesicular
stage. During the smallpox era, this complication was a minor
contributor to the case-fatality rate of classical smallpox (variola
major), the most common form of smallpox. Although sometimes slow,
recovery was usually complete.

**Gastrointestinal** -- Nausea and vomiting can occur in the earlier
stages of smallpox, especially in the prodromal period before rash
development and should be treated symptomatically. Diarrhea may
occasionally occur in the prodromal period or in the 2^nd^ week of
illness and should also be treated symptomatically as needed. Acute
dilation of the stomach occurred rarely and was more common in infants.
In some severe cases of smallpox (especially flat-type), extensive viral
infection of the intestinal mucosa occurred with sloughing of the
mucosal membrane. Most of these cases were fatal.

**Genitourinary system** -- Orchitis occurred in 0.1% of the Rao case
series and is usually unilateral. Hematuria can be present in
hemorrhagic type smallpox if bleeding into the pelvis of the kidney
occurs.

###### [Vaccination and Vaccination Adverse Events]{.underline}

## **Contraindications for Vaccination** 

In general, the risk of developing smallpox for face-to-face contacts to
smallpox cases outweighs the risk of developing complications for those
contacts with contraindications. When the level of exposure risk is
unclear, the decision to vaccinate should be made after careful
assessment of the potential risks verses benefits of smallpox
vaccination.

Household members of contacts with contraindications to vaccination
should consider housing themselves separately from vaccinated household
members until the vaccination site has healed to decrease the risk of
contact transmission of virus.

Persons with certain medical conditions are known to have a higher risk
of developing severe complications following vaccination with vaccinia
vaccine (smallpox vaccine). These include:

1.  Persons with [diseases or conditions which cause
    immunodeficiency]{.underline}, such as HIV, AIDS, leukemia,
    lymphoma, generalized malignancy, agammaglobulinemia, or therapy
    with alkylating agents, antimetabolites, radiation, or
    immunosuppressive doses of corticosteroids.

> *A household member with an immunodeficiency disease or who is
> undergoing one of the therapies listed who is exposed to a recently
> vaccinated household member is at risk of developing a postvaccine
> complication because of potential accidental inoculation with virus
> from the vaccination site of a vaccinated person.*

2.  Persons who have [been diagnosed with eczema]{.underline}, even if
    the condition is mild or not presently active.

> *A household member who has eczema or a history of eczema who is
> exposed to a recently vaccinated household member, is also at higher
> risk for developing a post-vaccine complication due to potential
> accidental inoculation with virus from the vaccination site of the
> vaccinated person.*

3.  Women who are pregnant or who are planning to become pregnant within
    a month following vaccination.

4.  Persons with other acute or chronic skin conditions such as atopic
    dermatitis, burns, impetigo, or varicella zoster (shingles) should
    not be vaccinated until the condition resolves.

5.  Persons with serious, life-threatening allergies to the antibiotics
    polymyxin B, streptomycin, tetracycline, or neomycin.

> **[Recognition of Expected Vaccine Reactions/Take]{.underline}**
>
> Successful vaccination, is normally associated with tenderness,
> redness, swelling, and a lesion at the vaccination site. Primary
> vaccination may also be associated with fever for a few days and
> enlarged, tender lymph nodes in the axilla of the vaccinated arm.
> These symptoms are more common in persons receiving their first dose
> of vaccine (15 to 20%) than in persons being revaccinated (0 to 10%).
>
> The clinical manifestations of vaccination with vaccinia virus are
> dependent upon the immune status of the vaccine recipient. Local
> reactions to vaccination may be classified as a major (primary)
> reaction or an equivocal reaction.

1.  [Primary (major) reaction]{.underline} -- This reaction would be
    expected for persons receiving their first or primary smallpox
    vaccination or in persons who received a primary vaccination many
    years previously. The majority of the population today would fall
    within one of these two groups. The inoculation site becomes
    reddened and pruritic 3 to 4 days after vaccination. A vesicle
    surrounded by a red areola then forms which becomes umbilicated and
    then pustular by the 7^th^ to 11^th^ day after vaccination. The red
    areola has enlarged tremendously by this time. The pustule begins to
    dry, the redness subsides, and the lesion becomes crusted between
    the 2^nd^ and 3^rd^ [week]{.underline}. By the end of the 3^rd^
    week, the scab falls off leaving a permanent scar that at first is
    pink in color but eventually becomes flesh-colored. (Fig. 1) At the
    end of the first week between the vesicular and pustular phases,
    there may be a variable amount of fever, malaise, and regional
    lymphadenitis. These symptoms usually subside within 1 to 2 days and
    are more likely to occur in older children and adults than in
    infants.

![](media/image1.png){width="4.010416666666667in" height="2.75in"}

Fig. 1 -- Major (primary) reaction - Expected local reaction after
[primary]{.underline} smallpox vaccination or revaccination after a
prolonged period since primary vaccination using the multiple pressure
technique.

> 2\. Equivocal -- All responses other than a major (primary) reaction
> are defined as equivocal reactions. These blunted reactions could be a
> result of a high level of immunity (i.e., a person who has received
> multiple previous smallpox vaccinations) or vaccination failure caused
> by improper vaccine administration technique or less potent vaccine.
> If an equivocal reaction is observed, the vaccination procedures
> should be checked and vaccination repeated with vaccine from another
> vial or vaccine lot as it would be difficult to determine if the
> blunted reaction was caused by immunity or vaccine-take failure.

**[Recognition of Adverse Reactions (AEs)]{.underline}**

The overall risk of serious complications following vaccination with
vaccinia vaccine is low. Complications occur more frequently in persons
receiving their first dose of vaccine, and among young children
([\<]{.underline}5 years of age). The [most frequent]{.underline}
complications of vaccination and their descriptions are listed below:

**A. Inadvertent inoculation at other sites** -- This is the most
frequent complication of vaccinia vaccination and accounts for about 50%
of all complications following primary and revaccination. This
complication occurs at a rate of about 1 in 2000 primary vaccinations
and usually results from auto-inoculation when the virus is transferred
by hand from the site of vaccination to other areas. The most common
sites involved are the face, eyelid (Fig. 7), nose, mouth, genitalia,
and rectum. Most lesions will heal without specific therapy, but
Vaccinia Immune Globulin (VIG) may be useful for some cases of
inadvertent ocular inoculation (see Indications and Guidelines for VIG
Use below). VIG is contraindicated, however, if vaccinial keratitis is
present. Inadvertent inoculation can be prevented by handwashing after
touching the vaccination site.

![](media/image2.jpeg){width="1.74375in" height="2.1590277777777778in"}

Fig. 7 -- Inadvertent inoculation of lower eyelid \[Fenner F, Henderson,
DA, et al. Smallpox and its Eradication. WHO. 1988, Reprinted with
permission of WHO\]

**B. Generalized vaccinia** -- This complication is characterized by a
vesicular rash of varying extent resulting from blood-borne
dissemination of vaccinia virus (Fig. 8). It is most frequently seen
following primary vaccination and occurs at a rate of about 1 in 5000
vaccinations. Lesions occur between 6 to 9 days following vaccination
and can be few or generalized. The rash of is generally self-limited in
persons with no underlying illnesses (immune deficiencies) and [usually
requires no treatment with VIG except in patients who appear toxic or
who have serious underlying conditions.]{.underline}