Smallpox

Diagnosis & Evaluation

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Smallpox Clinical Case Definition

An illness with acute onset of fever ≥101°F (38.3°C) followed by a rash characterized by firm, deep-
seated vesicles or pustules in the same stage of development without other apparent cause.

Patient Evaluation Algorithm

Many rash illnesses can present with vesicles and pustules. It is unlikely, though possible, that a
patient with a rash illness will have smallpox. The algorithm, “Evaluating Patients for Smallpox:
Acute, Generalized Vesicular or Pustular Rash Illness Protocol” provides a standard method for
evaluating patients with acute, severe vesicular or pustular rash illness by giving clinical clues for
differentiating smallpox from varicella and other rash illnesses.

If you have a patient with an acute, generalized vesicular or pustular rash, evaluate them for
smallpox using the algorithm and the instructions below. The algorithm will give a risk assessment,
which will guide the appropriate medical and public health response. Contact your state/local public
health department for consultation. State/local public health departments should call CDC at 770-
488-7100 for consultation for high risk patients or otherwise complicated cases.

Infection Control Precautions

1. Move the patient to airborne infection isolation room (AIIR). If one is not available, use a private
room. Do not leave patient in common waiting areas.
2. Notify Infection Control Department (if in a healthcare facility).
3. Use appropriate standard, airborne, and contact precautions. Staff and visitors should wear
properly fitted N95 respirators, gloves, and gowns.
4. If it is necessary to move the patient, use a sheet to cover the patient’s rash and a N95
respirator or a surgical mask to cover the patient’s mouth and nose.
History and Physical Examination
Ask your patient detailed questions about:

• Any symptoms preceding rash onset, including prodromal symptoms and clinical features in the
1 to 4 days before rash onset
• Contact with any ill individuals (especially those with a rash illness)
• Recent travel history
• Contact with ill or exotic animals
• Medical history including medications
• History of prior varicella or herpes zoster
• History of varicella vaccination (vaccine available since 1995)

Determine Risk Category

Use the major and minor diagnostic criteria for smallpox to categorize the patient’s risk of
smallpox. If you have questions or need help determining the risk category for your patient,
call your local or state health department. CDC is also available for consultation at 770-488-
7100.

Major Diagnostic Criteria for Smallpox:

1. Febrile prodrome occurring 1 to 4 days before rash onset:

a. Fever ≥101°F (38.3°C) AND at least one of the following:
i. prostration
ii. headache
iii. backache
iv. chills
v. vomiting
vi. severe abdominal pain
2. Classic smallpox lesions: deep-seated, firm/hard, round, well-circumscribed vesicles or pustules.
As they evolve, lesions may become umbilicated or confluent.
3. Lesions in the same stage of development (e.g., all are vesicles or all are pustules) on any ONE
part of the body (e.g., the face, arms).
Minor Diagnostic Criteria for Smallpox:

1. Centrifugal distribution of rash: greatest concentration of lesions on face and distal extremities
2. First lesions on the oral mucosa/palate, face, or forearms
3. Severity: Patient appears toxic or moribund
4. Slow rash evolution: lesions evolved from macules to papules to pustules over days (each stage
lasts 1 to 2 days)
5. Lesions on the palms and/or soles

Risk Clinical and Public Health

Category Risk Criteria Response

High risk Meets all Obtain urgent Infectious

three major Disease and/or
smallpox Dermatology consultation.
criteria*
If after consultation
patient is still
considered to have a
high risk for smallpox:

1. Classify as a
probable smallpox
case and treat as a
medical and public
health emergency.
2. Contact CDC’s
Emergency
Operations Center at
770-488-7100 for
assistance,
including specimen
collection and
testing.
Risk Clinical and Public Health
Category Risk Criteria Response

3. Take digital photos

for consultation with
experts.
4. Treat patient as
clinically indicated.
Do not delay
treatment for other
likely conditions in
the differential
diagnosis while
awaiting response
team.
5. Do not proceed with
laboratory testing for
other diagnoses until
smallpox has been
ruled out.

Moderate Febrile Obtain urgent Infectious

risk prodrome Disease and/or
AND 1 other Dermatology consultation.
major
smallpox If after consultation
criterion patient is still
considered to have a
OR
moderate risk for
Febrile smallpox:
prodrome
AND ≥ 4 1. Perform laboratory
minor testing for
confirmation or
exclusion of varicella
 Risk Clinical and Public Health
Category Risk Criteria Response

smallpox or other diagnoses in

criteria the differential
diagnosis.
2. Initiate treatment for
likely etiology as
clinically indicated.

Low risk No febrile If diagnosis is uncertain,

prodrome test for varicella. Manage
as clinically indicated.
OR

febrile
prodrome
AND < 4
minor
smallpox
criteria

*Note: meets the smallpox clinical definition and would therefore be classified as a probable
smallpox case, pending laboratory test results.

Common Conditions That Might Be Confused with

Smallpox
Condition Clinical Clues

Varicella (primary • Most common in children

infection with
<10 years
varicella-zoster
virus) • Children usually do not
have a viral prodrome
Condition Clinical Clues

Disseminated • Immunocompromised or
herpes zoster
elderly persons
• Rash looks like varicella,
usually begins in
dermatomal distribution

Impetigo • Honey-colored crusted

(Streptococcus
plaques with bullae are
pyogenes,
Staphylococcus classic but may begin as
aureus) vesicles
• Regional, not
disseminated rash
• Patients generally not ill

Drug eruptions • Exposure to medications

• Rash often generalized

Contact dermatitis • Itching

• Contact with possible
allergens
• Rash often localized in a
pattern suggesting
external contact

Erythema • Target, “bull’s eye,” or iris

multiforme minor
lesion
• Often follows recurrent
herpes simplex virus
infections
Condition Clinical Clues

• May involve hands and

feet (including palms and
soles)

Erythema • Major form involves

multiforme major
mucous membranes and
(Stevens-Johnson
syndrome) conjunctivae
• There may be target
lesions or vesicles

Enteroviruses • Summer and fall

infection, especially
• Fever and mild
Hand, Foot, and
Mouth Disease pharyngitis 1 to 2 days
before rash onset
• Lesions initially
maculopapular but evolve
into whitish-grey, tender,
flat, and often oval
vesicles
• Peripheral distribution
(hands, feet, mouth, or
disseminated)

Disseminated • Lesions indistinguishable

herpes simplex
from varicella
• Immunocompromised
host

Scabies; insect bite • Itching is a major

(including fleas)
symptom
 Condition Clinical Clues

• Patient is not febrile and

is otherwise well

Molluscum • May disseminate in

contagiosum
immunosuppressed
persons
• Can occur anywhere on
the body
• Presents as small, raised,
and usually white, pink, or
flesh-colored lesions with
a dimple or pit in the
center

Monkeypox
Also consider monkeypox in the differential diagnosis. The main difference between monkeypox and
smallpox is that monkeypox causes swelling in the lymph nodes (lymphadenopathy) while smallpox
does not. Swelling of the lymph nodes may be generalized (involving many different locations on the
body) or localized to several areas (e.g., neck and armpit). Ask the patient questions about recent
contact with any exotic or ill animals, as well as travel history to countries in Central or West Africa,
where monkeypox is endemic.

Laboratory Confirmation
For patients with a high risk of having smallpox, the state health department will contact CDC to
conduct laboratory testing to confirm or rule out smallpox. In the absence of known smallpox
disease, the predictive value of a positive smallpox test diagnosis is low, so only cases that meet the
clinical definition of the disease should be tested.
Laboratory Case Definition
Laboratory diagnostic testing for variola virus will occur in a CDC Laboratory Response Network
(LRN)laboratory using LRN-approved PCR tests and protocols for variola virus. Initial positive results
require confirmatory testing at CDC.

The laboratory criteria for diagnosis are:

• Polymerase chain reaction (PCR) identification of variola DNA in a clinical specimen, OR

• Isolation of smallpox (variola) virus from a clinical specimen (WHO Smallpox Reference
Laboratory or laboratory with appropriate reference capabilities) with variola PCR confirmation.

Note: Generic orthopoxvirus PCR and negative stain electron microscopy (EM) identification of a
poxvirus in a clinical specimen are suggestive of an orthopoxvirus infection but not diagnostic for
smallpox.