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Keywords:

  • Bioterrorism;
  • chickenpox;
  • immunocompromised host;
  • organ transplant;
  • smallpox;
  • vaccine;
  • vaccinia;
  • varicella;
  • variola;
  • virus

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Smallpox
  5. Smallpox Vaccine: Vaccinia Virus
  6. The Risks of Smallpox Vaccination in Immunocompromised Individuals
  7. Nosocomial Spread of Vaccinia
  8. References

Recent bioterrorism raises the specter of reemergence of smallpox as a clinical entity. The mortality of variola major infection (‘typical smallpox’) was approximately 30% in past outbreaks. Programs for smallpox immunization for healthcare workers have been proposed. Atypical forms of smallpox presenting with flat or hemorrhagic skin lesions are most common in individuals with immune deficits with historic mortality approaching 100%. Smallpox vaccination, even after exposure, is highly effective. Smallpox vaccine contains a highly immunogenic live virus, vaccinia. Few data exist for the impact of variola or safety of vaccinia in immunocompromised hosts. Both disseminated infection by vaccinia and person-to-person spread after vaccination are uncommon. When it occurs, secondary vaccinia has usually affected individuals with pre-existing skin conditions (atopic dermatitis or eczema) or with other underlying immune deficits. Historically, disseminated vaccinia infection was uncommon but often fatal even in the absence of the most severe form of disease, “progressive vaccinia”. Some responded to vaccinia immune globulin. Smallpox exposure would be likely to cause significant mortality among immunocompromised hosts. In the absence of documented smallpox exposures, immunocompromised hosts should not be vaccinated against smallpox. Planning for bioterrorist events must include consideration of uniquely susceptible hosts.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Smallpox
  5. Smallpox Vaccine: Vaccinia Virus
  6. The Risks of Smallpox Vaccination in Immunocompromised Individuals
  7. Nosocomial Spread of Vaccinia
  8. References

Mummies with pox-like skin lesions have been found from 1500 BC. The first epidemic of smallpox in the New World occurred in 1507 on the island of Hispaniola and decimated the native Taino population. Similar outbreaks followed the Spanish conquistadors into Mexico, and Central and South America, killing over 3 million Aztecs and Incans. Epidemics of smallpox spread throughout Europe, Africa, and Asia during the 16th and 17th centuries, following trading routes and urban development. In the French and Indian Wars (1754–1767) in the United States, smallpox (variola virus infection) was used as a biological weapon by British soldiers who gave blankets used by smallpox victims to Native Americans (1). Epidemics resulted with over 50% mortality in affected tribes. The devastation of smallpox was arrested by the introduction of widespread vaccination programs. Despite international agreements, variola virus stocks were created in the 1980s and 1990s for possible use as biological weapons (2,3). Following the cessation of routine vaccination worldwide in 1980, most of the world's population has become susceptible to smallpox. Data are limited regarding the duration of the survival of variola virus in the environment; however, the infectious dose of virus is small and aerosol release of smallpox virus could cause widespread disease with significant morbidity and mortality.

In the aftermath of attacks with biological agents in the United States (i.e. Anthrax bacillus) and the current environment of uncertainty about bioterrorism, the Centers for Disease Control and Prevention (CDC) in the United States presented a plan for implementing a large-scale smallpox vaccination program consistent with recommendations made by the Advisory Committee on Immunization Practices (3–6). Similar programs have been developed in Israel, the United Kingdom, and by the World Health Organization (7). The vaccination program involves the formation of Smallpox Response Teams to be mobilized if cases of smallpox are identified, and targeted vaccination of individuals within geographic regions containing cases of smallpox exposures. This strategy is designed to establish teams of vaccinated clinicians to provide medical care to individuals infected with smallpox, to perform vaccinations, to keep medical facilities open, and to contain outbreaks. At present, it is not recommended that all members of the general public be vaccinated; however, enough vaccine is available for widespread vaccination if an outbreak should occur. More general vaccination programs have been suggested for future consideration.

The possible reintroduction of smallpox vaccination programs raises questions about smallpox (variola virus), the smallpox vaccine (live vaccinia virus), and the potential risks of such vaccines in transplant professionals and in immunocompromised patients who may have enhanced susceptibility to smallpox or to side-effects of vaccination. This review discusses the relevant issues as applied to organ transplant recipients and their healthcare providers.

Smallpox

  1. Top of page
  2. Abstract
  3. Introduction
  4. Smallpox
  5. Smallpox Vaccine: Vaccinia Virus
  6. The Risks of Smallpox Vaccination in Immunocompromised Individuals
  7. Nosocomial Spread of Vaccinia
  8. References

Smallpox is a disease caused by variola virus, a large, enveloped DNA virus of the Poxviridae (8–10). This virus replicates in the cytoplasm of host cells, producing inclusion bodies distinct from the nuclear inclusions of varicella or herpesviruses. The infectious dose of virus is thought to be low (10–100 organisms) (11). The portal of entry for smallpox is usually via the oropharynx or respiratory mucosa (aerosol droplets), although infections via conjunctiva, skin, and transplacentally have occurred. Close contact is generally needed for transmission, although fomite transmission (e.g. blankets) and infection via air currents have been implicated in small numbers of cases (12). Humans are the only natural reservoir for this infection.

Smallpox is a serious, contagious, and sometimes fatal infectious disease (3). The spread of smallpox in a community is slower than for chickenpox or measles. This is a reflection of the need for close contact for person-to-person spread of infection. Usually the individual with active smallpox is confined to bed by fever, headache, and myalgias, prior to the development of rash; transmission occurs only after the development of rash. Variola virus appears to retain infectivity in the environment and on surfaces for a prolonged, but uncertain, duration. There are two clinical forms of smallpox. Variola major is the severe and most common form of smallpox, with a more extensive rash and higher fever. There are four types of variola major smallpox: ordinary (the most frequent type, accounting for 90% or more of cases); modified (mild and occurring in previously vaccinated persons); flat; and hemorrhagic (both rare and very severe). Historically, variola major has an overall case fatality rate of about 30%; however, flat and hemorrhagic smallpox are usually fatal. Variola minor is less common and is less severe disease, with death rates historically of 1% or less.

After exposure, asymptomatic viremia occurs on the third or fourth day with secondary viremia by day 8–12. Secondary viremia is followed by fever and toxemia and the development of a florid, diffuse, uniform rash consisting of firm, round, tense, deeply embedded, raised pustules (11). The rash is the result of small vessel infection in the dermis and oropharynx. Initial papular lesions in the mouth (enanthem) progress to vesicles and ulceration over several days. Subsequent lesions appear on the face (‘herald lesions’) and then distal extremities, including palms and soles. With ulceration of the oral lesions, transmission may occur (about day 14 after infection or for the first 7–10 days of rash) with secondary attack rates variously reported at 37–70% in the absence of immunity. Individuals without rash are considered noninfectious. The vesicles scab over (7–9 days), with subsequent recovery in the presence of an immune response. Communicability is thought to persist until the scabs fall off. Smallpox may be confused with many other common forms of diffuse rashes (see Table 1). Of these, chickenpox, shingles, and disseminated varicella zoster virus infection are the most common in immunocompromised individuals (see Table 2). Notably, chickenpox produces a nonuniform rash with superficial lesions at multiple stages of development in the absence of a significant prodrome (Table 2). Any patient with an unidentified rash should be placed in respiratory and contact isolation away from other immunocompromised individuals during the period of evaluation.

Table 1. : Differential diagnosis of rash-associated illnesses in the immunocompromised individual in the era of bioterrorism*
  • *

    Not in order of severity or incidence.

• Smallpox (variola)
• Disseminated vaccinia or vaccine complications (see Table 3)
• Disseminated varicella zoster virus (VZV) & Chickenpox
• Disseminated Herpes simplex virus (HSV)
• Enteroviral infection (Hand, foot and mouth disease)
• Molluscum contagiosum
• Drug eruptions
• Allergic dermatitis or urticaria
• Secondary syphilis
• Rickettsial infection
• Erythema multiforme
• Acne
• Impetigo (Staphylococcus or Streptococcus)
• Scabies or insect bites
• Monkeypox
Table 2. : Features distinguishing smallpox (variola) infection from chickenpox (Varicella zoster) infection
Smallpox (Variola)Chickenpox (VZV)
Acute onset of prodrome including fever (often > 101°F), headache, backache, abdominal pain, rostration, chills, vomiting)No or mild prodrome (Disseminated VZV may present with abdominal pain, biliary colic, fever in compromised host)
Rash: slow evolution of firm, deep-seated, vesicles or pustulesRash: rapid evolution of superficial lesions
Lesions all at same stage of developmentCrops of lesions at different stages
Rash: Centrifugal distribution (oral mucosa, face, forearms first) may have lesions on palms and solesRash: Centripetal distribution (trunk first), rarely on palms or soles
Often toxicRarely toxic (except disseminated VZV in compromised host, pneumonitis, bacterial superinfection)
Exclude other causes including recent vaccination for vacciniaTzanck prep (α-herpesviruses), DFA, PCR, exclude other causes including recent vaccinations (varicella)
Airborne and contact precautions (Isolation), Alert authorities, AssessIsolation, consider Varicella immune globulin, antiviral agents

In individuals with deficient cell-mediated immunity, flat-type smallpox may be more common (10,12–14). The course of the disease is similar to that of other nonimmune hosts, with lesions developing more slowly without progression to pustule formation. Instead, the lesions remain soft and flattened and may become confluent, warm, and tender. Such lesions do not scab over but may proceed to desquamation. The case fatality rate of flat smallpox prior to universal vaccination was over 97%; this rate may be reduced with current supportive medical technologies. Hemorrhagic smallpox is uncommon (2–3% in past outbreaks) but was more common in adults and pregnant women (15–17). These individuals have a syndrome consistent with disseminated intravascular coagulation with diffuse hemorrhage into skin and mucous membranes. This form of disease may be more common in the setting of defective humoral immunity.

Overall death rates are estimated at 22.5% among unvaccinated individuals who develop disease, 8.5% among persons vaccinated in the past and 0.43% if recently vaccinated. Deaths usually occur in less than 18 days (generally < 14) after the onset of symptoms. The cause of death is controversial. Viral infection of lungs, trachea, esophagus, and larynx may progress to lethal interstitial pneumonitis and renal failure due to tubulointerstitial nephritis (18). In addition, immune complex disease and bacterial superinfection may occur (19). There is no specific treatment for smallpox disease although symptoms may be ameliorated using varicella immune globulin; antiviral agents are under investigation. In vitro, both ribavirin and cidofovir have activity against the pox viruses and merit consideration for use in progressive infection due to variola or vaccinia (20). Both humoral and cell-mediated immunity contribute to control of variola infection (8). The prevalence of such deficiencies in the general population is not known. In the absence of data to the contrary, it is anticipated that the mortality rate would be higher in immunocompromised individuals.

Smallpox Vaccine: Vaccinia Virus

  1. Top of page
  2. Abstract
  3. Introduction
  4. Smallpox
  5. Smallpox Vaccine: Vaccinia Virus
  6. The Risks of Smallpox Vaccination in Immunocompromised Individuals
  7. Nosocomial Spread of Vaccinia
  8. References

Smallpox was a major epidemic disease by the mid-1700's. Vaccination with variola virus derived from lesions of infected individuals was practised in China as early as 1000 AD. Such practices had a fatality rate of up to 2%. Edward Jenner developed a safer vaccine against smallpox in the late 1700's using the related cowpox virus. A vaccinia virus vaccine replaced the Jenner vaccine in the 1800's. Vaccinia is related to variola but the origins of this virus remain unknown. The prolonged presymptomatic phase of smallpox (∼ 10–14 days) is generally sufficient to allow interruption of the course of the disease after exposure through early vaccination (usually less than 4–5 days). Immunity to smallpox develops 8–11 days after vaccination. In smallpox emergencies, exposed individuals will be vaccinated and individuals with smallpox isolated. Containment is achieved through ‘targeted vaccination’ of individuals in the immediate community, usually on a large-scale but voluntary basis. A new, culture-derived vaccinia vaccine is in production but has not yet been tested in large-scale clinical trials.

As a result of universal vaccination, no cases of smallpox have been reported anywhere in the world since 1977; the last case in the United States was in 1949. This observation is key in that many of the known conditions associated with immune compromise (e.g. solid organ transplantation, hematopoietic transplantation, AIDS, connective tissue diseases, many cancer therapies) have been recognized only since 1977. Many such individuals either have not been vaccinated or may have lost immunity as a result of immune deficits.

Historically, the vaccinia vaccine has been effective in preventing smallpox infection in 95% of those vaccinated. In addition, the vaccine was proven to prevent or substantially lessen infection when given within a few days of exposure. In normal hosts, smallpox vaccination provides a high level of immunity for 3 to 5–10 years and decreasing immunity thereafter. Most Americans aged > 30 years received smallpox vaccinations. In normal individuals, there is no longer detectable vaccinia antibody. However, there appears to be some residual immunity that reduces the duration of viral shedding after re-vaccination and reduces the incidence of side-effects from vaccination. These advantages are less likely to be present in immunosuppressed individuals. Immune responses of transplant patients to common vaccines are, in general, decreased in amplitude but measurable. Multiple courses of vaccination may augment efficacy in these hosts.

Despite obscure origins, vaccinia virus has been extensively studied as a vaccine for smallpox (variola virus) and as a vector for other genes. Vaccinia provokes strong cellular and humoral immune responses. Recombinant vaccinia vaccines have been investigated for cancer therapy (e.g. melanoma, cytokines), and in vaccines for HIV, Epstein-Barr virus, and other pathogens. Dendritic cells infected or pulsed with vaccinia virus have been used to express native and recombinant antigens in the context of MHC class I molecules (21,22). Dendritic cells present antigens from infecting virus and from apoptotic and necrotic cells, stimulating memory cells, priming naïve T-cells, and generating humoral immune responses (23–25). Vaccinia induces a variety of mechanisms for immune evasion that may reduce the direct cellular immune response to these cells (26). These features may contribute to the susceptibility of individuals with abnormal cutaneous immunity (e.g. those with eczema and atopic dermatitis) to disseminated infection and fatal disease after vaccinia exposure.

The Risks of Smallpox Vaccination in Immunocompromised Individuals

  1. Top of page
  2. Abstract
  3. Introduction
  4. Smallpox
  5. Smallpox Vaccine: Vaccinia Virus
  6. The Risks of Smallpox Vaccination in Immunocompromised Individuals
  7. Nosocomial Spread of Vaccinia
  8. References

Current CDC guidelines for pre-event (exposure) vaccination state: ‘If a potential vaccinee or any of their household contacts have conditions such as HIV/AIDS, solid organ or stem cell transplant, generalized malignancy, leukemia, lymphoma, agammaglobulinemia, or autoimmune disease, they should not be vaccinated. If a potential vaccinee or any of their household contacts are undergoing treatment with radiation, antimetabolites, alkylating agents, corticosteroids, chemotherapy agents, or organ transplant medications, they should not be vaccinated. People with these conditions are at greater risk of developing a serious adverse reaction resulting from unchecked replication of the vaccine virus (progressive vaccinia)’ (full guidelines for vaccination at http://www.cdc.gov). In addition, individuals with a history of atopic dermatitis or eczema (risk for eczema vaccinatum), and pregnant woman should not be vaccinated unless exposure to smallpox has occurred. Consistent with these guidelines, transplant recipients should NOT receive this vaccine unless exposure to smallpox has occurred. Such vaccination would occur only in the context of either direct exposure to an individual with smallpox rash or with widespread vaccination in the community after a documented bioterrorist event. In the setting of bioterrorism, primary vaccination with careful follow-up is likely preferable to unknown, inadvertent secondary exposure to vaccinia by social contacts.

The risks associated with vaccination of transplant recipients with any live, attenuated, vaccines have not been well quantified. Vaccination prior to transplantation is preferred (27–29). Experience with live viral vaccines in transplantation is limited (30,31). Varicella vaccine, a live, attenuated, viral vaccine, was given to leukemic children, with 50% developing mild rash and no serious complications (32). Seroconversion was obtained in 90% only after two doses of vaccine, but protection against severe disease was universal. We have also observed mild, disseminated varicella (chicken pox) without severe complications in some varicella-vaccinated pediatric transplant recipients. Similar to our experience, varicella vaccine was administered to 17 pediatric renal transplant recipients with 65% seroconversion and one mild rash (33–35). Measles vaccination in small groups of post-transplant patients has been achieved without complications but the efficacy is unknown and pretransplant vaccination is preferred. Mumps and rubella vaccines have been given to small series of bone marrow transplant recipients and renal transplant recipients without incident (36,37). Anecdotal reports of rejection associated with live-virus vaccination have not been confirmed in our transplant population (38). However, protection against viral infection has been variable.

Vaccinia vaccine has many potential adverse effects (see Table 3). The overall complication rate is approximately 0.4 per 10 000 vaccinees, with approximately one death per million primary vaccinations (39–41). The rate of side-effects is expected to be lower in the previously vaccinated, partially immune population. These include:

Table 3. : Possible side-effects of vaccinia vaccination
Side-effectDescriptionRisk factors
Local‘Robust take’ (> 7.5 mm erythema) ∼ 8–10 days post vaccination, pain,First-time vaccination
 fever, bacterial superinfection 
Erythema multiformeSkin (bull's eye) target lesions, edema, sloughing, pruritis, ∼10 days post vaccinationNone known
or Stevens–Johnson  
syndrome  
InadvertentSpread to other sites by direct contact with the vaccination siteManipulation of site (esp. young children),
inoculation skin conditions (psoriasis, acne)
Ocular vacciniaKeratitis, Conjunctivitis, BlepharitisSite manipulation without hand decontamination
  (eye rubbing), eye injuries (abrasions), children
Eczema vaccinatumFever, Diffuse vesicular or pustular rash containing virus over abnormal areas ofEczema (past or present)
 skin, lymphadenopathy, 5–19 days post vaccinationAtopic dermatitis (past or present)
Progressive vacciniaNon-healing site with central necrosis, disseminated infection (skin, viscera),Immune deficits (humoral or cellular)
 toxic, superinfection, often fatal(exclude other disseminated viral infections)
Post-vacciniaAbrupt onset of headache, fever, lethargy, confusion, coma, seizuresAge < 1 year
encephalitis or(Note: similar to other post-viral encephalitis syndromes) 
encephalomyelitis  
Fetal vacciniaFetal loss, prematurityGreatest in 3rd trimester
Generalized vacciniaDiffuse maculopapular or vesicular rash 6–9 days post vaccination, nontoxicImmune deficits may exacerbate
  • • 
    Fever.
  • • 
    Localized reactions including satellite lesions, cellulitis-like reactions, bacterial superinfections, robust reactions (>7.5 mm area of erythema), erythema multiforme, or lymphadenopathy. These have been observed in some recent vaccinees.
  • • 
    Generalized vaccinia (vesicles or pustules on normal skin distant from the vaccination site). This is usually a self-limited infection that occurs 6–9 days after vaccination but would be of unknown duration in immunocompromised individuals and might require therapy with vaccinia immune globulin (VIG) (42). At least one case has been described (February, 2003) in a vaccinated nurse with normal immunity.
  • • 
    Progressive, disseminated, vaccinia (or vaccinia necrosum) estimated to occur in 1.5 out of each 1 million individuals vaccinated with a 33% mortality (10,43). This complication has been described in patients with decreased cell-mediated immunity, including organ transplant recipients, and patients with AIDS, hematologic malignancies, cancer chemotherapy, chronic corticosteroids, and primary and acquired immunodeficiency disorders. In this condition, lesions of disseminated vaccinia fail to heal and develop new satellite ulcers at the site of inoculation with a widespread, disseminated pustular rash and viremic spread to other sites. This complication may occur after primary vaccination or revaccination and is usually fatal. In AIDS patients, a recombinant vaccinia trial was complicated by local necrosis and deaths in three of eight patients with CD4 counts <50/mm3 (44). VIG and other therapies would be utilized in progressive vaccinia infections.
  • • 
    Eczema vaccinatum (38 cases per million vaccinees with estimated 1% mortality) with localized or disseminated vaccinia in individuals with eczema or atopic dermatitis (up to 20% of the population), particularly in skin previously affected by these conditions. Such patients may manifest systemic toxicity and require VIG therapy.
  • • 
    Post-vaccination encephalitis/encephalopathy (12.5 cases per million with estimated 5–25% mortality and 25% permanent neurological injury). Such patients may present with cerebral or cerebellar dysfunction with headache, fever, vomiting, altered mental status, lethargy, seizures, or coma. This is not thought to be a reflection of replicating virus.
  • • 
    Vaccinia keratitis.
  • • 
    Inadvertent inoculation that occurs when vaccinia virus is transferred from a vaccination site to a second location on the vaccinee or to a close contact. Usually, this condition is self-limited. Inoculations of the eye require evaluation by an ophthalmologist.
  • • 
    Secondary spread of vaccinia (see below), as was recently observed in a contact of a vaccinated soldier.
  • • 
    Fetal vaccinia (congenital infection, often stillbirth).
  • • 
    The vaccine contains small amounts of polymyxin B sulfate, streptomycin sulfate, chlortetracycline hydrochloride, neomycin sulfate, and phenol to which an individual may be allergic. The vial is sealed with a latex stopper.
  • • 
    Possible graft rejection (as with all acute systemic viral infections).
  • • 
    Activation of other latent viral infections (e.g. CMV).

Nosocomial Spread of Vaccinia

  1. Top of page
  2. Abstract
  3. Introduction
  4. Smallpox
  5. Smallpox Vaccine: Vaccinia Virus
  6. The Risks of Smallpox Vaccination in Immunocompromised Individuals
  7. Nosocomial Spread of Vaccinia
  8. References

Medical personnel should consider whether they might place immunocompromised individuals at risk by receipt of vaccine. Vaccinia virus from the vaccination site can be transmitted to other persons, generally only with direct contact with the site (at a historic rate of up to 44.6 per million primary vaccinations) (45–49). Vaccine virus is shed from the vaccination site for 19–21 days in individuals vaccinated for the first time and a shorter, variable period in persons who have been previously vaccinated. Historically, secondary spread of vaccinia after vaccination was uncommon. When this has been reported, the most severe forms of disseminated infection (‘progressive vaccinia’) have not occurred. Individuals developing secondary vaccinia have been those with preexisting skin conditions (atopic dermatitis or eczema) or with underlying immune deficits including hypogammaglobulinemia, cellular immune defects, or hematologic malignancies (especially chronic lymphocytic leukemia) (12,39,41,48,50,51). While these infections were generally in the form of eczema vaccinatum, they were often fatal. Some responded to treatment with vaccinia immune globulin.

Little is known about the risk of vaccinia virus transmission in hospitals. Many patients have varying degrees of immune impairment, and health care workers who are largely unvaccinated may, themselves, be immunocompromised. Nosocomial spread of vaccinia virus is uncommon historically [see Sepkowitz for recent review (39)], but the population of immunocompromised individuals has increased substantially in recent years. Virus can be carried on the skin and oropharynx and on clothes, blankets and equipment.

Physicians, surgeons, nursing staff and other medical staff who are vaccinated should cover the vaccination site carefully and minimize contacts with immunocompromised individuals to the degree possible. Covering the site will generally prevent transmission. However, virus may occasionally spread through bandages (42,45,47–49). To minimize secondary spread of vaccinia, vaccinees should decontaminate their hands after manipulating the vaccination site and carefully dispose of used bandages.

It may be safest for transplant recipients to avoid direct contact with a vaccinated individual's vaccination site for approximately 3 weeks. In the hospital setting, this restriction may not be feasible. The risks of such contacts in a given individual remain undefined. Thus, healthcare workers with significant contacts with immunocompromised individuals should consider avoiding vaccination, vaccination followed by adequate (3-week) furlough from patient contact activities, or delayed vaccination until data regarding the nosocomial spread of infection are further elucidated.

If contacts between a vaccinee and an immunocompromised host should occur, and if the patient becomes ill as a result, the patient should be isolated and vaccinia immune globulin (VIG) should be considered for treatment. Other potential diagnoses should be excluded and the diagnosis of vaccinia infection confirmed (see Tables 1 and 2). Serologic testing for vaccinia is generally uninformative, as seroconversion may not occur in a timely fashion in compromised individuals; such tests do not distinguish vaccinia immunity from vaccinia infection. Diagnostic tests for vaccinia include molecular assays (PCR), electron microscopy, or viral culture. These tests have not yet been validated for general use. Specimen collection guidelines are available at http://www.bt.cdc.gov/agent/smallpox/vaccination/vaccinia-specimen-collection.asp. Local health authorities should be notified of adverse reactions to vaccinia.

Should an individual develop progressive vaccinia, VIG may be administered; historical experience suggests the response to VIG is variable (52–54). VIG is available from the CDC (404-639-3670) with a usual dose of 0.6 mL/kg intramuscularly or about 40 mL given in divided doses over 24–36 h. In severe cases of progressive vaccinia or eczema vaccinatum, higher doses (1–10 mL/kg in divided doses at multiple sites) have been used. VIG is not recommended for prophylaxis, mild vaccinia rash, erythema multiforme, or encephalitis post vaccination. In the absence of data regarding the efficacy of VIG in prevention of sequelae of vaccination, VIG is not currently recommended for use with vaccination. Cidofovir and ribavirin have been suggested for therapy of progressive infection based on in vitro activity, activity in vivo in a rodent model, and anecdotal reports (20,55). There are, as yet, no in vivo data to support this use. Cidofovir is available under an Investigational New Drug protocol when VIG is not effective in vaccine-related infections. Cidofovir may be associated with significant renal toxicity, particularly in the presence of pre-existing renal dysfunction or other nephrotoxic agents including calcineurin inhibitors. Cidofovir should be used with hydration; probenecid is generally used with cidofovir in the nontransplant population, but is generally contraindicated in transplant patients with any degree of renal impairment.

With regard to current public health programs, the following points are emphasized:

  • • 
    Smallpox vaccination will be voluntary.
  • • 
    In the presence of an outbreak, everyone who has been in contact with a case of smallpox or is determined to have been exposed to smallpox virus is advised to get smallpox vaccine regardless of medical condition.
  • • 
    In the absence of contact or other type of exposure, smallpox vaccination is not recommended for persons with immune deficiency, eczema, or other conditions outlined above.
  • • 
    It is recommended that family members and social and sexual contacts of the compromised host not be vaccinated. If vaccinated, they should consider living apart for 3 weeks to avoid secondary spread. Careful care of the vaccination site and hand washing are essential to avoid secondary vaccinia.
  • • 
    The consequences of nosocomial spread are less dramatic than for either primary variola or disseminated vaccinia. To the degree possible, vaccinated medical personnel should be removed from direct contact with immunocompromised individuals until inoculation sites no longer shed virus.
  • • 
    Recent vaccinees should not serve as living or cadaveric organ donors. Vaccinia virus is shed for up to 3 weeks after vaccination. During this time, immunity sufficient to prevent person-to-person spread of vaccinia and variola develops. It is not known whether individuals continue to harbor live virus beyond this period. Given that primary viral infections (e.g. West Nile Virus) have been transmitted from asymptomatic organ donors to allograft recipients, virologic data (e.g. viral PCR) should be obtained before such organs are utilized.

There is considerable uncertainty regarding the risk of a bioterrorist event due to smallpox and the risks and benefits of widespread vaccination (56,57). There are some differences of opinion as to the best way to protect local communities. The impact of widespread vaccination on immunocompromised individuals remains unknown. It is the obligation of physicians and medical institutions to assure that they are prepared to respond in the event of any type of terrorist attack. Thus, each institution must participate in on-going dialogues regarding smallpox and other possible biological weapons.

The CDC guidelines for the Smallpox Vaccination Program and the reports of the Advisory Committee on Immunization Practices (ACIP) can be found at the Centers for Disease Control and Prevention (CDC) website at http://www.CDC.gov. An overview of some aspects of smallpox vaccination strategies is presented in the New England Journal of Medicine, 2003; 348 (5).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Smallpox
  5. Smallpox Vaccine: Vaccinia Virus
  6. The Risks of Smallpox Vaccination in Immunocompromised Individuals
  7. Nosocomial Spread of Vaccinia
  8. References
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