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Smallpox

Disease Details

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Description: Smallpox is a contagious and often deadly viral disease characterized by fever, body aches, and a distinctive progressive skin rash.
Type: Smallpox is an infectious disease caused by the variola virus. It is not genetically transmitted; rather, it is spread from person to person through respiratory droplets or direct contact with contaminated bodily fluids or objects.
Signs And Symptoms: The initial symptoms were similar to other viral diseases that are still extant, such as influenza and the common cold: fever of at least 38.3 °C (101 °F), muscle pain, malaise, headache and fatigue. As the digestive tract was commonly involved, nausea, vomiting, and backache often occurred. The early prodromal stage usually lasted 2–4 days. By days 12–15, the first visible lesions – small reddish spots called enanthem – appeared on mucous membranes of the mouth, tongue, palate, and throat, and the temperature fell to near-normal. These lesions rapidly enlarged and ruptured, releasing large amounts of virus into the saliva.Variola virus tended to attack skin cells, causing the characteristic pimples, or macules, associated with the disease. A rash developed on the skin 24 to 48 hours after lesions on the mucous membranes appeared. Typically the macules first appeared on the forehead, then rapidly spread to the whole face, proximal portions of extremities, the trunk, and lastly to distal portions of extremities. The process took no more than 24 to 36 hours, after which no new lesions appeared. At this point, variola major disease could take several very different courses, which resulted in four types of smallpox disease based on the Rao classification: ordinary, modified, malignant (or flat), and hemorrhagic smallpox. Historically, ordinary smallpox had an overall fatality rate of about 30%, and the malignant and hemorrhagic forms were usually fatal. The modified form was almost never fatal. In early hemorrhagic cases, hemorrhages occurred before any skin lesions developed. The incubation period between contraction and the first obvious symptoms of the disease was 7–14 days.
Prognosis: The mortality rate from variola minor is approximately 1%, while the mortality rate from variola major is approximately 30%.Ordinary type-confluent is fatal about 50–75% of the time, ordinary-type semi-confluent about 25–50% of the time, in cases where the rash is discrete the case-fatality rate is less than 10%. The overall fatality rate for children younger than 1 year of age is 40–50%. Hemorrhagic and flat types have the highest fatality rates. The fatality rate for flat or late hemorrhagic type smallpox is 90% or greater and nearly 100% is observed in cases of early hemorrhagic smallpox. The case-fatality rate for variola minor is 1% or less. There is no evidence of chronic or recurrent infection with variola virus. In cases of flat smallpox in vaccinated people, the condition was extremely rare but less lethal, with one case series showing a 66.7% death rate.In fatal cases of ordinary smallpox, death usually occurs between days 10-16 of the illness. The cause of death from smallpox is not clear, but the infection is now known to involve multiple organs. Circulating immune complexes, overwhelming viremia, or an uncontrolled immune response may be contributing factors. In early hemorrhagic smallpox, death occurs suddenly about six days after the fever develops. The cause of death in early hemorrhagic cases is commonly due to heart failure and pulmonary edema. In late hemorrhagic cases, high and sustained viremia, severe platelet loss and poor immune response were often cited as causes of death. In flat smallpox modes of death are similar to those in burns, with loss of fluid, protein and electrolytes, and fulminating sepsis.
Onset: Smallpox has an incubation period of approximately 7 to 19 days after exposure, with an average of around 10 to 14 days. During this time, individuals might not show any symptoms. Once symptoms begin, they typically include fever, malaise, and body aches, followed by a characteristic rash that progresses from macules to papules and then to pustules.
Prevalence: Smallpox has been eradicated. The World Health Organization (WHO) declared smallpox eradicated in 1980 following a successful global vaccination campaign. As a result, there are no new naturally occurring cases of the disease.
Epidemiology: Epidemiology refers to the study of the distribution and determinants of health-related states or events in specified populations. In the context of smallpox, here are some key points:

- **Causative Agent**: Smallpox is caused by the variola virus, which has two main forms: variola major and variola minor. Variola major is more severe and has a higher mortality rate.

- **Transmission**: The virus primarily spreads through respiratory droplets, but it can also be transmitted via contaminated clothing and bedding.

- **Incubation Period**: Typically 7 to 17 days after exposure, individuals develop symptoms.

- **Symptoms**: Initial symptoms include high fever, fatigue, and severe head and body aches, followed by a characteristic rash that progresses from macules to papules, vesicles, pustules, and finally, scabs.

- **Epidemiological History**:
- **Pre-Eradication**: Smallpox had a global distribution, causing periodic epidemics and significant mortality and morbidity. It was a leading cause of death in many parts of the world.
- **Eradication Effort**: A global vaccination campaign led by the World Health Organization (WHO) resulted in the last naturally occurring case being reported in Somalia in 1977. The disease was declared eradicated in 1980.

- **Post-Eradication**: Since eradication, routine vaccination has ceased. However, the virus is kept under strict security in two laboratories, one in the United States and one in Russia, for research purposes.

- **Preparedness and Bioterrorism Concerns**: Due to its potential use as a bioterrorism agent, there are continued efforts for surveillance and maintaining vaccine stockpiles for emergency use.

Understanding and monitoring smallpox through epidemiology helped public health officials implement and achieve successful eradication campaigns.
Intractability: Smallpox is not considered intractable. It was declared eradicated in 1980 following a successful global vaccination campaign led by the World Health Organization. The disease is highly contagious and was once a serious threat, but the smallpox vaccine proved highly effective in controlling and eventually eliminating the virus.
Disease Severity: Smallpox was a severe and highly contagious disease caused by the variola virus. It had a high mortality rate, with approximately 30% of those infected succumbing to the disease. Survivors often suffered significant and permanent scarring, and sometimes blindness. However, the disease has been eradicated since 1980 following a successful global vaccination campaign.
Healthcare Professionals: Disease Ontology ID - DOID:8736
Pathophysiology: Pathophysiology of smallpox:

Smallpox is caused by the variola virus, which belongs to the Orthopoxvirus genus. The virus is transmitted through respiratory droplets, direct contact with infected bodily fluids, or contaminated objects. Once inside the body, the virus initially infects the respiratory tract and regional lymph nodes. It then undergoes primary viremia, spreading to internal organs, especially the spleen, bone marrow, and liver, where it replicates extensively.

Secondary viremia follows, leading to the characteristic widespread rash. The virus invades small blood vessels in the skin and mucous membranes, causing cells to lyse and die, which results in the classic pustular lesions. The intense immune response, along with direct viral cytopathic effects, contributes to the extensive tissue damage and systemic symptoms observed in smallpox patients.
Carrier Status: Smallpox does not have a carrier status. The disease is not known to be carried asymptomatically by humans. It has no natural animal reservoir, and the virus cannot survive outside a host for long periods. Transmission occurs through direct contact with an infected person or contaminated materials.
Mechanism: Once inhaled, the variola virus invaded the mucus membranes of the mouth, throat, and respiratory tract. From there, it migrated to regional lymph nodes and began to multiply. In the initial growth phase, the virus seemed to move from cell to cell, but by around the 12th day, widespread lysis of infected cells occurred and the virus could be found in the bloodstream in large numbers, a condition known as viremia. This resulted in the second wave of multiplication in the spleen, bone marrow, and lymph nodes.
Treatment: Smallpox vaccination within three days of exposure will prevent or significantly lessen the severity of smallpox symptoms in the vast majority of people. Vaccination four to seven days after exposure can offer some protection from disease or may modify the severity of the disease. Other than vaccination, treatment of smallpox is primarily supportive, such as wound care and infection control, fluid therapy, and possible ventilator assistance. Flat and hemorrhagic types of smallpox are treated with the same therapies used to treat shock, such as fluid resuscitation. People with semi-confluent and confluent types of smallpox may have therapeutic issues similar to patients with extensive skin burns.In July 2018, the Food and Drug Administration approved tecovirimat, the first drug approved for treatment of smallpox. Antiviral treatments have improved since the last large smallpox epidemics, and studies suggest that the antiviral drug cidofovir might be useful as a therapeutic agent. The drug must be administered intravenously, and may cause serious kidney toxicity.ACAM2000 is a smallpox vaccine developed by Acambis. It was approved for use in the United States by the U.S. FDA on August 31, 2007. It contains live vaccinia virus, cloned from the same strain used in an earlier vaccine, Dryvax. While the Dryvax virus was cultured in the skin of calves and freeze-dried, ACAM2000s virus is cultured in kidney epithelial cells (Vero cells) from an African green monkey. Efficacy and adverse reaction incidence are similar to Dryvax. The vaccine is not routinely available to the US public; it is, however, used in the military and maintained in the Strategic National Stockpile.In June 2021, brincidofovir was approved for medical use in the United States for the treatment of human smallpox disease caused by variola virus.
Compassionate Use Treatment: Smallpox, caused by the variola virus, has been eradicated since 1980 due to a global vaccination campaign. However, in the context of bioterrorism or accidental release, specific treatments and off-label or experimental options may be considered.

1. **Compassionate Use Treatment**: In the case of a smallpox outbreak, treatments might be provided under compassionate use when standard options are not available or are deemed insufficient. This includes antiviral drugs, primarily researched and repurposed due to limited availability.

2. **Off-label or Experimental Treatments**:
- **Tecovirimat (TPOXX)**: An antiviral approved by the FDA specifically for the treatment of smallpox. It can be used off-label in situations involving other orthopoxvirus infections.
- **Cidofovir**: An antiviral initially developed for cytomegalovirus infections, it may be used off-label for smallpox due to its broad-spectrum antiviral activity against orthopoxviruses.
- **Brincidofovir**: Another antiviral similar to cidofovir, with enhanced safety and usability, showing promise in experimental settings for smallpox.
- **Vaccinia Immune Globulin Intravenous (VIGIV)**: An antibody treatment derived from the blood of individuals vaccinated against smallpox. It’s used primarily for complications arising from the smallpox vaccine but could be considered experimentally for actual smallpox cases.

These treatments are generally reserved for emergencies due to smallpox’s eradication and the absence of naturally occurring cases.
Lifestyle Recommendations: Smallpox is an infectious disease caused by the variola virus. There is no specific "lifestyle recommendation" for smallpox because the disease was declared eradicated in 1980 due to a successful global vaccination campaign. However, general preventive measures for contagious diseases that were relevant for smallpox include:

1. **Vaccination**: Before its eradication, vaccination was the primary means of preventing smallpox.
2. **Isolation and Quarantine**: In the event of an outbreak, isolating infected individuals and implementing quarantine measures for exposed persons were critical to preventing the spread.

Since smallpox has been eradicated, the current focus is on ensuring that laboratory stocks of the virus are secure and that populations are informed and prepared in the event of an accidental or deliberate release. Regular immunization practices for other diseases and maintaining good hygiene standards are essential for general health and prevention of infectious diseases.
Medication: Smallpox has no specific medication. Treatment primarily involves supportive care to relieve symptoms, and preventive measures include vaccination with the vaccinia virus.
Repurposable Drugs: Smallpox, caused by the variola virus, has been eradicated since 1980. However, in the context of bioterrorism or research on similar viruses, the following repurposable drugs might be considered based on their antiviral properties:

1. **Tecovirimat (TPOXX or ST-246)**: Approved specifically for treatment of smallpox. It inhibits a protein essential for viral release from infected cells.
2. **Cidofovir**: Primarily used for cytomegalovirus infections but has shown efficacy against poxviruses in vitro.
3. **Brincidofovir**: A derivative of Cidofovir, designed to have an improved safety profile for long-term use.

There isn't significant information on direct nano-based therapeutic agents for smallpox treatment as of now. However, nanomedicine is an emerging field and may provide future innovative treatment options through nanoparticle delivery systems enhancing the efficacy of antiviral drugs.
Metabolites: Smallpox is a serious infectious disease caused by the variola virus. The primary metabolites involved in the progression of smallpox are not specific, as the disease primarily affects the immune system and skin cells. During infection, the body's metabolism may show alterations typical of viral infections, including changes in amino acids, lipids, and carbohydrate metabolism, as well as biomarkers related to inflammatory and immune responses. Detailed metabolic pathways specifically associated with smallpox could include disruptions in energy production, lipid metabolism, and nucleic acid synthesis. However, these metabolites are not unique to smallpox and may overlap with other viral infections.
Nutraceuticals: Nutraceuticals typically refer to food-derived products that offer health and medical benefits. There are no nutraceuticals that have been proven to treat or prevent smallpox. Smallpox is a viral disease eradicated by vaccination, and prevention or treatment strategies must focus on antiviral drugs and vaccines. Nutraaceuticals are not a substitute for these scientifically backed methods.
Peptides: Smallpox is caused by the Variola virus. Peptides are short chains of amino acids and can be involved in various functions within the immune response context. Smallpox vaccines, like the vaccinia virus vaccine, elicit an immune response where specific peptides play critical roles as antigens, helping the body recognize and fight the infection.

Nanotechnology (nan) has potential applications in smallpox treatment and prevention, such as developing advanced vaccine delivery systems that use nanoparticles to enhance the immune response or create more stable vaccine formulations. Research in this area continues to evolve, aiming to improve efficacy and safety.