Diagnosis & Evaluation

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:
    1. Fever ≥101°F (38.3°C) AND at least one of the following:
      1. prostration
      2. headache
      3. backache
      4. chills
      5. vomiting
      6. 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 and Clinical and Public Health Response

Risk Category Risk Criteria Clinical and Public Health Response
High risk Meets all three major smallpox criteria* Obtain urgent Infectious Disease and/or Dermatology consultation.

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.
  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 risk Febrile prodrome AND 1 other major smallpox criterion


Febrile prodrome AND ≥ 4 minor smallpox criteria

Obtain urgent Infectious Disease and/or Dermatology consultation.

If after consultation patient is still considered to have a moderate risk for smallpox:

  1. Perform laboratory testing for confirmation or exclusion of varicella or other diagnoses in the differential diagnosis.
  2. Initiate treatment for likely etiology as clinically indicated.
Low risk No febrile prodrome


febrile prodrome AND < 4 minor smallpox criteria

If diagnosis is uncertain, test for varicella. Manage as clinically indicated.

*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 infection with varicella-zoster virus)
  • Most common in children <10 years
  • Children usually do not have a viral prodrome
Disseminated herpes zoster
  • Immunocompromised or elderly persons
  • Rash looks like varicella, usually begins in dermatomal distribution
Impetigo (Streptococcus pyogenes, Staphylococcus aureus)
  • Honey-colored crusted plaques with bullae are classic but may begin as 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 multiforme minor
  • Target, “bull’s eye,” or iris lesion
  • Often follows recurrent herpes simplex virus infections
  • May involve hands and feet (including palms and soles)
Erythema multiforme major (Stevens-Johnson syndrome)
  • Major form involves mucous membranes and conjunctivae
  • There may be target lesions or vesicles
Enteroviruses infection, especially Hand, Foot, and Mouth Disease
  • Summer and fall
  • Fever and mild 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 herpes simplex
  • Lesions indistinguishable from varicella
  • Immunocompromised host
Scabies; insect bite (including fleas)
  • Itching is a major symptom
  • Patient is not febrile and is otherwise well
Molluscum contagiosum
  • May disseminate in 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


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.

Preparation & Collection of Specimens

If consultation with CDC determines that laboratory testing is warranted, follow the instructions to prepare, collect, and ship the specimens to CDC. Do not ship specimens for diagnosis of smallpox without consulting CDC.