Orthopoxvirus: Symptoms, Types, Causes and Treatment

Orthopoxviruses have shaped human history, from the devastation of smallpox to the recent re-emergence of mpox (monkeypox). These viruses, known for their large DNA genomes and distinctive skin lesions, continue to pose public health challenges due to their zoonotic nature and potential for outbreaks. In this article, we explore orthopoxvirus infections in depth, covering their symptoms, the main types affecting humans, causes and transmission routes, and the latest approaches to treatment.

Symptoms of Orthopoxvirus

Orthopoxvirus infections can cause a wide range of symptoms, from mild skin lesions to severe systemic disease. Recognizing these symptoms is crucial for early diagnosis and containment of outbreaks, especially as some forms can mimic other viral illnesses.

Symptom	Description	Example Virus	Source(s)
Skin Lesions	Vesicular, pustular, or umbilicated rashes	Smallpox, Mpox	1, 3, 7
Fever	Sudden onset, often precedes rash	Smallpox, Mpox	1, 3, 4, 7
Lymphadenopathy	Swollen lymph nodes, more common in mpox	Mpox	4, 7
Fatigue/Asthenia	Generalized weakness and tiredness	Mpox	1
Headache	Common early symptom	Smallpox, Mpox	3, 4, 7
GI Symptoms	Nausea, vomiting, diarrhea, proctitis	Mpox	2
Ocular Manifestations	Conjunctivitis, keratitis, photophobia	Mpox	4
Myalgia	Muscle pain	Smallpox, Mpox	3, 7

Table 1: Key Symptoms of Orthopoxvirus Infection

Skin Manifestations

Skin lesions are the hallmark of orthopoxvirus infections. They typically present as:

• Vesicular or pustular rashes: These start as flat red spots (macules), progress to raised bumps (papules), become fluid-filled (vesicles), and then pus-filled (pustules). In mpox, lesions are often umbilicated (depressed in the center) and may cluster in genital or perianal areas, particularly linked to sexual contact 1, 3, 7.
• Distribution: In smallpox, the rash appears in a centrifugal pattern—dense on the face and extremities. Mpox lesions can be more localized, especially in recent outbreaks 1, 7.

Systemic and Early Symptoms

• Fever is a classic early sign, often accompanied by headache and myalgia (muscle pains). In mpox, fatigue (asthenia) is also frequently reported 1, 3.
• Lymphadenopathy: Swollen lymph nodes are a distinguishing feature of mpox, not typically seen in smallpox 4, 7.
• Gastrointestinal (GI) symptoms: These are increasingly recognized, especially in mpox. Patients may experience nausea, vomiting, diarrhea, proctitis (inflammation of the rectum), and abdominal pain. These symptoms can be severe, particularly when the virus is transmitted through sexual contact involving the anal area 2.

Ocular and Rare Manifestations

Mpox and other orthopoxvirus infections can also cause eye problems, including conjunctivitis (red eyes), keratitis (corneal inflammation), and photophobia (light sensitivity). These are more likely in unvaccinated individuals and can sometimes lead to complications affecting vision 4.

Disease Course and Severity

• Self-limited in most cases: Many orthopoxvirus infections, especially mpox, resolve without severe complications, but can cause considerable discomfort 1.
• Severe outcomes: Smallpox was historically fatal in up to 30% of cases, while mpox mortality is usually lower, but can be higher in vulnerable groups such as children, pregnant women, and the immunocompromised 7.

Types of Orthopoxvirus

The orthopoxvirus genus includes several notable species, four of which commonly infect humans. Understanding the differences between them is essential for diagnosis, prevention, and treatment.

Virus Type	Main Hosts/Reservoirs	Typical Human Disease	Source(s)
Variola	Humans	Smallpox	7, 8, 10
Monkeypox	Rodents, primates, humans	Mpox (Monkeypox)	3, 7, 11
Vaccinia	Cattle, buffalo, humans (rare)	Vaccine complications, rare	7
Cowpox	Rodents, cattle, cats, humans	Localized pustular lesions	7

Table 2: Major Orthopoxvirus Types Affecting Humans

Variola Virus (Smallpox)

• Historical significance: Variola virus caused smallpox, a devastating disease eradicated in 1980 through global vaccination 7, 10.
• Human-only pathogen: Unlike other orthopoxviruses, variola infects only humans 7.
• Symptoms: High fever, characteristic rash, and high mortality (up to 30%) 7, 10.

Monkeypox Virus (Mpox)

• Zoonotic origins: Natural reservoirs are thought to be African rodents and primates 3, 7, 11.
• Two clades: Central African (Congo Basin) and West African, with the former historically more severe 3.
• Outbreaks: Increasing in frequency, with notable recent global outbreaks since 2022 3, 6, 11.
• Symptoms: Similar to smallpox but includes lymphadenopathy; typically less lethal 1, 3, 4, 7.

Vaccinia Virus

• Used in vaccines: The live virus used to eradicate smallpox 7.
• Human infections: Mostly related to vaccination; can cause self-limited lesions but may lead to severe complications in immunocompromised individuals 7.

Cowpox Virus

• Zoonotic transmission: Often from rodents, cattle, or domestic cats 7.
• Symptoms: Usually mild, causing localized skin lesions, but can be severe in immunosuppressed people 7.

Other Orthopoxviruses

• Camelpox, Ectromelia (mousepox), and others: Mostly infect animals but can provide models for studying orthopoxvirus infections 6, 10.

Causes of Orthopoxvirus

Understanding how orthopoxviruses spread and what puts individuals at risk is vital for controlling outbreaks and protecting vulnerable populations.

Cause/Route	Description	Notable Viruses	Source(s)
Zoonotic Spillover	Transmission from animals (rodents, primates)	Mpox, Cowpox	3, 6, 7
Human-to-Human	Direct contact, respiratory droplets, fomites	Smallpox, Mpox	1, 3, 7
Vaccination-related	Vaccinia virus exposure via vaccine lesions	Vaccinia	7, 13
Bioterrorism/Labs	Potential release/weaponization of variola/others	Smallpox	8, 10, 15

Table 3: Main Causes and Transmission Routes

Animal Reservoirs and Zoonotic Transmission

• Mpox and cowpox: Frequently originate from wild rodents, with occasional spillover to humans through bites, scratches, or contact with animal fluids 3, 6, 7.
• Reservoir uncertainty: While some hosts are well established (e.g., rodents for mpox), others are less clear, complicating control efforts 5.
• Pet and exotic animal trade: International movement of animals has enabled outbreaks in non-endemic areas, such as the 2003 U.S. mpox outbreak 3.

Human-to-Human Transmission

• Smallpox: Spread efficiently via respiratory droplets, close contact, and contaminated objects (fomites) 7, 10.
• Mpox: Can spread through direct contact with lesions, body fluids, respiratory droplets, and contaminated materials. Recent outbreaks have highlighted sexual transmission, especially among men who have sex with men (MSM) 1, 2, 3.
• Risk factors: Non-vaccinated individuals, close contacts, healthcare workers, and immunocompromised persons are at higher risk 4, 8.

Vaccination-Related and Laboratory Exposure

• Vaccinia virus: Most human cases are related to the smallpox vaccine, either through direct inoculation or accidental spread from vaccine sites 7.
• Laboratory/bioterror risk: Following smallpox eradication, concern remains around accidental or intentional release of variola or engineered orthopoxviruses 8, 10, 15.

Genetic Factors and Viral Evolution

• Genomic plasticity: Orthopoxviruses can undergo genetic recombination and mutations, potentially increasing virulence or host range 9.
• Loss of immunity: The cessation of routine smallpox vaccination has led to a growing population susceptible to orthopoxvirus infections, contributing to mpox re-emergence 3, 7.

Treatment of Orthopoxvirus

While prevention through vaccination remains key, treatment options for orthopoxvirus infections are evolving, especially with renewed attention following recent outbreaks and bioterrorism concerns.

Treatment	Mechanism/Use	Indications	Source(s)
Vaccinia Immune Globulin (VIG)	Passive antibody therapy	Severe vaccinia, complications	7, 13
Tecovirimat (ST-246)	Inhibits viral envelope formation	Smallpox, mpox (under EUA)	14, 15, 17
Cidofovir/Brincidofovir	Inhibit viral DNA polymerase	Severe orthopoxvirus infections	17
Novel Antivirals	Adamantane-monoterpene conjugates, etc.	Experimental	16
Supportive Care	Symptom management, wound care	All orthopoxvirus diseases	1, 7
Vaccination	Prevention, post-exposure prophylaxis	At-risk or exposed individuals	7, 8, 11

Table 4: Current and Emerging Treatments

Antiviral Drugs

Tecovirimat (TPOXX®, ST-246)

• Mechanism: Blocks the formation of the viral envelope, preventing virus spread within the body 14, 15.
• Efficacy: Proven effective in animal models for smallpox and mpox; now approved for smallpox and used under emergency authorization for mpox 14, 15, 17.
• Timing: Most effective when administered early, but still beneficial even after symptom onset 14.

Cidofovir and Brincidofovir

• Mechanism: Inhibit viral DNA synthesis 17.
• Use: Reserved for severe or complicated cases due to potential toxicity; not licensed specifically for orthopoxvirus infections but can be considered in life-threatening situations 17.

Vaccinia Immune Globulin (VIG)

• Source: Antibodies collected from vaccinated individuals 7, 13.
• Use: Used primarily for severe complications of vaccinia vaccination and may have a role in treating other orthopoxvirus infections 7, 13.

Experimental and Emerging Therapies

• New compounds: Research is ongoing into novel antiviral agents with activity against a range of orthopoxviruses, such as adamantane-monoterpene conjugates, which have shown promise in laboratory studies 16.

Supportive Care

• Symptomatic management: Includes hydration, fever control, wound care, and treatment of secondary bacterial infections 1, 7.
• Hospitalization: May be required for severe cases, especially in children, pregnant women, or immunocompromised patients 1, 7.

Vaccination

• Preventive strategy: Smallpox vaccine offers cross-protection against mpox and other orthopoxviruses 3, 7, 11.
• Post-exposure prophylaxis: Can be effective when administered within a few days of exposure 7.
• Target groups: Healthcare workers, laboratory personnel, and at-risk populations during outbreaks 4, 8, 11.

Conclusion

Orthopoxviruses remain a dynamic and evolving threat, despite the eradication of smallpox. Their ability to cross species barriers, adapt genetically, and cause outbreaks in a world with waning immunity underscores the importance of ongoing vigilance.

Key Takeaways:

• Symptoms: Range from characteristic skin lesions to severe systemic disease, with mpox often including lymphadenopathy and GI symptoms.
• Types: Four main species infect humans—variola, monkeypox, vaccinia, and cowpox.
• Causes: Zoonotic transmission, human-to-human spread, and possible laboratory or bioterror risks are all important; loss of herd immunity is a major factor in recent outbreaks.
• Treatment: Includes supportive care, antivirals like tecovirimat and cidofovir, immune globulin for severe cases, and, most importantly, vaccination for prevention and outbreak control.

A coordinated approach involving surveillance, rapid diagnosis, vaccination, and research into new therapeutics is essential to prevent future outbreaks and mitigate the impact of these remarkable viruses.