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
- 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.
- Notify Infection Control Department (if in a healthcare facility).
- Use appropriate standard, airborne, and contact precautions. Staff and visitors should wear properly fitted N95 respirators, gloves, and gowns.
- 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:
- Febrile prodrome occurring 1 to 4 days before rash onset:
- Fever ≥101°F (38.3°C) AND at least one of the following:
- severe abdominal pain
- Fever ≥101°F (38.3°C) AND at least one of the following:
- Classic smallpox lesions: deep-seated, firm/hard, round, well-circumscribed vesicles or pustules. As they evolve, lesions may become umbilicated or confluent.
- 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:
- Centrifugal distribution of rash: greatest concentration of lesions on face and distal extremities
- First lesions on the oral mucosa/palate, face, or forearms
- Severity: Patient appears toxic or moribund
- Slow rash evolution: lesions evolved from macules to papules to pustules over days (each stage lasts 1 to 2 days)
- Lesions on the palms and/or soles
|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:
|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:
|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.
|Varicella (primary infection with varicella-zoster virus)||
|Disseminated herpes zoster||
|Impetigo (Streptococcus pyogenes, Staphylococcus aureus)||
|Erythema multiforme minor||
|Erythema multiforme major (Stevens-Johnson syndrome)||
|Enteroviruses infection, especially Hand, Foot, and Mouth Disease||
|Disseminated herpes simplex||
|Scabies; insect bite (including fleas)||
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.
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.
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.