Smallpox: Symptoms, Types, Causes and Treatment

Smallpox, once one of humanity’s most feared diseases, has left a deep mark on the history of medicine and society. Though eradicated in 1980, the disease—and its causative agent, the variola virus—remains a focus of scientific vigilance due to concerns about its potential re-emergence, whether by accident or as a bioterrorist threat. Understanding smallpox’s symptoms, types, causes, and treatment strategies is essential for preparedness, even decades after the last natural case.

Symptoms of Smallpox

Smallpox was notorious for its dramatic and distressing symptoms, which evolved in distinct stages. Early identification of its signs was critical for controlling outbreaks and differentiating it from other similar diseases, such as chickenpox. Although the world is now free from naturally occurring smallpox, recognizing its clinical presentation remains vital for surveillance and potential emergency response.

Stage	Key Features	Duration	Source(s)
Prodrome	Fever, chills, headache, severe muscle aches, vomiting, backache, prostration	2-4 days	1 3 5
Rash	Starts as macules, progresses to papules, then vesicles, pustules, and scabs	3-4 weeks	1 3 5
Scabbing	Pustules form scabs, which fall off leaving scars	Final 1-2 weeks	1 3 5
Complications	Blindness, secondary infections, scarring, rarely encephalitis	Variable	5

Table 1: Key Symptoms

The Evolution of Smallpox Symptoms

Early Symptoms (Prodrome Phase)

• Most patients developed flu-like symptoms: high fever, chills, severe headache, nausea, vomiting, and muscle aches.
• This phase lasted for about 2-4 days, and many felt extremely weak or prostrated, often remaining bedridden 1 3 5.

Rash and Lesion Development

• Around the fourth day, the fever dropped, and a rash appeared—first as flat spots (macules) mainly on the face, hands, and forearms.
• Over the next 1-2 days, these spots became raised (papules), then filled with clear fluid (vesicles), and later thickened with pus (pustules).
• Unlike chickenpox, all smallpox lesions were at the same stage on any given body area, and the rash was most dense on the face and extremities, including palms and soles—a distinguishing feature 1 3 5.

Scabbing and Recovery

• Pustules would harden and form scabs, which fell off about three to four weeks after onset, often leaving deep, pitted scars (pockmarks).
• The patient remained infectious until the last scab had separated 1 3 5.

Complications

• Up to a third of survivors suffered permanent blindness, usually due to corneal involvement.
• Scarring was common, affecting 65–80% of survivors.
• Secondary infections and, rarely, encephalitis could also occur 5.

Types of Smallpox

Smallpox was not a single clinical entity but manifested in several forms, ranging from mild to highly lethal. Understanding these variations is crucial for accurate diagnosis, prognosis, and historical epidemiology.

Type	Severity	Mortality Rate	Key Features	Source(s)
Variola major	Severe	~30%	Extensive rash, high fever, scarring	5 7
Variola minor	Mild	~1%	Milder rash, less severe	5 7
Malignant (Flat)	Very severe	95–100% (unvaccinated)	Lesions remain soft, flat, often confluent	1 5
Hemorrhagic	Extremely severe	~94% (unvaccinated)	Widespread bleeding under skin, mucosa	5
Modified	Mild (vaccinated)	Very low	Mild symptoms, fewer lesions	5

Table 2: Clinical Types of Smallpox

Clinical Presentations and Their Features

Variola Major

• The classic and most common form.
• Characterized by a high fever, prostration, and a dense, uniform rash that progresses through the typical stages.
• Mortality was about 30% in unvaccinated populations, and survivors were often left with disfiguring scars 5 7.

Variola Minor

• A less severe variant, also known as "alastrim."
• Mortality averaged around 1%, and the disease presented with milder symptoms and fewer lesions 5 7.

Malignant (Flat) Smallpox

• Very rare and almost always fatal.
• Lesions remained flat, soft, and did not form typical pustules; the skin could look like "crepe rubber."
• Patients often died within a week of rash onset 1 5.

Hemorrhagic Smallpox

• Also extremely rare and rapidly fatal.
• Marked by bleeding into the skin and mucous membranes, resulting in a darkened, sometimes "black" appearance of the lesions.
• Death often occurred before the characteristic rash fully developed 5.

Modified Smallpox

• Occurred in individuals with partial immunity, usually from prior vaccination.
• Symptoms were milder, with fewer lesions, and rarely resulted in death 5.

Causes of Smallpox

The cause of smallpox is rooted in a unique human-specific virus—the variola virus. Understanding its origins, transmission, and factors leading to outbreaks is essential, especially in the context of potential future threats.

Agent	Origin	Transmission	Reservoir	Source(s)
Variola virus	East Africa, ~3000-4000 years ago	Airborne droplets, direct contact, fomites	Humans only	5 6 7 8

Table 3: Causative Factors

The Variola Virus: A Strictly Human Pathogen

Virology and Evolution

• Smallpox is caused by the variola virus, a member of the Orthopoxvirus genus.
• Genomic analyses suggest it evolved from a cowpox-like ancestor 3,000–4,000 years ago in East Africa, possibly triggered by environmental changes and the introduction of camels 6 7 8.
• Unlike other poxviruses, variola infects only humans—there are no animal or insect reservoirs 5 6.

Modes of Transmission

• Person-to-person: Primarily through inhalation of airborne droplets from coughing, sneezing, or close face-to-face interaction.
• Contact: Direct contact with the skin lesions or bodily fluids of an infected person.
• Fomites: Touching contaminated items (clothing, bedding) can transmit the virus, as it remains viable for up to a week outside the body 5.
• Smallpox is not transmitted by animals or insects 5 6.

Contagiousness and Outbreak Dynamics

• Patients became most contagious with the onset of the rash, approximately 14–18 days after infection, and remained so until all scabs had fallen off 5.
• Variola major often left patients bedridden during the most contagious phase, somewhat limiting the spread.
• In contrast, the milder variola minor allowed patients to remain ambulatory, increasing the risk of wider transmission 5.

Historical and Modern Context

• Smallpox caused widespread pandemics and epidemics, decimating populations and altering the course of history (e.g., the collapse of Indigenous civilizations in the Americas after European contact) 5 7.
• Today, the only known stocks of variola virus are held in secure laboratories in the USA and Russia, but the potential for accidental or intentional release, especially as a bioweapon, remains a concern 5 7.

Treatment of Smallpox

Although there is no specific cure for smallpox, advances in supportive care and recent antiviral developments offer hope for future outbreak management. Prevention through vaccination was, and remains, the cornerstone of control.

Approach	Description	Efficacy	Source(s)
Supportive Care	Symptom management, hydration, infection control	Essential	5
Vaccination	Pre- and post-exposure with vaccinia-based vaccine	Preventive, reduces severity	5 2
Antivirals	Tecovirimat (TPOXX), brincidofovir, cidofovir derivatives	Promising, animal model evidence	9 10 11 12 13

Table 4: Treatment and Prevention Strategies

Supportive Care

• Mainstay of historical treatment: Included pain management, fluid support, and prevention/treatment of secondary bacterial infections.
• No specific antiviral therapy was available until the 21st century 5.

Vaccination

• Historical impact: The introduction of vaccination, beginning with Edward Jenner’s cowpox-based inoculation in 1798, revolutionized smallpox control and led to global eradication 5 7.
• Modern policy: Routine vaccination ended after eradication, but vaccine stocks are maintained for emergency use.
• Post-exposure utility: Vaccination within four days of exposure can prevent or significantly reduce disease severity 5.
• Adverse effects: Vaccination can cause side effects, more frequently in unvaccinated adults, including joint pain, muscle aches, and rare but serious complications 2.

Antiviral Therapies

Tecovirimat (TPOXX®, ST-246)

• Mechanism: Inhibits the function of a viral envelope protein required for virus spread.
• Approval: FDA-approved for smallpox treatment in 2018 based on animal studies and human safety trials 10 11.
• Efficacy: Achieved >90% survival in animal models; effective even when started up to 5 days after exposure 10 13.
• Safety: Well-tolerated in human trials with no concerning pattern of adverse events 10 11.

Brincidofovir and Cidofovir Derivatives

• Mechanism: Inhibit poxvirus DNA polymerase.
• Evidence: Shown to be effective against related viruses (monkeypox, cowpox) in animal models; promising for smallpox but not yet licensed specifically for this indication 9 12.
• Advantages: Orally bioavailable derivatives may be suitable for those who cannot receive the vaccine due to immune compromise 12.

Preparedness and Response

• Ring vaccination: The preferred strategy for outbreak control—vaccinating contacts of cases to contain spread 5.
• Stockpiles and surveillance: Many countries maintain vaccine and antiviral reserves, and robust disease surveillance infrastructure is crucial for rapid response 5 11.
• Current recommendations: Mass vaccination is not advised unless there is a credible threat due to potential vaccine-related side effects 5.

Conclusion

Smallpox, a disease that once shaped the destiny of civilizations, remains a topic of scientific and public health importance. Understanding its symptoms, types, causes, and the available treatments is crucial for preparedness in a world where accidental or deliberate reintroduction is a remote but real possibility.

Key Takeaways:

• Symptoms progress from a severe prodrome to a characteristic rash and scarring, often with significant complications 1 3 5.
• Types include variola major, variola minor, malignant, hemorrhagic, and modified forms, each with distinct severity and features 1 5 7.
• Causes are rooted in the human-specific variola virus, transmitted mainly by airborne droplets and direct contact, with no animal reservoirs 5 6 7.
• Treatment is primarily supportive, but new antivirals (tecovirimat, brincidofovir) and the strategic use of vaccination offer hope for outbreak control and individual care 5 9 10 11 12 13.

By maintaining vigilance, robust public health systems, and ongoing research, humanity stands prepared to face any future challenge posed by smallpox.