Smallpox Vaccination and the Patient with an Organ Transplant
- Donald A. Henderson, Section Editor,
- Thomas V. Inglesby Jr., Section Editor, and
- Tara O'Toole, Section Editor
- 1Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
- 2Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Reprints or correspondence: Dr. Lesia Dropulic, Dept. of Medicine, Johns Hopkins Medical Institutions, 720 Rutland Ave., Ross Bldg., Rm. 1151, Baltimore, MD 21205 (lesia{at}jhmi.edu).
Abstract
Organ transplant recipients are vulnerable to a variety of infections because of the immunosuppressed state required to prevent organ rejection. We review the recommendations of the Centers for Disease Control and Prevention (Atlanta, Georgia) for smallpox vaccination and the possible complications of vaccination in the population with organ transplants. The risk of these complications is presumably dependent on the extent of deficient cell-mediated immunity.
On 23 September 2002, the Centers for Disease Control and Prevention (CDC; Atlanta, GA) presented a detailed operational plan for large-scale smallpox vaccination [1], and the US President has now officially recommended this course of action. Phase 1 began on 24 January 2003 and targeted ∼450,000 public health officials and hospital-based health care workers who, in the event of a smallpox outbreak caused by a biological-weapon attack, are to provide smallpox care for 7–10 days, until a larger hospital workforce can be vaccinated. In the event of an attack, all exposed persons would be vaccinated. Phase 2 targets 10 million health care workers and first responders, but it will not begin until later in 2003, with a plan that is somewhat contingent on the experience with phase I. The purpose of this report is to review the CDC plan and the relevant issues as they apply to persons who have received organ transplants.
The main points of the CDC plan are as follows:
Smallpox vaccination will be voluntary.
In the event of an outbreak, everyone who has been in contact with a person with smallpox or who has been exposed to a biological weapon that disseminated the smallpox virus is advised to undergo smallpox vaccination regardless of their medical condition. Close contacts of such persons will also be offered the vaccine.
In the absence of exposure, smallpox vaccination is not recommended for persons with compromised cell-mediated immunity (CMI), including organ transplant recipients.
Because of the possibility of contact vaccinia, vaccination should also be avoided for anyone who is a household contact of a person with defective CMI.
Persons with severe immune deficiencies may develop severe complications following smallpox vaccination—primarily, progressive vaccinia, which is frequently lethal.
Severe reactions to the vaccine, such as progressive vaccinia, may be treated with vaccinia immune globulin (VIG) and/or cidofovir; both treatments are considered investigational.
The risks of mortality from smallpox or progressive vaccinia following smallpox vaccination are presumably dependent on the extent of deficient CMI.
We provide the following additional relevant points regarding smallpox vaccination for organ transplant recipients.
What is the expected outcome of smallpox in the organ transplant recipient who has not been vaccinated? The answer is unknown, because smallpox was eradicated before there was extensive experience with organ transplantation. However, such patients would be expected to be particularly vulnerable to serious consequences of variola infection because of the immunosuppressed state that is maintained to prevent organ rejection. Such patients demonstrate major defects in CMI and humoral immunity [2], both of which are considered important for containing variola virus infection [3]. The mortality rate associated with major variola infection among unvaccinated immunocompetent persons is 10%-30%, so the assumption is that the rate would be greater among patients with immunosuppression and that the extent of the increase would depend primarily on the extent of defective CMI.
Would patients with organ transplants generate an immune response to smallpox vaccine? Patients who are immunosuppressed following organ transplantation and who receive Pneumovax (Merck) or other vaccines do mount a serologic response [4, 5]. However, the quality of this response is unclear, and the CMI response is probably more important in preventing infection with the vaccinia or variola viruses. The ability to mount an adequate CMI response depends on the degree of immunosuppression, as described below.
What are the risks of smallpox vaccination for patients with organ transplants? The major risk is progressive vaccinia (vaccinia necrosum or vaccinia gangrenosum). This is the most dreaded complication of smallpox vaccination and is seen primarily in patients with compromised CMI, such as patients with AIDS, patients receiving cancer chemotherapy or long-term corticosteroid therapy, patients with combined immunodeficiency disorders, and organ transplant recipients. The reaction consists of progressive enlargement of the primary site of vaccination with viremic spread to other sites; usually, 10–20 new cutaneous lesions evolve over days or weeks. In some cases, the vaccinia remains limited to the region of the vaccination site [3, 6–10]. This complication may occur following primary vaccination (i.e., in patients not previously vaccinated) or revaccination. One soldier with AIDS had this reaction in 1984 [10], but an analysis suggested that >300 other soldiers with HIV infection had received smallpox vaccine without incident; thus, the assumption is that progressive vaccinia is rare even among persons with compromised CMI or occurs only in persons with a very severe immune defect. The fatality rate is reported to be 43%-80% and is presumed to be dependent on the extent of CMI deficiency. The highest mortality is among infants with congenital immunodeficiencies [7]; adults often survive or show partial response before dying of their underlying disease.
Is there a treatment for progressive vaccinia? The standard treatment is administration of VIG [3, 6–11]. The efficacy of VIG therapy is not known, because no controlled trial has been done. The anecdotal experience is variable. The supply of VIG is currently controlled by the CDC (for information, telephone [404] 639-3670). The usual dose is 0.6 mL/kg given intramuscularly, for a total dose of ∼40 mL, usually administered in 24–36 h. There are in vitro data showing cidofovir is active against vaccinia virus and animal data showing in vivo activity against vaccinia virus and other poxviruses [12–15], but the clinical experience is nil. Ribavirin may also be effective, but the clinical experience is limited to a single patient, who was also given VIG [15, 16].
Is the organ transplant recipient at risk for secondary spread of vaccinia virus among contacts? Vaccination with vaccinia virus causes a pustule, often with satellite lesions that shed virus for up to 20 days after vaccination [17]. Shedding may occur through standard semipermeable bandages, and this can become the source of vaccinia virus exposure for contacts. This complication, referred to as“contact vaccinia,” is rare: it occurs in 2–6 per 100,000 persons who receive primary vaccination, according to published reports [17–19]. This type of transmission requires close contact, and it occurs almost exclusively among household contacts and rarely in the hospital [17]. Complications of contact vaccinia are obviously of much greater concern if the household contact has an immunodeficiency that might result in progressive vaccinia. The implication is that a person who lives with an organ transplant recipient should avoid vaccination or, if vaccinated, should avoid direct contact with the transplant recipient until the vaccination scab dislodges, which usually occurs ∼3 weeks after vaccination. Despite these concerns, virtually all reported cases of progressive vaccinia have occurred in vaccine recipients rather than in their contacts. An exception is a case that occurred in a hospital engineer in New Zealand with lymphocytic leukemia, who developed a vaccinia infection on the leg, presumably from contact with contaminated hospital equipment [20].
Does the level of immunosuppression matter? The level of immunosuppression is the underlying critical factor in rendering a person susceptible to both smallpox and vaccinia infection. In organ transplant recipients, the degree of immunosuppression is defined, to a large extent, by the immunosuppressive drugs taken, which include corticosteroids, mycophenolate mofetil, cyclosporine, and tacrolimus. The risk of infection can be quantified according to the immunosuppressive agents used, their dosages, and the duration of immunosuppressive treatment. It is clear that patients receiving full doses of immunosuppressive agents during the early posttransplantation period would be highly vulnerable. Whether patients receiving relatively low doses of immunosuppressive agents who have a stable clinical course can be vaccinated safely is unknown. Therefore, the conservative approach is to avoid voluntary vaccination in the absence of smallpox exposure. The degree of immunosuppression presumably dictates the risk of death from smallpox infection and the probability of development of progressive vaccinia following vaccination or following contact vaccinia.
Are there transplant recipients for whom smallpox vaccination could be considered safe? The recommendations for organ transplant recipients do not apply to transplant recipients for whom systemic immunosuppressive therapy is not used, such as recipients of cornea, bone, or cartilage transplants [21, 22]. Vaccination is also probably safe for patients who have received organ transplants and are clinically stable and receiving no immunosuppressive therapy, but recommendations for such exceptions are not included in the current guidelines, because there is no relevant experience.
Are there situations in which organ transplant recipients who are receiving immunosuppressants would be considered candidates for vaccination? All of the exclusions for smallpox vaccination apply to voluntary vaccination, in the absence of an attack that disseminates the smallpox virus. If there is such an attack, vaccination would be voluntary but would be recommended for all who are exposed.
Does prior smallpox vaccination make a difference? Routine smallpox vaccinations were suspended in the United States in 1971 because of the successful elimination of variola virus infection in the United States. The World Health Organization declared in 1980 that the world was free of smallpox, and vaccination for civilians was subsequently available only to laboratory workers working with variola virus and related orthopox viruses [23]. Persons aged <30 years in the United States are generally unvaccinated. Persons who have been vaccinated previously generally show no detectable antivariola antibody 5–10 years after vaccination, but even those vaccinated >50 years ago still show clinical evidence of protection against severe or fatal smallpox, which suggests the importance and persistence of the CMI response. Also, persons vaccinated previously generally are less likely to have a reaction to revaccination and possibly to experience an amnestic response after revaccination. For this reason, some first-response teams will give higher priority to vaccination of persons who have been vaccinated previously. On the basis of experience with other vaccines, it is thought that some organ transplant recipients may experience an amnestic response after revaccination, but this response would be blunted because of the intervening immunosuppression.
- Received January 9, 2003.
- Accepted January 30, 2003.
- © 2003 by the Infectious Diseases Society of America
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