Smallpox

1. Background Smallpox is an acute, contagious disease caused by the variola virus, a member of the genus Orthopoxvirus, in the Poxviridae family (see the image below). Virologists have speculated that it evolved from an African rodent poxvirus 10 millennia ago. Because of the absence of an animal vector, communities had to reach a critical population (estimated at 200,000 around 3000 BCE) before endemic smallpox could be established. The name is derived from the Latin word for "spotted" and refers to the raised bumps on the face and body of the patient. (See Etiology.)

Smallpox virion. Courtesy of US Centers for Disease Control and Prevention.

Poxviridae are linear, double-stranded deoxyribonucleic acid (DNA) viruses that replicate in the cytoplasm. Poxviridae consists of 2 subfamilies: Chordopoxvirinae, which infects vertebrates, and Entomopoxvirinae, which infects insects. Vaccinia virus, monkeypox virus, cowpox virus, and camelpox virus [1, 2] are other members of Orthopoxvirus that infect humans. (See Etiology.) Cowpox virus "scarification" by Jenner, used to induce protective immunity against smallpox, is not a single species but a group of up to 5 virus species that infects cows, humans, and other animals. [3]The history of smallpox is remarkable not only because of the spectacular devastation it wreaked upon civilization since the dawn of humankind, but also for the astounding achievement of modern medicine, which eradicated this plague through the concerted efforts of global vaccination (see the image below). (See Treatment and Medication.)

Adult with variola major with hundreds of pustular lesions centrifugally distributed. Photo from Fitzsimmons Army Medical Center slide file.

The earliest evidence of smallpox comes from ancient Egypt circa 1157 BCE, where the mummified remains of a pockmarked Ramses V were uncovered. International traders spread smallpox throughout the Old World during the 4th-15th centuries CE, while European explorers and conquerors brought the disease to the Western Hemisphere in the early 16th century.Smallpox directly and profoundly influenced the course of human history. Its tremendous morbidity and mortality led to indiscriminate killing of kings and warlords and tipped the balance of power with regularity in Europe and elsewhere. As a result of smallpox infection, whole civilizations, including the Incas and the Aztecs, were destroyed in a single generation, and efforts to ward off the disease indelibly affected the practice of religion and medicine.Characteristics of variola virus The variola virus is a large, brick-shaped, double-stranded DNA virus that serologically cross-reacts with other members of the poxvirus family, including ectromelia, cowpox, monkeypox, vaccinia, and camelpox. Unlike other DNA viruses, the variola virus multiplies in the cytoplasm of parasitized host cells.Smallpox only naturally infects humans and does not exist in a carrier state. Experimentally infected cynomolgus macaques (Macaca fascicularis) develop ordinary or hemorrhagic smallpox depending on the size of the inoculum. [4] The virus can survive in the environment for a short period, and it is most stable at low temperatures and low humidity. Variola is spread most efficiently by means of inhalation and less efficiently by means of direct contact with scabs or pustular material from skin lesions. (See the images below.) Swinepox (Suipoxvirus genus of the related Poxviridae family) may be spread by pig lice in addition to direct contact. [5]

Characteristic skin lesion of variola viral infection on the arms and the legs of an adolescent. Photo used with the permission of the World Health Organization (WHO).

Small child with pustular lesions due to variola viral infection. Photo used with the permission of the World Health Organization (WHO).

Infant with advanced lesions due to variola viral infection. Photo used with the permission of the World Health Organization (WHO). Types of smallpox The 2 predominant variants of variola, major and minor, differ greatly in their mortality rates (30% vs 1%, respectively). Variola major was the predominant endemic strain throughout the world, and by the end of the 18th century, it was responsible for approximately 400,000 deaths a year in Europe. In patients who recovered from the disease, blindness was common, and disfiguring scars were nearly universal. During the first half of the 20th century, all outbreaks of smallpox in Asia and most in Africa were due to variola major. Variola minor was endemic in some countries in Europe, North America, South America, and many parts of Africa. Variola major smallpox has 4 subtypes, as follows: Ordinary smallpox - The most common form, which accounts for 90% or more of smallpox cases Modified smallpox - A mild form that develops in previously vaccinated persons Flat smallpox (malignant smallpox) - A severe variety of smallpox in which lesions do not project above the skin surface Hemorrhagic smallpox (fulminant smallpox) - A rare, very severe, highly fatal variety of smallpox in which hemorrhages develop in the skin and mucous membranes Variola minor is less common and much less virulent; it was previously found mainly in South Africa, South America, Europe, and Australia. Other types of smallpox include the following: Variola sine eruptione (variola sine exanthemata) - Another less common form of smallpox Pulmonary form of smallpox - Characterized by severe symptoms, cyanosis, and bilateral infiltrates; has been described in individuals with little or no smallpox immunity; the mortality rate of this type is undetermined Pharyngeal form of smallpox - Develops in immunized individuals; this form presents with a spotty enanthem over the soft palate, uvula, and pharynx Influenzalike form of smallpox - Rarely results in a rash The pharyngeal and influenzalike forms are relatively mild, usually affect individuals who have been previously immunized, and do not cause mortality. Immunity Cellular immunity and humoral immunity are elicited in response to variola infection. Neutralizing antibodies can be detected during the first week of clinical illness, whereas hemagglutination-inhibition and complement-fixation antibodies are found in the second to third weeks. Neutralizing antibodies persist for many years or decades after infection, whereas levels of hemagglutination-inhibition and complement-fixation antibodies generally decrease within a year. Cell-mediated immunity likely plays an important role in controlling disease; virus-specific cytotoxic T cells are detectable in lymphoid organs as early as 4 days after infection. These cytotoxic T cells are believed to limit viral spread by causing lysis of infected cells in the reticuloendothelial system and the skin. The relative importance of the cellular immune response against smallpox has been demonstrated in animals. Studies show that mice with defective T cells are able to generate normal humoral responses to a viral challenge, yet they die when exposed to Orthopoxvirus concentrations that are sublethal in healthy mice. Studies in rodents and sheep have demonstrated memory in the form of virus-specific, cytotoxic lymphocyte immune responses that occur long after the initial variola infection. Because of potential bioterrorism, interest in smallpox pathogenesis has increased. Protein analysis indicates that the variola virus G1R protein binds to cellular nuclear factor kappa-B (NF-kB), thereby inhibiting its function in cell signalling. [6] The G1R protein is highly conserved among pathogenic orthopoxviruses and is absent from the less-pathogenic vaccinia strains, thus suggesting that it may serve as a molecular therapeutic target. One report identified a novel peptide with the ability to inhibit vaccinia virus cell entry. [7] Other studies developed a method of reliably classifying species of variola virus into major and minor species by genotype using novel real-time polymerase chain reaction (PCR) assay probes. [8] Further investigation into genetic variations between species of variola virus may reveal variable response to therapeutic targets. History of inoculation Intentional inoculation with subvirulent strains of variola to protect against variola major (variolation) began in India sometime before the first millennium CE. This practice spread throughout the Old World and eventually reached Europe in the early 18th century. Although variolation was capable of inducing lifelong immunity in vaccinated individuals, the practice was a risky procedure, and those inoculated had a mortality rate of approximately one tenth that of individuals with naturally occurring disease. Furthermore, treated individuals were capable of transmitting disease to untreated individuals for some time after variolation. In one of the major accomplishments in modern medicine, Edward Jenner demonstrated in 1796 that an individual could be protected against disease. The skin could be inoculated with pustular material containing the cowpox virus, an orthopoxvirus closely related to variola. Although the heterologous immunity induced by vaccination (from the Latin word vacca, meaning cow) was not lifelong, this approach was significantly safer than variolation, and vaccination quickly spread throughout the world. In subsequent decades, the strain of virus used was sustained by means of arm-to-arm inoculation or maintained as dried material on threads. Over time, the virus mysteriously changed from its original cowpox form to the strain of vaccinia used in current vaccines. In the latter half of the 19th century, the practice of growing virus for vaccines on the flank of calves was adopted to lessen the risk of transmitting other human diseases (eg, syphilis) during vaccination. In the late 1940s, large-scale production of freeze-dried vaccine enabled mass vaccination campaigns and, eventually, the global eradication of smallpox. In the latter half of the 1960s, the World Health Assembly intensified its efforts to eradicate the disease by using highly potent and stable vaccine, by rapidly identifying outbreaks, and by performing ring vaccination in all contacts of a person who was infected. (See Treatment and Medication.) The last case of endemic smallpox occurred in Somalia in 1977, and the last recorded case in humans occurred in England in 1978; this final case resulted from an accidental laboratory infection. In 1980, the World Health Organization (WHO) officially declared that smallpox had been eradicated. Currently, the only remaining known variola virus isolates are frozen in closely guarded repositories at the US Centers for Disease Control and Prevention (CDC) in the United States and at the VECTOR Institute in Russia. After the disease was eliminated from the world, routine smallpox vaccination was stopped. The long-term consequence of eradication is that much of the world's population is now unvaccinated and at risk for smallpox infection. Currently, nearly half of the US population has not been vaccinated and has no immunity to vaccinia or variola. The remainder of the population was vaccinated 30 or more years ago and may retain partial protection from the disease. [9, 10] Bioterrorism Smallpox is a high-priority (category A) agent for bioterrorism, defined as follows by the CDC (see the PDF file below): Easily disseminated or transmitted from person to person High mortality rate and potential for significant public health effect Probable instigator of panic and social disruption Special actions required for public health preparedness Bioterrorist Agents. Signs and symptoms. Chart courtesy of North Carolina Statewide Program for Infection Control and Epidemiology (SPICE), copyright University of North Carolina at Chapel Hill, www.unc.edu/depts/spice/bioterrorism.html. Patient education For patient education information, see Smallpox.

Etiology Smallpox is a double-stranded, 135- to 375-kilobase (kb) DNA virus that replicates in the cytoplasm of the host cell and forms B-type inclusion bodies (Guarnieri bodies). This is in contrast to herpes viruses, which replicate in the nucleus. The orthopoxviruses are among the largest and most complex of all viruses. The virion is brick shaped, with a diameter of approximately 200 nm. (See the image below.)

Smallpox virion. Courtesy of US Centers for Disease Control and Prevention. Transmission The smallpox virus is transmitted mainly through the airborne route and adheres via droplet spread of viral particles onto the mucosal surfaces of the oropharyngeal and respiratory tract. This transmission occurs through close personal contact (eg, face-to-face within 6 ft, household contact) for extended periods. Respiratory spread over long distances (eg, from one hospital floor to another) has been reported. Exposure to clothing or blankets contaminated with infected material can also result in disease. [11, 12]

Smallpox has a lower transmission rate than measles, pertussis, and influenza. Transmission through casual and limited contact has been reported in military personnel. Although rare, airborne (ie, suspended viral particles) and fomite transmission can occur. Humans are the only natural hosts of variola; nonhuman animals and insects do not carry the variola virus. Pregnant women with smallpox tend to develop hemorrhagic disease; intrauterine infection occurs in even the mildest maternal infections, resulting in premature delivery and high fetal and neonatal mortality rates. Course of the infection Implantation of just a few virions of smallpox into the oropharynx or respiratory tracts can cause infection. The virus infects macrophages during the first 72 hours of the incubation phase. The virus migrates and multiplies in the regional lymph nodes, resulting in asymptomatic viremia by the fourth day. The virus multiplies in the spleen, bone marrow, and lymph nodes, resulting in a symptomatic secondary viremia (ie, fever, toxemia) by the eighth day. Finally, the virus reenters the blood in leukocytes, producing fever and toxemia, and then passes from leukocytes to adjacent cells in small blood vessels of the dermis and beneath the oropharyngeal mucosa, leading to the initial onset of the enanthem and exanthem, at which point (approximately day 14) the patient becomes infectious. (See the image below.)

This patient with smallpox survived toxemia to succumb to secondary tissue damage days after this photo was taken. Courtesy of the US Centers for Disease Control and Prevention. The spleen, lymph nodes, kidneys, liver, bone marrow, and other viscera may also contain large amounts of smallpox virus. Incubation periods are typically 10-12 days but can range from 7-17 days. Intrauterine infections rarely occur and usually have shorter incubation periods. Patients exposed to smallpox through routes other than the person-to-person respiratory route also have shorter incubation periods. Prior immunization, vaccinia immunoglobulin (VIG), and, possibly, antiviral chemotherapy may extend the incubation period. Patients with smallpox are sometimes contagious upon the onset of fever (prodromal phase) but are most contagious upon rash onset. Infected persons are contagious until the last smallpox scab separates. The highest intensity of viral shedding is during the first 10 days of the rash. Infection rates among close contacts of infected persons have been reported to be between 37% and 88%. Survivors of natural smallpox infection acquire lifelong immunity. Because of potential bioterrorism, interest in smallpox pathogenesis has increased. Protein analysis indicates that the variola virus G1R protein binds to cellular nuclear factor kappa-B (NF-kB), thereby inhibiting its function in cell signalling. [6] The G1R protein is highly conserved among pathogenic orthopoxviruses and is absent from the less-pathogenic vaccinia strains, thus suggesting that it may serve as a molecular therapeutic target. One report identified a novel peptide with the ability to inhibit vaccinia virus cell entry. [7]

Epidemiology Occurrence in the United States The last outbreak of smallpox in the United States was in 1947, when 12 cases were reported in New York City. In the United States, routine vaccination of the civilian population ended in 1972, and in 1990 it ended for the US military. The most current statistics indicate that approximately 41% of the resident US population is younger than age 30 years, and that most of this group has not been vaccinated against smallpox. The immune status of those who were vaccinated 30 or more years ago has not been satisfactorily established, but some evidence shows residual immunity. Reports from the late 19th century indicate that smallpox vaccination 20-30 years previously may not protect against infection but often prevents death. No conclusive studies have shown whether people with residual immunity can transmit smallpox to nonvaccinated individuals. International occurrence Since 1978, no cases of smallpox have been reported in the world. The last endemic case of variola major was reported in Bangladesh in 1975; the last endemic case of variola minor was reported in Somalia in 1977. In 1978, a laboratory accident in Birmingham, England, resulted in a single case of the disease. Smallpox is authorized to be kept for research purposes only at 2 WHO reference laboratories. One is the CDC, in Atlanta, Ga, and the other is the State Research Centre of Virology and Biotechnology, also known as the VECTOR Institute, in Koltsovo, Russia. Routine smallpox vaccinations were stopped in 1972 and smallpox was declared eradicated in 1980 after a worldwide vaccination program. In 2002, The Washington Post reported that the Central Intelligence Agency (CIA) identified possible clandestine smallpox virus stocks in 4 other nations. Age-related demographics The age distribution of smallpox mirrors that of the general population, although residual immunity from previous vaccination could potentially decrease disease in the older population. Historically, young or old individuals are more susceptible to severe smallpox.

1. Prognosis The mortality rate in patients with untreated smallpox is 30% or higher. The more severe hemorrhagic and malignant forms of smallpox are usually fatal. Complications Morbidity is commonly associated with smallpox. Most patients (65-80%) recovering from infection have cutaneous scarring, which is made worse if secondary bacterial infections develop during the course of smallpox. Other complications of smallpox included dehydration and orchitis. Encephalitis occurs in 1 in 500 cases. Dermatologic complications of smallpox include the following: Formation of furuncles and/or abscesses secondary to bacterial infection Sepsis Pockmarks Ophthalmologic complications of smallpox include the following: Blepharitis Conjunctivitis Corneal ulceration Keratitis Blindness (1% of cases) Orthopedic complications include the following: Arthritis (2% of cases) Osteomyelitis variolosa Symmetrical elbow joint involvement Respiratory complications include the following: Pulmonary edema Pneumonitis Bronchopneumonia Mortality Overwhelming toxemia has been the usual cause of death in smallpox. Variola major infection carries an overall fatality rate of approximately 30% (range, 15-50%) in an unvaccinated population and 3% in a vaccinated population. However, flat smallpox carries a 45.4% mortality rate in patients with discrete lesions who have been immunized. Unimmunized patients with confluent disease have a 99.3% mortality rate. Patients with hemorrhagic smallpox have a mortality rate of more than 96%, regardless of immunization status. Variola minor infection is a less common type of smallpox and a much less severe disease, with a death rate of 1% or less. Congenital smallpox infection results in a stillbirth rate of 35%; 50% of neonates die within their first few days of life.

Clinical Presentation

1. History The incubation period of smallpox ranges from 7-17 days but is usually 10-12 days. During the incubation period, patients are not contagious.The prodromal phase of smallpox lasts 2-4 days and is characterized by the following: Fever (38.8-40°C [101-104°F]) Severe headache Backache Pharyngitis Nausea Vomiting (rare) Prostration Enanthema on the mucous membranes of the tongue and the oropharynxAs many as 10% of fair-skinned individuals with smallpox may also present with a fine, erythematous, macular rash during the prodromal phase. Virus shedding and subsequent infectivity are maximal at the beginning of the enanthema, and they last until scab separation of the skin lesions. For a few days, the virus can be found in respiratory secretions, skin lesions, and contaminated objects.Respiratory infectivity occurs with face-to-face contact, although reports of infection due to viral spread through ventilation systems are well documented.The characteristic rash of smallpox begins after the prodromal phase. Small, red macules first appear on the face and then spread to the extremities and trunk. Over 1-2 days, the macules develop into firm, 2- to 3-mm papules. Within 1-2 more days, the papules evolve into 2- to 5-mm vesicles.Most patients with smallpox report severe headaches and spinal pain. Few patients develop neuropsychiatric symptoms (hallucinations, delirium, depression and psychosis, manic depression). Autopsies of patients with smallpox have demonstrated perivenular demyelination. Ten to 20% of patients with smallpox develop ophthalmologic complications (variola residua). Conjunctivitis is most common, appearing 5 days after rash onset. Some patients develop painful pustules and bulbar conjunctivitis. During epidemics, corneal ulceration was common (complicated by bacterial superinfection and perforation).Two to 5% of children develop osteomyelitis (osteomyelitis variolosa), due to viral invasion of the bone rather than as a result of secondary infection. Radiographic surveys in children have found rates as high as 20%. Depending on the presenting clinical symptoms, other diseases, such as meningococcemia, leukemia, herpes viruses, and drug eruptions, must be ruled out. A meticulous drug history should be obtained.
   

2. Physical Examination The initial cutaneous lesions of smallpox appear as small, red spots on the face, in the mouth and pharynx, and on the forearms. Initially, smallpox lesions are small papules, but they change into vesicles and pustules within 1-2 days. The initial lesions are shotty and do not disappear with pressure. These spots develop into sores that break open and spread large amounts of the virus into the mouth and throat. The patient becomes most contagious at this time. Around the time the sores in the mouth break down, a rash appears on the skin, starting on the face, spreading to the arms and legs, and progressing to the hands and feet. Usually, the rash spreads to all parts of the body within 24 hours. As the rash appears, the fever reduces and the patient may start to feel better. By the third day of the rash, it turns into raised papules. By the fourth day, the papules fill with a thick, opaque fluid and often have a depression in the center that resembles an umbilicus (bellybutton), which is a major distinguishing characteristic of smallpox. At this time, the fever often rises again and remains high until scabs form over the papules. (See the images below.)
   

📷After exposure to the smallpox virus, a symptom-free incubation period follows. It normally lasts 10-12 days but may vary from 7-17 days. Smallpox begins with fever, headache, and severe backache. A rash appears after 2-4 days and progresses through characteristic stages of papules, vesicles, pustules, and, finally, scabs. The scabs desquamate at the end of the third or fourth week. Courtesy of the World Health Organization.

📷Smallpox rash at days 3, 5, and 7 of evolution. Lesions are denser on the face and extremities than on the trunk. They also appear on the palms of the hand and have a similar appearance. Courtesy of the World Health Organization.

📷Unvaccinated infant with the ordinary form of the variola major strain of smallpox has centrifugally distributed umbilicated pustules on day 3 in the course of the disease. Reprinted with permission from the World Health Organization (WHO). By days 4-7 after the appearance of the rash, the lesions develop into 4- to 6-mm pustules. The pustules are sharply raised and are usually round and firm to the touch, as if a small, round object is present under the skin. Many of the pustules become confluent, particularly on the face. In the past, these pustules have been described as deep-seated, particularly on the palms and soles; however, this is likely due to thick stratum corneum at those sites. (See the images below.)

📷Unvaccinated infant with the ordinary form of the variola major strain of smallpox has centrifugally distributed umbilicated pustules on day 5 in the course of the disease. Reprinted with permission from the World Health Organization (WHO).

📷Unvaccinated infant with the ordinary form of the variola major strain of smallpox has centrifugally distributed umbilicated pustules on day 7 in the course of the disease. Reprinted with permission from the World Health Organization (WHO). The pustules reach their maximal size by day 10. By the end of the second week after the rash appears, most of the sores have formed scabs. The scabs begin to separate, leaving marks on the skin that eventually become pitted scars. Most scabs separate by the third week after the rash appears. The person is contagious until all of the scabs are gone. All skin lesions tend to be in the same stage of development at any given time in the course of the infection. Compared with unvaccinated persons, vaccinated individuals who contract smallpox tend to have less severe toxemia, fewer constitutional symptoms, and smaller and fewer numbers of lesions, which tend to be more superficial and to mimic those of chickenpox. The smallpox rash has a centrifugal distribution, with more lesions on the arms and legs than on the trunk. Rash on the palms and soles is common. In comparison, a chickenpox rash has a centripetal distribution, with more lesions on the trunk and with fewer or no lesions on the palms and soles. Most patients with smallpox report severe headaches and spinal pain. Few patients develop neuropsychiatric symptoms (hallucinations, delirium, depression and psychosis, manic depression). Autopsies of patients with smallpox have demonstrated perivenular demyelination. Ten to 20% of patients with smallpox develop ophthalmologic complications (variola residua). Conjunctivitis is most common, appearing 5 days after rash onset. Some patients develop painful pustules and bulbar conjunctivitis. During epidemics, corneal ulceration was common (complicated by bacterial superinfection and perforation). Two to 5% of children develop osteomyelitis (osteomyelitis variolosa), due to viral invasion of the bone rather than as a result of secondary infection. Radiographic surveys in children have found rates as high as 20%. Flat-type smallpox is slower to evolve, but it results in confluent, velvety macular lesions and is associated with severe prostration. (See the image below.)

📷Flat-type smallpox on day 6 of the rash. Courtesy of the US Centers for Disease Control and Prevention. Variola minor is characterized by constitutional symptoms, with fewer and smaller skin lesions than variola major. (See the images below.)

📷The ordinary form of the variola minor strain of smallpox (alastrim) in an unvaccinated woman 12 days after the onset of skin lesions. The facial lesions are sparser and evolved more rapidly than the extremity lesions. Reprinted with permission from the World Health Organization (WHO).

📷The ordinary form of the variola minor strain of smallpox (alastrim) in an unvaccinated woman 12 days after the onset of skin lesions. The facial lesions are sparser and evolved more rapidly than the extremity lesions. Reprinted with permission from the World Health Organization (WHO).

📷The ordinary form of the variola minor strain of smallpox (alastrim) in an unvaccinated woman 12 days after the onset of skin lesions. The facial lesions are sparser and evolved more rapidly than the extremity lesions. Reprinted with permission from the World Health Organization (WHO). An excellent algorithm for evaluating generalized vesicular or pustular rash illness is provided on the CDC Web site; this was compiled jointly by the CDC and the American Academy of Dermatology Task Force on Bioterrorism. Summary of criteria Major criteria for diagnosing smallpox include the following: Febrile prodrome occurring 1-4 days before rash onset - Fever greater than 102°F and at least 1 of the following: prostration, headache, backache, chills, vomiting, severe abdominal pain Classic smallpox lesions - Round and well circumscribed; may be umbilicated or confluent Lesions in same stage of development on any 1 part of the body Minor criteria for diagnosing smallpox include the following: Centrifugal distribution of rash - Greatest concentration of lesions on the face and distal extremities First lesions on the oral mucosa/palate, face, forearms Patient appears toxic or moribund Slow (several days each stage) evolution of rash from macules to papules to pustules to scabs Lesions on the palms and soles

Smallpox Differential Diagnoses

Diagnostic Considerations

The rash of chickenpox was frequently mistaken for that of smallpox during the days of natural infection. Both conditions can result in pustular scarring lesions that involve the face. Varicella typically does not have a prodromal phase, and the evolution of the rash from its appearance to scab separation takes approximately 7 days in varicella. Often, individuals who were previously vaccinated had only a mild prodrome without any rash.

1. 
   

The fever and vesicular rash of herpes zoster and erythema multiforme also were often confused with those of variola major.

Hemorrhagic smallpox, seen in the image below, develops fulminantly and was most often confused with meningococcemia or severe acute leukemia.

📷Hemorrhagic-type variola major lesions. Death usually ensued before typical pustules developed. Reprinted with permission from the World Health Organization (WHO). 1988; 10-14, 35-36.

Contact dermatitis, although often vesicular, is distinguishable from smallpox lesions because contact dermatitis is pruritic and is not accompanied by fever or constitutional symptoms.

Conditions to consider in the differential diagnosis of smallpox include the following:

1. Rocky Mountain spotted fever

2. Syphilis

3. Varicella-zoster virus

4. Drug eruptions

5. Insect bites

6. Kawasaki disease

7. Measles, rubeola

8. Monkeypox

9. Rubella

10. Generalized vaccinia and eczema vaccinatum

11. Insect bites

12. Viral hemorrhagic fevers (may be confused with hemorrhagic smallpox)

13. Varicella virus

14. Acne

15. Atypical measles

16. Coxsackievirus

17. Acute leukemia

18. Secondary syphilis

19. Rat-bite fever

20. Infectious mononucleosis

21. Toxic erythemas

22. Parvovirus B19

23. Cytomegalovirus

24. Erythema multiforme (Stevens-Johnson syndrome)

25. Molluscum contagiosum

26. Scarlet fever

Differential Diagnoses

Enteroviruses

Herpes Simplex

Herpes Zoster

Impetigo

Influenza

Malaria

Meningitis

Meningococcemia

Poxviruses

Rickettsialpox

Smallpox Workup

1. Approach Considerations Suitably vaccinated and trained personnel should obtain viral swabs of the patient's pharynx and/or open skin lesions (eg, pustule contents, material from the base of the scab).Under biosafety level 4 (BSL4) laboratory conditions, these samples can be examined for the presence of virions by using electron microscopy, PCR assay, or immunohistochemical analysis or by growing the virus on live cell cultures. [13, 14]Serologic testing can be performed to detect neutralizing antibodies, but the results cannot be used to differentiate Orthopoxvirus species.Although smallpox and all other viruses in the Orthopoxvirus genus exhibit identically appearing brick-shaped virions, the clinical aspects of these diseases generally suffice for distinguishing cowpox and vaccinia from smallpox. Monkeypox virions may also be indistinguishable from smallpox virions, but naturally occurring monkeypox is typically limited to tropical rain forest areas of Africa.Smallpox infection may be confirmed based on the presence of brick-shaped virions viewed with electron microscopy examination of vesicular or pustular fluid or scabs. PCR assay and electron microscopy can be used to examine inactivated samples and therefore do not require such high levels of isolation and can be performed in local laboratories.However, although electron microscopy can help to identify the virus as a member of the Orthopoxvirus genus, it cannot help to determine the exact species.PCR assay can be used to identify the species and can even distinguish minor genetic variations in the different strains. PCR assay has been used to identify variola only twice previously, and never in a clinical situation. PCR assay can amplify small and specific lengths of DNA and can accurately differentiate variola virus DNA from other species in the genus. The sensitivity is 5-10 copies of DNA. PCR assay can be useful in distinguishing between chickenpox and smallpox. Cell culture is seldom used, because it is not as effective as the other methods and because it requires the use of live virus, which, in turn, requires the use of a BSL-4 laboratory. Depending on the presenting clinical symptoms, other diseases, such as meningococcemia, leukemia, herpes viruses, and drug eruptions, must be ruled out. A meticulous drug history should be obtained. Tests likely to be performed include the following: Tzanck preparations Direct fluorescent antibody testing for herpes viruses Blood tests Skin biopsy Lumbar puncture
   

2. Specimen Collection and Handling A smallpox skin specimen should be collected with precautions in place. Gloves should be worn during collection; fluid from lesions can be harvested on a cotton swab. Prior to shipping specimens, state and local health department laboratories should be contacted for specific instructions. The CDC recommends the following procedures for handling specimens obtained from a patient thought to be infected with the smallpox virus: Specimens should be collected by someone who has recently been vaccinated (or who has been vaccinated that day) and who is wearing gloves and a mask To obtain vesicular or pustular fluid, the lesions may need to be opened with the blunt edge of a scalpel; the fluid can then be harvested on a cotton swab; scabs can be picked off with forceps Specimens should be deposited in a Vacutainer tube; the tube should be sealed with adhesive tape at the juncture of the stopper and the tube, and this tube, in turn, should be enclosed in a second durable and watertight container State or local health department laboratories should be contacted immediately for proper specimen shipping protocols. Laboratory examination should be performed only in designated BSL-4 laboratories. Once it has been established that an epidemic is being caused by the smallpox virus, clinically similar cases do not require further laboratory testing.

Smallpox Treatment & Management

1. Approach Considerations No known treatment is effective for smallpox. Medical management of smallpox is mainly supportive. Supportive care in patients with symptomatic smallpox consists of the following:The patient should be isolated until all scabs have fallen off (about 3-4 wk after rash onset) to prevent transmission of the variola virus to nonimmune persons. The fluid and electrolyte balance should be monitored and maintained to avoid dehydration. Oral antiviral agents (ie, tecovirimat, cidofovir) are available from the US government’s Strategic National Stockpile (SNS). Medications should be given for fever and pain. Good nutritional support should be maintained. Skin care should be instituted. Complications should be monitored for and treated. Unless the diagnosis of smallpox is confirmed in a laboratory, patients should receive smallpox vaccination if they will be isolated with other patients with confirmed or suspected smallpox, to prevent accidental transmission. Corneal lesions may be treated with topical idoxuridine. Whenever possible, patients should be cared for at home in the event of a large smallpox outbreak. However, in the event of an outbreak with only a few cases or when patients cannot be cared for at home, hospital admission is advisable. The CDC recommends that authorities consider designating specific hospitals for smallpox care.Treatment of patients with possible or known exposure to smallpox The smallpox vaccine is the only known way to prevent smallpox in an exposed person. If given within 4 days of viral exposure, the vaccine can prevent or significantly lessen the severity of smallpox symptoms. Vaccination 4-7 days after exposure may offer some protection from the disease and may lessen its severity. Isolate patients possibly infected with smallpox virus in negative-pressure rooms under airborne precautions [15] and vaccinate them within the first 4 days after exposure. Supportive and symptomatic treatment (eg, hydration, nutrition) should be provided.In July 2018, the US Food and Drug Administration approved tecovirimat (TPOXX), the first drug indicated for the treatment of smallpox, should smallpox ever be used as a bioweapon. Tecovirimat is an antiviral that inhibits the activity of the orthopoxvirus VP37 protein. The effectiveness of tecovirimat against smallpox was established by studies in animals infected with viruses closely related to variola virus, which demonstrated higher survival rates compared with those of placebo. The safety of tecovirimat was demonstrated in 359 healthy human volunteers in whom the most frequently reported adverse effects included headache, nausea, and abdominal pain. [16]To obtain tecovirimat, clinicians should contact the Centers for Disease Control and Prevention (CDC) Emergency Operations Center at 770-488-7100, which will coordinate shipment with the SNS.Vaccinia immunoglobulin (VIG) does not appear to offer a survival benefit when given to patients during the incubation or active-disease stages of smallpox. However, new drugs are under investigation. For example, cidofovir may be beneficial if given in the early stages of illness, although the effectiveness of this treatment has not been proven in humans. [17, 18, 19, 20]Transfer Smallpox patients should be transferred as necessary, with appropriate respiratory and contact isolation.Consultations Infectious disease specialists and public health officials should be consulted in cases of smallpox. CDC officials and state health authorities should be notified immediately. Outpatient care Further outpatient care for smallpox patients includes cosmetic management of scars and corrective vision care.
   

2. Vaccination One of the best ways to prevent smallpox is through vaccination. Vaccine given to individuals before exposure to smallpox can completely protect them. Vaccination within 3 days after exposure prevents or greatly lessens the severity of smallpox in most people. Vaccination 4-7 days after exposure likely offers some protection from disease or may decrease the severity of disease. Vaccination does not protect patients with smallpox who have already developed a rash. [21, 22, 23, 24, 25] The FDA approved an attenuated, live, nonreplicating smallpox and monkeypox vaccine (Jynneos) for immunization of adults at high risk for smallpox or monkeypox infection in September 2019. Approval was determined in a clinical study comparing the immune responses in study participants who received either Jynneos or ACAM2000, an FDA-approved vaccine for the prevention of smallpox. The study included approximately 400 healthy adults aged 18-42 years who had never been vaccinated for smallpox. Half of the study participants received 2 doses of Jynneos administered 28 days apart, and half received 1 dose of ACAM2000. The group vaccinated with Jynneos had an immune response that was not inferior to immune responses to ACAM2000. [26, 27] Cross-protective immunity from vaccinia is most effective during the first 10 years after vaccination and slowly wanes thereafter. Persons who have been vaccinated several times are likely to have longer-lasting immunity of unclear duration. The level of protection in individuals who were vaccinated 30 or more years ago, should they be exposed to smallpox today, is unclear. Vaccinated persons normally exhibit an accelerated immune response. Thus, whenever possible, assigning those who have previously been vaccinated to duties involving close patient contact is prudent. Persons with known or possible exposure to smallpox should be vaccinated if the exposure has occurred within 3 days, unless the patient has specific contraindications for which the risks of immunization are considered even greater than the dangers associated with contracting smallpox. Persons with known cardiac disease (eg, previous myocardial infarction, angina, congestive heart failure, cardiomyopathy) should receive smallpox vaccination. Myocardial infarctions and angina without myocardial infarction have been reported following smallpox vaccinations. The association between smallpox vaccination and these cardiac events is not clear. The US military ended vaccination in 1990, but vaccination was subsequently reinstituted in December 2002 for potential use against variola virus as bioterrorism agent. Since smallpox vaccination can lead to progressive vaccinia among immunocompromised individuals, HIV-infected individuals are excluded from preemptive vaccination. Pregnant women who receive the smallpox vaccine are at risk of fetal vaccinia, which usually results in stillbirth or death of the infant. Pregnant women should not receive smallpox vaccination, and women should be advised against becoming pregnant for 4 weeks after smallpox vaccination. [28] Vaccinia immunoglobulin Vaccinia immunoglobulin (VIG) is indicated when the vaccination is contraindicated.
   

3. Isolation Recommendations From the CDC In a smallpox outbreak, patients with confirmed or suspected smallpox may be isolated in several ways. The goal of isolation is to prevent transmission of smallpox from an infected patient to nonimmune individuals while maintaining an appropriate care and comfort level for the patient. Medical personnel should consult with public health officials to determine the most appropriate method for isolation of patients with smallpox. Hospital isolation If a patient with confirmed or suspected smallpox requires hospital care, the steps below must be taken while the patient is hospitalized. The patient should be kept in strict airborne and contact isolation in a room with negative air pressure (and an individual high-efficiency particulate air [HEPA]–filtered ventilation exhaust, if available). This room should have private shower and bathroom facilities and not share ventilation with any other part of the hospital. Unvaccinated personnel who enter and leave the isolation room should wear protective clothing, including gowns, masks (properly fitted N95 respirator masks), gloves, protective eyewear, and surgical booties. Recently successfully vaccinated personnel should exercise contact precautions (eg, gowns, gloves) and should wear a surgical mask and eye protection, as indicated, for procedures in which contact with body fluids is possible. All protective clothing should be removed and placed into biohazard waste disposal containers before leaving the isolation room and reentering other areas of the hospital. All infectious waste and contaminated protective clothing should be disposed of or sterilized in an appropriate manner (incineration for disposable materials; autoclaving, ethylene oxide decontamination, or laundering in hot water and bleach for reusable equipment or clothing). Public health officials should be consulted for specific waste-disposal and decontamination guidelines. Personnel entering the isolation room or handling infectious waste or clinical specimens from the patient should be vaccinated or should have had recent, documented, successful smallpox vaccinations (within 3 y). Public health officials should be contacted for vaccination requests. Steps should be taken to confirm or rule out the diagnosis of smallpox. Public health officials should be consulted for assistance with the laboratory diagnosis. Nonhospital isolation Public health officials should be consulted before nonhospital isolation is initiated. Patients with confirmed or suspected smallpox who do not require hospital care may be isolated in nonhospital facilities that do not share ventilation systems with other facilities. These facilities should have appropriate climate-control capabilities (heating and air conditioning), running water, and bathroom facilities. If patients with suspected or confirmed smallpox are isolated together, all patients should receive smallpox vaccination to prevent accidental transmission due to misdiagnosis. All persons entering these facilities must have had recent, documented, successful smallpox vaccinations (within 3 y).
   

4. Additional Infection-Control Considerations Avoid transporting the patient through the hospital (eg, use in-room portable radiographic equipment); if transporting the patient is unavoidable, have the patient wear a surgical mask and the health care worker a mask with an N-95 respirator. If smallpox infection is confirmed, place contacts under fever surveillance for 18 days after their last contact with the infected patient. Contacts or a supervisor should monitor the patient’s temperature twice daily. If the patient’s temperature is higher than 38.1°C (100.5°F), public health authorities should be notified immediately. (See the graph below.)
   

📷Typical temperature chart of a patient with smallpox infection (from Henderson, 1999).

1. Deterrence and Prevention Isolation and mass and/or ring vaccination can prevent the spread of smallpox. The reemergence of smallpox would constitute an international emergency, and failure to immediately report cases to public health authorities would severely impair their ability to contain the disease. [9, 29] An informed public could better comply with vaccination and quarantine procedures if smallpox reemerged. If the disease did reemerge, management strategies would include the following: Isolation Barrier protection - Gown, mask, gloves Cremation of corpses Isolation of contacts if fever or rash develops Surveillance of all face-to-face contacts Any suspected index case of smallpox should be immediately reported to state health officials and the CDC. The 24-hour emergency telephone number of the Emergency Preparedness and Response Branch of the CDC is 770-488-7100 or 404-639-3532. General clinician information regarding smallpox and smallpox vaccine can be obtained from the CDC Web site or by calling 877-554-4625.
   

2. Medical Care The first drug for the treatment of smallpox, tecovirimat, was approved in July 2018 should smallpox ever be used as a bioweapon. Tecovirimat is an antiviral that inhibits the activity of the orthopoxvirus VP37 protein. The effectiveness of tecovirimat against smallpox was established by studies in animals infected with viruses closely related to variola virus, which demonstrated higher survival rates compared with those of placebo. The safety of tecovirimat was demonstrated in 359 healthy human volunteers, in whom the most frequently reported adverse effects included headache, nausea, and abdominal pain. [16] To obtain tecovirimat, clinicians should contact the Centers for Disease Control and Prevention (CDC) Emergency Operations Center at 770-488-7100, which will coordinate shipment with the US government’s Strategic National Stockpile (SNS). Brincidofovir is a broad-spectrum and long-acting antiviral therapy that has been used to prevent cytomegalovirus (CMV) and adenovirus infections in hematopoietic cell transplantation recipients. It is an effective treatment for infection with orthopoxviruses (eg, variola virus) and is investigational in the US. It is being developed as an effective therapy for smallpox with a recommended oral dose of 200 mg weekly for 3 consecutive weeks. The antiviral agent cidofovir is available from the SNS as an investigational agent for the treatment of smallpox. Cidofovir is approved in the United States for CMV retinitis.
   

3. Complications The most common complications of smallpox vaccination in the modern era range from mild to severe reactions encompassing localized redness, enlarged lymph nodes, fever, insomnia, cross-contamination, eczema vaccinatum, bullseye (progressive vaccinia), postvaccinal encephalitis, myocarditis, pericarditis, angina, myocardial infarction, and death.

4. Medication Summary The first antiviral for treatment of smallpox disease, tecovirimat (TPOXX), was approved by the US Food and Drug Administration (FDA) in July 2018.The only prevention is vaccination. Certain medications, including topical idoxuridine and cidofovir, can be used under investigational new drug (IND) protocol for the management of smallpox. [30]Secondary bacterial infections of the skin can be treated with semisynthetic penicillins (nafcillin, oxacillin, dicloxacillin) or first-generation cephalosporins (eg, cefazolin, cephalexin) or clindamycin. Ampicillin/sulbactam or amoxicillin/clavulanate can also be used. A history of prior adverse reactions or hypersensitivity is the primary contraindication.The vaccinia virus vaccine is delivered by the scarification method, which involves dipping a bifurcated needle into the vaccine and poking the tip of the needle into the skin 3 times (15 times if revaccination). Successful vaccination is marked by the typical vaccinia (jennerian or major) reaction, which consists of a visible papule by day 3 that becomes vesicular by day 5-6 and pustular by day 7-10. The pustule resolves with scab separation by day 21. Maximal erythema and induration associated with vaccination usually occurs at days 8-12. (See the images below.)
   

📷Smallpox vaccination with bifurcated needle. Reconstituted vaccine is held between the prongs of the needle and injected subcutaneously by multiple punctures; 15 rapid strokes, at right angles to the skin over the deltoid muscle, are made within a 5-mm area. Courtesy of the World Health Organization.

📷Smallpox vaccination. Evolving primary vaccination appearance. Courtesy of the US Centers for Disease Control and Prevention.

1. Antivirals, Other Class Summary The first antiviral, tecovirimat (TPOXX), for the treatment of smallpox disease was approved by the US Food and Drug Administration (FDA) in July 2018. Cidofovir is currently approved for the treatment of cytomegalovirus (CMV) infections, but not for smallpox. However, animal models support the potential usefulness of this agent in smallpox. Given immediately after exposure, cidofovir has shown some benefit in the prevention of vaccinia, monkeypox, and cowpox. Pulmonary viral levels and pneumonitis were also reduced in animal models of cowpox. [31] Tecovirimat (TPOXX) Antiviral agent; targets and inhibits the activity of the orthopoxvirus VP37 protein (encoded by and highly conserved in all members of the orthopoxvirus genus) and blocks its interaction with cellular Rab9 GTPase and TIP47, which prevents the formation of egress-competent enveloped virions necessary for cell-to-cell and long-range dissemination of virus. It is approved by the FDA and indicated for treatment of human smallpox disease caused by variola virus in adults and children who weigh at least 13 kg. Cidofovir Cidofovir is a viral DNA polymerase inhibitor licensed for use in humans for the treatment of CMV retinitis in patients infected with the human immunodeficiency virus (HIV). Based on animal models, this agent may have some benefit in prevention of Orthopoxvirus infection and may decrease the risk of pneumonitis. It has not been studied in humans for smallpox infections. A liposomal cidofovir is in late developmental stages. In case of bioterrorism or outbreak, cidofovir would be available through emergency use authorization.
   

2. Vaccines, Live, Viral Class Summary Vaccinia vaccine promotes active immunity against the smallpox virus by inducing specific antibodies. Currently available stocks of vaccinia vaccine were derived from the vaccinia strain maintained at the New York Board of Health. Wyeth Laboratories manufactured the last batches of the vaccine (Dryvax) in the early 1980s. These batches were made by using the calf lymph method, and they were lyophilized but are no longer available. The vaccine contains live vaccinia virus but does not contain variola virus, the virus that causes smallpox. Vaccinia is a member of the Orthopoxvirus genus, which includes smallpox (variola), cowpox, monkeypox, gerbilpox, camelpox, and others. Following inoculation, the vaccine induces an immune reaction that serves to protect against smallpox. [32] Several attenuated vaccinia vaccine candidates are undergoing investigation, with ACAM2000 receiving FDA approval as a replacement for Dryvax. [33, 34]  Another vaccine (smallpox [vaccinia] and monkeypox vaccine, live, nonreplicating [Jynneos]) has also been approved by the FDA for immunization of adults at high risk for smallpox or monkeypox infection. [26, 27] New, cell-derived lots of vaccinia appear to have adverse effect profiles similar to the older, calf lymph–derived lots. Primary immunization as soon as possible after exposure or at the first sign of infection is indicated for the prevention and management of smallpox. Currently, US military personnel, US Department of Defense civilian employees, and health care professionals are recommended candidates to receive the vaccination because they will likely be at highest risk in case of a biologic attack (eg, bioterrorism). Next-generation vaccines are available from the SNS and may prove useful in patients with severe immunosuppression. [35] Aventis Pasteur smallpox vaccine (APSV) and Imvamune (Bavarian Nordic) are the next-generation vaccines for this subgroup of patients and are not FDA approved. However, Imvamune is part of the national strategic stockpile and would be released in case of national emergency under EUA. [36, 37, 38] Vaccinia virus vaccine (ACAM2000) This agent is made from vaccinia, which is related to, but different from, the virus that causes smallpox. It contains live vaccinia virus and works by causing a mild infection that stimulates an immune response that effectively protects against smallpox without actually causing disease. The vaccine contains live vaccinia virus but does not contain variola virus, the virus that causes smallpox. Vaccinia is a member of the Orthopoxvirus genus, which includes smallpox (variola), cowpox, monkeypox, gerbilpox, camelpox, and others. Following inoculation, the vaccine induces an immune reaction that serves to protect against smallpox. ACAM2000 is derived from Dryvax, a smallpox vaccine that was approved in 1931 but that is no longer being manufactured. The US military resumed vaccination of at-risk personnel in 1999 after concluding that the disease posed a potential bioterrorism threat. ACAM2000 was studied in 2 populations: (1) persons who had never been vaccinated for smallpox and (2) those who had received smallpox vaccination many years earlier. The percentage of unvaccinated persons who developed a successful immunization reaction was similar to that of Dryvax. ACAM2000 was also found to be acceptable as a booster in persons previously vaccinated for smallpox. Because ACAM2000 contains live vaccinia virus, care must be taken to prevent the virus from spreading from the inoculation site to other parts of the body and to other individuals. To minimize known risks, vaccine licensing is subject to a Risk Minimization Action Plan (RiskMAP), which requires providers of the vaccine and patients to be educated about vaccination risks. The medication guide explains proper care of the vaccination site and provides information about serious adverse effects associated with ACAM2000. In studies, about 1 in 175 healthy adults who received smallpox vaccine for the first time developed myocarditis and/or pericarditis. Of the 10 affected adults, 4 had no symptoms at the end of the study, and symptoms resolved in all but 1 patient. It is administered in a single percutaneous dose. Its use after exposure, but prior to rash, can eradicate clinical manifestations of smallpox. It is contraindicated in patients with severe immunosuppression. Smallpox (vaccinia) and monkeypox vaccine, live, nonreplicating (Jynneos) View full drug information Vaccine is derived from a vaccinia virus, a virus that is closely related to, but less harmful than, variola or monkeypox viruses and can protect against both of these diseases. It is indicated for prevention of smallpox and monkeypox disease in adults who are at high risk for smallpox or monkeypox infection. It is administered as a 2-dose series administered 4 weeks apart.
   

3. Immune Globulins Class Summary Indicated for passive immunity. Vaccinia immunoglobulin (VIG) is used for amelioration of some vaccinia-related complications. VIG is produced from pooled human sera taken from vaccinia-immunized individuals and is available only from the CDC. VIG has been effective when administered early in cases of vaccinia necrosum and eczema vaccinatum. VIG has not been effective in cases of encephalopathy. The use of VIG for generalized vaccinia reactions is usually not necessary. Intravenous VIG (CNJ-016) has been approved by the FDA. Vaccinia immune globulin intravenous (VIGIV, CNJ-016) View full drug information VIGIV is derived from human plasma and is manufactured from pooled plasma donors who received booster immunizations with smallpox vaccine. It contains increased antibody levels against vaccinia virus. It is indicated to treat rare adverse reactions and aberrant infections caused by vaccinia virus, including accidental implantation in the eyes, mouth, other potentially hazardous areas; eczema vaccinatum; progressive vaccinia; severe, generalized vaccinia; and vaccinia infections in immunocompromised individuals.

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