Smallpox: What You as a Health Care Provider Should Know Sue Royappa, MD

1. Smallpox: What You as a Health Care Provider Should Know Sue Royappa, MD

2. After an extensive worldwide eradication program, the last non-laboratory case of smallpox occurred in 1977 in Somalia. In 1972, routine smallpox immunization was discontinued in the U.S. Since 1983, vaccine production has been halted. Stockpiled vaccine has been used only for laboratory researchers. There has however been recent concern that smallpox virus stocks may be in the hands of bioterrorists. This concern was heightened by the terrorist attack on the World Trade Center and the Pentagon on September 11, 2001. Since most of the population is now considered nonimmune, there is considerable debate as to whether smallpox vaccination should be resumed.

3. Historical significance · Smallpox is an acute contagious disease caused by a variola virus. · The name smallpox is derived from the Latin word for “spotted” and refers to the raised bumps that appear on the face and body of an infected person. · A serious and sometimes fatal infectious disease. No specific treatment for smallpox disease, only prevention is vaccination. · Believed to have originated over 3,000 years ago in India or Egypt, is one of the most devastating diseases known to humanity. · Killed as many as 30% of those infected. Between 65–80% of survivors were marked with deep pitted scars (pockmarks), most prominent on the face. · Blindness was another complication. In 18th century Europe, a third of all reported cases of blindness was due to smallpox. In 1898, 95% of adolescent children in Vietnam were pockmarked and nine-tenths of all blindness was ascribed to smallpox. · As late as the 18th century, smallpox killed every 10th child born in Sweden and France. During the same century, every 7th child born in Russia died from smallpox.

4. · In some ancient cultures, smallpox was such a major killer of infants that custom forbade the naming of a newborn until the infant had caught the disease and proved it would survive. · In 1798, Edward Jenner's demonstrated that inoculation with cowpox could protect against smallpox. · In the early 1950s – 150 years after the introduction of vaccination – an estimated 50 million cases of smallpox occurred in the world each year, this fell to around 10–15 million by 1967 because of vaccination. · The disease is now eradicated after a successful worldwide vaccination program. The last case of smallpox in the United States was in 1949. The last naturally occurring case in the world was in Somalia in 1977. · Immunization stopped in many countries, such as the US, in 1972. In 1979, the WHO recommended that vaccination against smallpox be stopped in all countries, the only exception being researchers working with smallpox and related viruses. By 1982, routine vaccination had been officially discontinued in 149 of the 158 member countries of WHO. By 1986, routine vaccination had ceased in all countries.

5. Smallpox – why fear it now? After the events of September, 2001 there is considerable concern that smallpox might be used as an agent of bioterrorism. After the virus was delared to have been eradicated in 1980, stocks of smallpox virus were retained in the U.S. and the former Soviet Union. There have been reports that before the dissolution of the Soviet Union, smallpox was being developed there as a weapon of biological warfare. Concerns that the virus and the expertise to propagate a large amount of virus may have fallen into non-Russian hands. The current U.S. population essentially nonimmune to smallpox. An aerosol release of smallpox virus would disseminate readily. Stable in aerosol form. Infectious dose is very small. As few as 50-100 cases could generate widespread panic.

6. Factors that fuel this concern: -Historically feared as one of the most serious of diseases -High case-fatality rates - 30% in the past -Physically disfiguring -No treatment -Communicable from person to person -Virus able to spread throughout the population unless checked by vaccination and/or isolation of patients and their close contacts How real is the threat? How good of a biological weapon is smallpox?

7. About the virus The causative agent, variola virus, is a member of the genus Orthopoxvirus. Other members of the genus include cowpox, camelpox, and monkeypox. Monkeypox virus has caused the most serious recent human poxvirus infections. The entire 186,000 base pair genome of variola virus has been sequenced. Majority of the genes of the variola virus are closley related to the vaccinia virus used to vaccinate against smallpox. Not been able to identify why variola has such high virulence compared to vaccinia. Pathogenesis and Pathology The oropharynx served as the reservoir for virus spread. Contacts became infected by inhaling the virus. Multiplication occurred within lymphoid organs leading to secondary development of viremia. Virus localized with small dermal blood vessels produced endothelial swelling and intraepidermal vesicles. Extension of infection into sebaceous glands produced pock marks. Virus infection stimulated cytotoxic T cells, antibodies and production of interferons. These responses restricted viral replication and induced prolonged immunity in patients who recovered.

8. Forms of the disease Smallpox has two main forms: variola major and variola minor. The two forms showed similar lesions. The disease follows a milder course in variola minor, which had a case fatality rate of less than 1 per cent. The fatality rate of variola major was around 30%. Both were caused by the same virus and difficult to distinguish in cases of mild variola major. The main distinguishing feature was the outcome. The rash in variola minor accelerated rapidly but without severe sequelae. The entire genome of variola minor strains have not been sequenced. The analyzed portions show very high similarity to variola major. Have not identified the gene, differential expressionof genes or viral replication that may account for the differences in mortality. There were two rare forms of smallpox: hemorrhagic and malignant. Both were invariably fatal. In the former, the rash was accompanied by hemorrhage into the mucous membranes and the skin. Malignant smallpox was characterized by lesions that did not develop to the pustular stage but remain soft and flat.

9. Clinical Presentation Incubation Period (duration 7 to 17 days) Not contagious No symptoms Initial Symptoms (Prodrome) ( 2 to 4 days) Sometimes contagious fever (101 to 104F), malaise, headach, myalgia, vomiting Early Rash (4 days) M ost contagious Starts as small red spots on the tongue and in mouth. Develop into sores that break open and spread large amounts of virus. Then a rash begins on face and spreads to arms and legs. Spreads to all parts of the body within 24 hours. Fever usually falls and the person may start to feel better. On third day rash becomes raised bumps. On fourth day, the bumps fill with a thick, opaque fluid and often have a depression in the center, umbilicated appearance characteristic of smallpox. Fever often rises again and remains high until scabs form.

10. Pustular Rash (5 days) ContagiousThe bumps become pustules – bumps feel like BB pellets embedded in the skin Pustules and Scabs ( 5 days) Contagious Pustules begin to form a crust and then scab By the end of second week after rash appears, most sores have scabbed over Resolving Scabs (6 days) Contagious Scabs begin to fall off, leaving pitted scars Most scabs will have fallen off three weeks after the rash appears The person is contagious to others until all of the scabs have fallen off Scabs resolved - Not contagious In the past sometimes confused with chickenpox, a worldwide infection of children that is seldom lethal. Chickenpox can be distinguished from smallpox by its much more superficial lesions, their presence more on the trunk than on the face and extremities, the development of successive crops of lesions in the same area and by the development of fever concurrently with the rash. Early infection can sometimes be difficult to distinguish, although the difference does become apparent within a few days.

14. Infectivity · Persons carrying the virus during the incubation period cannot infect others. · The frequency of infection is highest after face-to-face contact with a patient after fever has begun and during the first week of rash, when the virus is released via the respiratory tract. · Although patients remain infectious until the last scabs fall off, the large amounts of virus shed from the skin are not highly infectious. Exposure to patients in the late stages of the disease is much less likely to produce infection in susceptible contacts.

15. Transmission Nonimmunized humans universally susceptible to infection with smallpox virus. Noanimal reservoir. Insects play no role in transmission. Transmission occurs from person to person by infected aerosols and air droplets, especially if symptoms include coughing. Variola virus is relatively stable in the natural environment. If aerosolized, it retains its infectivity for at least several hours if not exposed to sunlight or ultraviolet light. Can be transmitted via contaminated clothes and bedding, risk of infection is much lower. Patients with variola major bed ridden - spread limited to close contacts in a small vicinity. Variola minor was so mild that these patients remained ambulatory and spread the virus far more widely. Epidemics developed comparatively slowly. The interval between each generation of cases was 2–3 weeks.

16. Treatment Vaccine administered up to 4 days after exposure to the virus, and before the rash appears, provides protective immunity and can prevent infection or ameliorate the severity of the disease. No effective treatment, other than the management of symptoms, is currently available. A number of compounds are under investigation as chemotherapeutic agents. One of these, Cidofovir, has produced promising results in laboratory studies. Control It was noted as early as the 10th century that accidental exposure to smallpox by a scratch on the skin reduced the severity of infection. Led to the practice of variolation in India and China. Involved intentional administration of pustular fluids of scabs to uninfected patients. In 1796, Edward Jenner showed that innoculation with cowpox virus protected against smallpox and carried less risk of illness than variolation. Subsequently vaccinia virus became the basis for smallpox vaccine.

17. In 1959, WHO adopted the global eradication program with surveillance and contact vaccination. It was successful because of the following: - Long incubation period which allows vaccination to modify the course of disease - Ease of clinical diagnosis - Does not establish latent or persistent infection - Lack of reservoir for variola other than humans In 1980, the WHO declared that smallpox had been eradicated successfully. Smallpox vaccine was last used in the in the general population in the U.S. in 1971. In 1983, the distribution of the vaccine to civilian population was disontinued and vaccination production stopped. Response teams from CDC with special expertise in smallpox management were immunized in 2001. President Bush himself has been vaccinated. It has been given to adult volunteers specifically for determining if stockpiled vaccine and diluted vaccine hve retained immunogenicity.

18. Vaccines • •Dryvax, produced by Wyeth is a live-virus preparations of infectious vaccinia virus. It does not contain smallpox (variola) virus. • •The seed virus held by the WHO Collaborating Center for Smallpox Vaccine in the Netherlands. This Center also tests batches of the smallpox vaccine for potency every five years. Vaccines properly stored for as long as 18 years have not lost their potency. • •The vaccine is provided as a freeze-dried powder in a 100-dose vial, and contains the antibiotics polymyxin B, streptomycin, tetracycline and neomycin. The diluent used to reconstitute the vaccine is 50 percent glycerin and a small amount of phenol as a preservative. • •The vaccine is given as an intradermal inoculation into the deltoid area by multiple punctures with a bifurcated needle. • Approximately 140,000 vials of vaccine are in storage at the CDC, each with doses for 50-60 people, and an additional 50-100 million doses are estimated to exist worldwide. This stock cannot be immediately replenished, since all vaccine production facilities were dismantled after 1980, and renewed vaccine production is estimated to require at least 24-36 months. • In 2000, CDC awarded a contract to Oravax of Cambridge, Massachusetts to produce smallpox vaccine. Initially producing 40 million doses, Oravax anticipates delivery of the first full scale production lots in 2004.

19. A "take" is defined as presence of a papule, vesicle, ulcer, or crusted lesion, surrounded by an area of induration, on days 6-8 after primary vaccination or revaccination. In the first week, the bump becomes a large blister, fills with pus, and begins to drain. During the second week, the blister begins to dry up and a scab forms. The scab falls off in the third week, leaving a small scar. People who are being vaccinated for the first time have a stronger reaction than those who are being revaccinated. More than 95% of primary vaccinees who experience this reaction will have a serologic response. "Equivocal reaction" is the term for other reactions that do not meet these criteria because of suboptimal vaccination, suboptimal vaccine, or prior immunity; such a reaction should be interpreted as a "nontake" and implies inadequate immune response and the need for revaccination, which can be done at the time that a reaction interpreted as being a nontake. Since the vaccine virus is live, it can spread to other parts of the body, or to other people. The vaccinia virus may cause rash, fever, and head and body aches. In certain groups of people complications from the vaccinia virus can be severe.

26. Duration of protection following vaccination •Smallpox vaccination provides high-level immunity for 3 to 5 years and decreasing immunity thereafter for up to ten years. If a person is vaccinated again later, immunity lasts even longer. •Historically, the vaccine has been effective in preventing smallpox infection in 95% of those vaccinated. •If symptoms appear, they are milder and mortality is less in vaccinated than in non-vaccinated persons. •Even when immunity has waned, vaccinated persons shed less virus and are less likely to transmit the disease. •One study of smallpox following the importation of cases into Europe and Canada (1950–1971) showed that mortality was 52% in unvaccinated persons, 1.4% in those vaccinated up to 10 years before exposure, and only 11% in those vaccinated over 20 years before exposure. For the age group of 10–49 years, the mortality rate was 49% in the unvaccinated and 4.3% in those vaccinated 20 years earlier.

27. Contraindications Because the vaccinia virus used in smallpox vaccine can be spread to others from the vaccine site of an immunized person, the contraindications below apply to both potential vaccinees and their household contacts (“household contacts” include persons with prolonged intimate contact with the potential vaccinee, including the potential for direct contact with the vaccination site, e.g., sexual contacts). Eczema or atopic dermatitis and other acute, chronic, or exfoliative skin conditions. Should not be vaccinated, even if the condition is not currently active. At high risk of developing eczema vaccinatum, a potentially severe and sometimes fatal complication. Other acute, chronic, or exfoliative skin conditions (e.g., burns, impetigo, chicken pox, contact dermatitis, shingles, herpes, severe acne, severe diaper dermatitis with extensive areas of denuded skin, or psoriasis), are at risk for inadvertent autoinoculation of the affected skin and should not be vaccinated until the condition(s) resolves. Diseases or conditions which cause immunodeficiency or immunosuppression HIV/AIDS, solid organ or stem cell transplant, generalized malignancy, leukemia, lymphoma, agammaglobulinemia or severe autoimmune disease. At greater risk of developing a serious adverse reaction resulting from unchecked replication of the vaccine virus (progressive vaccinia). HIV testing should be readily available to all persons considering smallpox vaccination.

28. Treatments which cause immunodeficiency or immunosuppression If a potential vaccinee or any of their household contacts are undergoing treatment with radiation, high-dose corticosteroids, chemotherapy agents, or organ transplant medications, they should not be vaccinated. Pregnancy At risk of fetal vaccinia. Although this is a very rare condition (fewer than 50 cases have ever been reported), it usually results in stillbirth or death of the infant shortly after delivery. Women who are vaccinated should be counseled not to become pregnant during the 4 weeks after vaccination, and abstinence or highly effective contraceptive measures should be recommended to reduce the risk of pregnancy within four weeks of vaccination. If a pregnant woman is inadvertently vaccinated or if she becomes pregnant within 4 weeks after vaccinia vaccination, she should be counseled regarding the basis of concern for the fetus. However, vaccination during pregnancy should not ordinarily be a reason to terminate pregnancy.

29. The following additional contraindications apply only to potential vaccinees: Previous allergic reaction to smallpox vaccine or any of the vaccine’s components. Moderate or severe acute illness is generally a contraindication to vaccination. Vaccination should be deferred until the acute illness has resolved. Smallpox vaccine is contraindicated for children under 12 months of age. Breastfeeding mothers should not receive the smallpox vaccine. The close physical contact that occurs during breastfeeding increases the chance of inadvertent inoculation. It is not known whether vaccine virus or antibodies are excreted in human milk. CDC recommends that persons with known cardiac disease such as previous myocardial infarction, angina, congestive heart failure, or cardiomyopathy not be vaccinated at this time. This recommendation follows reports of cardiac events following smallpox vaccinations including myocardial infarctions and angina without myocardial infarction. It is unclear whether or not there is any association between smallpox vaccination and these cardiac events. This exclusion may be removed as more information becomes available. Contraindications to Vaccination During a Smallpox Emergency During a smallpox emergency, all contraindications to vaccination would be reconsidered in the light of the risk of smallpox exposure.

30. One analysis concluded that 15% of the US population will be excluded on the basis of contraindications. An additional 10% will be excluded because they regularly come into household or close contact with persons who have 1 of the contraindications. These groups combined would total 25% of the US population. Recent information suggests that 25% may even be an underestimate. The military vaccination program began on 13 December 2002; of the first 276 persons screened, 102 (37%) were exempted for medical reasons. Approximately one-half of them were exempted because of a contraindication in a household contact.

31. Adverse Reactions Following Smallpox Vaccination Smallpox vaccination (vaccinia) is generally a safe and effective means of preventing smallpox. However, in a number of individuals, smallpox vaccination can produce adverse reactions. Most are totally benign, but may be alarming in appearance. Some are serious, but treatable. A few, which rarely occur, are serious, life threatening and can be fatal. Severe adverse reactions are more common in persons receiving primary vaccination compared to those being revaccinated. Local Reactions Primary vaccination can produce swelling and tenderness of regional lymph nodes beginning 3 to 10 days after vaccination and in some cases persisting up to 2 to 4 weeks after the skin lesion has healed. Other normal local reactions can include local satellite lesions (which appear similar to the primary lesion), considerable local edema, what may be confused with bacterial cellulitis, but is simply intense inflammation accompanying the vaccination (viral cellulitis). In a recent study of adult primary vaccinees, 36% were sufficiently ill to miss work, school, or recreational activities or to have trouble sleeping.

32. Systemic Reactions In a recent study, 17% of adult primary vaccinees experienced fever of at least 100°F within two weeks of vaccination; 7% had a fever of 101°F or more, and 1.4% experienced a fever of 102°F or more. Other expected systemic reactions include malaise, soreness at the vaccination site, myalgia, local lymphadenopathy, and intense erythema ringing the vaccination site. A variety of erythematous or urticarial rashes occur approximately 10 days after primary vaccination in one person per 3700 vaccinated. Vaccinees who develop these rashes are usually afebrile and the rash resolves spontaneously within 2 to 4 days. Rarely, bullous erythema multiforme (or Stevens-Johnson syndrome) occurs.

36. Inadvertent Inoculation Successful vaccination produces a lesion at the vaccination site. Beginning about four days after vaccination, the florid site contains high titers of vaccinia virus. This surface is easily transferred to the hands and to fomites, especially since itching is a common part of the local reaction. Accidental implantation occurs due to transfer of vaccinia virus from the primary site to other parts of the body, or to other individuals. This is the most frequent complication of smallpox vaccination (529 per million primary vaccinees), accounting for approximately half of all complications of primary vaccination and revaccination. Lesions of inadvertent inoculation can occur anywhere on the body, but the most common sites are the face, eyelid, nose, mouth, genitalia, and rectum. Lesions in eczematous skin, in disrupted skin and in the eye pose special hazards, as the infection can be extensive in skin lesions and a threat to eyesight. Most lesions heal without specific treatment.

41. Generalized Vaccinia Generalized vaccinia consists of vesicles or pustules appearing on normal skin distant from the vaccination site. In the past, it was estimated to occur in 242 per million primary vaccinees. It is believed to result from a vaccinia viremia with skin manifestations. Most rashes labeled as generalized vaccinia produce only minor illness with little residual damage. The rash is generally self-limited and usually requires only supportive therapy. However, patients with underlying immunosuppressed illnesses may have a toxic course and require Vaccinia Immune Globulin.

42. Eczema Vaccinatum Eczema vaccinatum is a localized or systemic spread of vaccinia virus. In the past, it was estimated to occur in 10-39 per million primary vaccinees. Transfer of vaccinia virus can occur from autoinoculation or from contact with a vaccinee whose lesion is in the florid stages. Individuals with eczema or atopic dermatitis are at increased risk. Eczema vaccinatum can occur regardless of whether the eczema/atopic dermatitis is active at the time of vaccination. Virus implanted in disrupted skin (may be at multiple sites) spreads from cell to cell producing extensive lesions dependent on extent of abnormal skin. Treatment should include hospitalization and urgent treatment with VIG. Mortality has been prevented in patients treated promptly and adequately. Severe cases and fatalities have been observed after contact of recently vaccinated persons with persons who have active eczema/atopic dermatitis or a history of eczema/atopic dermatitis.

44. Vaccinia Keratitis Vaccinia keratitis results in lesions of the cornea due to accidental implantation of vaccinia virus, and is potentially threatening to eyesight. Symptoms appear ten days after transfer of vaccinia virus. Left untreated, considerable corneal scarring may result as lesion heals resulting in significant impairment of vision. Topical antiviral agents are the treatment of choice; therapy should be determined in immediate consultation with an experienced ophthalmologist.

46. Progressive Vaccinia Progressive vaccinia, also known as vaccinia necrosum, is a severe, potentially fatal illness characterized by progressive necrosis in the area of vaccination, often with metastatic lesions (e.g., lesions at places other than the vaccination site). In the past, it was estimated that progressive vaccinia occurred in approximately 1 to 2 per million primary vaccinations, and was almost always fatal before the introduction of VIG and antiviral agents. Rare in the past, it may be a greater threat today, given the larger proportion of susceptible persons in the population and the greater number with immunocompromise. Nearly all instances have been in people with defined cell-mediated immune defect (T-cell deficiency). Prompt hospitalization and aggressive use of VIG are required. Massive doses of VIG are necessary to control viremia. There is no proven antiviral therapy. Preliminary studies with cidofovir show some antiviral effect in vitro; studies in animals are pending. Immediate consultation with the CDC is recommended to determine if any experimental antiviral drugs are available.

49. Post-Vaccinial Encephalitis A serious complication, occurred in two main forms. The first, seen most often in infants under 2 years of age, had a violent onset, characterized by convulsions. Recovery was often incomplete, leaving the patient with cerebral impairment and paralysis. The second form, seen most often in children older than 2 years, had an abrupt onset, with fever, vomiting, headache, and malaise, followed by such symptoms as loss of consciousness, amnesia, confusion, restlessness, convulsions and coma. Encephalitis or meningoencephalitis following vaccination has been reported in about 3 to 12 per million primary vaccinees; how many such cases are coincidental in time and how many are related to the vaccination itself is impossible to know. Most cases are believed to result from autoimmune or allergic reactions rather than direct viral invasion of the nervous system. In general, this is a severe disease with high mortality and morbidity. Approximately 15-25% percent of affected vaccinees with this complication die, and 25% develop permanent neurological sequelae. There is no specific therapy. Supportive care, anticonvulsants and hospitalization in intensive care may be required in individual cases. VIG is not effective and is not recommended.

50. Fetal Vaccinia Fetal vaccinia is a rare complication of smallpox vaccination. Fewer than 50 cases of fetal vaccinia infection have been reported, usually after primary vaccination of the mother in early pregnancy. Fetal vaccinia usually results in stillbirth or death of the infant soon after delivery. Smallpox vaccine is not known to cause congenital malformations. Death Death resulting from smallpox vaccination is rare, in the past approximately 1 to 2 primary vaccinees died per million vaccinated. Death is most often the result of postvaccinial encephalitis or progressive vaccinia.