How would smallpox be diagnosed?

What to expect at the doctor’s office

Due to the official eradication of the disease, it is not currently a likely possibility that a person will have contracted smallpox. Should there be an outbreak, now or in the foreseeable future, as a result of an uncontained laboratory accident, which is highly unlikely, or bioterrorism, medical attention is required as soon as possible and will be handled with utmost care and strict procedures.

If a person suspects a smallpox infection, a medical diagnosis is advisable as early as possible. A medical doctor is likely to conduct a quick medical review and recommend a physical examination.

A full medical history will need to cover the following areas:

• All noticeable symptoms and their timeline – e.g. What symptoms were noticeable before a rash developed?
• Possible virus exposure and risk factors – e.g. Was there any contact will an ill person in the days / weeks leading up to the development of symptoms? Has the patient been travelling recently? Where have they been to? Has there been any contact with an ill or exotic animal?
• Personal and family health history (including vaccination history and prior infections – such as herpes or chickenpox) and medication use (including supplements and herbal varieties).

Physical examination considerations

A doctor will take extra precaution when examining rash lesions on the skin (should they have developed by the time of consultation). If a smallpox rash is suspected (although highly unlikely), a doctor will determine the stage of formation the lesions are currently at, and thereby gauge how far along an infection is.

If lesions are in their initial stage of formation, the sores or bumps are not likely to disappear when pressure is placed on them. If at the raised papule stage, the characteristic dent / depression (which looks similar to that of a bellybutton) will likely indicate a smallpox infection to the examining medical doctor. Some of the papules / pustules will form in a confluent (or joining) pattern, measuring between 4 and 6 mm in diameter.

If a diagnosis is made in a person who has been vaccinated, it is expected that less of the viral pathogen will be present in the bloodstream (than would occur in an unvaccinated individual). Symptoms are also likely to be less severe with fewer smaller rash lesions present.

Smallpox lesions in a vaccinated individual may sometimes resemble those of chickenpox (varicella). A doctor will look at the distribution patterns in order to distinguish between the two infection types:

• A smallpox rash has a centrifugal distribution (more lesions or sores will be apparent on the face and limbs than on the trunk and remainder of the body)
• A chickenpox rash has a centripetal distribution (more lesions and sores will be apparent on the trunk than the limbs, hands and feet)

What will happen if smallpox is suspected?

Should a doctor suspect smallpox, he or she will act quickly to implement very specific procedures for the safety of the patient and anyone else in the vicinity or who may have been exposed to the virus.

1. Precautionary measures to get the possible infection under control include:

• Moving the patient to what is referred to as a AIIR (airborne infection isolation room). Should one not be available to a doctor, a private room (of any kind) will be quickly arranged for the patient (keeping him or her away from any other patients or individuals who may be at risk of contracting the virus).
• Notifying healthcare facilities (i.e. an infection control department at a hospital) of a potential outbreak / isolated case of smallpox.
• Taking precautions to minimise the risk of transmission when handling the patient, such as the use of gloves and gowns etc.

If a patient must be moved for any reason, a doctor will cover the rash affected skin of the patient with something clean and available (like a sheet) and also put on a surgical mask to cover his or her nose and mouth.

2. Assessing major versus minor VARV infections

A doctor will assess the patient to make a distinction between major and minor infections by looking at the size of lesions. Smaller and fewer rash sores are more characteristic of minor VARV infections than those of major infections. Other factors to consider will involve the following:

• Major VARV infection: A patient will have a high fever (38.8°C / 102°F) during the early symptom stages accompanied by at least one of the other early symptoms, such as a severe headache, backache and vomiting (which may be accompanied by abdominal pain). At the stage of lesion formation, sores will appear round, confluent, deep-seated and with or without the characteristic depression / dent. Lesions will typically be in the same formation stage throughout the body. A doctor will determine the presence of the major subtypes by assessing symptoms and rash characteristics.
• Minor VARV infection: The concentration of lesions will be highest around the facial and limb areas. Progression through formation stages (including the scabbing over and shedding process) may be slower. Lesions will also display on the palms of the hands and soles of the feet. A patient will appear very sickly.

3. Determining risk category

A doctor will make use of the following guidelines as per the recommendations of the CDC ⁽⁷⁾:

Risk category	Risk criteria	Recommended clinical course of action
High risk	All major VARV infection diagnostic criteria apply	Arrange an urgent consultation with an infectious disease specialist and dermatologist. If all specialists are in agreement regarding the high risk of smallpox infection, healthcare authorities will be notified of a possible isolated case or a potential outbreak. Photograph the skin lesions for further assessment and analysis by the medical doctors involved. Implement recommended treatment immediately (which involves antiviral therapies and supportive care) Conduct a differential diagnosis in order to rule out or diagnose other possible illnesses. Collect samples for laboratory testing specifically for smallpox. Testing for other potential illnesses can commence should smallpox be ruled out.
Moderate risk	Fever and at least one other major VARV symptoms are apparent	Arrange an immediate consultation with an infectious disease specialist and dermatologist. If all specialists are in agreement regarding a moderate risk of smallpox infection, samples will be taken to make a differential diagnosis – i.e. to diagnose or rule out other possible infections like chickenpox (varicella). Implement treatment (antiviral therapies and supportive care as needed).
Low risk	No fever or a low fever with minor VARV infection indications	A doctor will implement testing for chickenpox (to either diagnose or rule out) and manage any symptoms being experienced as appropriate.

Some conditions which may all present with rash symptoms that a doctor will wish to either diagnose or rule out include:

• Chickenpox (varicella-zoster virus)
• Herpes zoster (shingles)
• Herpes simplex virus (types 1 and 2 – oral or genital)
• Impetigo (Streptococcus pyogenes and Staphylococcus aureus bacteria)
• Contact dermatitis
• Erythema multiforme minor (this often occurs following recurring herpes simplex virus infections)
• Erythema multiforme major (Stevens-Johnson syndrome)
• Skin rash reactions as a result of medication exposure
• Infection with enteroviruses (such as Hand, foot and mouth disease)
• Molluscum contagiosum
• Scabies
• Reactions to medication use or insect bites / stings
• Monkeypox (a distinctive difference between this infection and smallpox is that monkeypox includes swelling of the lymph nodes)

Testing procedures to identify VARV for laboratory analysis are highly recommended for suspicious high-risk cases. A doctor will take a viral cotton swab of a patient’s pharynx (back of the mouth and opening to the throat) and from a lesion which has broken open (collecting a sample of papule / pustule contents). If the sores have not broken open, a doctor may need to carefully encourage rupture so as to collect a sample of the lesion’s contents. Samples can also be taken from the base of a scab formation. Samples collected will be placed in a sealed tube. The tube will then need to be placed in a watertight, durable container.

The medical professional taking the samples must be confirmed as immune or have been recently vaccinated (even if on the same day prior to taking the samples). Gloves and a surgical mask covering the mouth and nose must be worn while in contact with the infected patient.

The CDC (and local healthcare providers) will need to be notified regarding the taking of samples so that arrangements for their collection can be made (as per protocol). Thereafter a laboratory will be contacted for sample analysis.

Samples collected will be treated with particular precaution due to the nature of disease and how easily transmission can occur. They will be marked for analysis under biosafety level 4 (BSL4) conditions – the highest level of biological safety. Analysis under these conditions are considered rare but will be required in the case of a high-risk smallpox infection – this is because the virus causing the disease is regarded as highly dangerous and has the potential to cause life-threatening illness which does not have an official treatment regimen.

Laboratories with the capacity to analyse these types of viruses have strict containment requirements and are extremely isolated environments. So much so that the labs may be located either in a restricted zone of a building or as another free-standing structure of its own. These labs are equipped with their own air supply (to ensure sustained directional air flow – any exhaust air is not re-circulated) and decontamination systems.

Laboratory personnel working with the samples provided will be under strict medical surveillance and will be checked for immunity to the virus causing smallpox.

Samples will be examined for the virus causing smallpox using electron microscopy, Polymerase chain reaction (PCR assay) or immunohistochemical analysis. The virus causing smallpox may be cultured in order to stimulate proliferation for analysis. Analysis may be able to distinguish smallpox from cowpox, vaccinia and monkeypox pathogens.

To identify any neutralising antibodies (proteins produced by the immune system), serologic testing (blood tests) may be recommended and conducted. These blood tests are not likely to be used to differentiate between known Orthopoxvirus species.

From the fluid and scab samples, electron microscopy analysis can determine the presence of one of the orthopoxvirus species. The PCR assay process amplifies the DNA of the pathogen (including length differences) which can help to differentiate between the species. This testing procedure can also be useful in differentiating between suspected chickenpox or smallpox viruses.

Reference:

^{7. Centers for Disease Control and Prevention.  July 2017. Smallpox Diagnosis and Evaluation: https://www.cdc.gov/smallpox/clinicians/diagnosis-evaluation.html [Accessed 06.04.2018]}