As the country gears up for smallpox vaccinations, physicians find themselves on the front lines
From the January ACP-ASIM Observer, copyright © 2003 by the American College of Physicians-American Society of Internal Medicine.
By Phyllis Maguire
Within weeks or months, physicians will be called upon to consider doing something virtually no Americans have done in 30 years: Roll up their sleeves and get vaccinated against smallpox.
In December, the Bush administration announced a far-reaching vaccination policy. The first phase calls for inoculating as many as 440,000 health care workers in American hospitals with smallpox vaccine later this month. Government officials believe that vaccinating some hospital staff is a crucial first step in containing any potential smallpox bioterrorist attack.
The next phase of the policy, which is slated to begin in March and end this summer, promises to affect all practicing physicians. The government will offer the vaccine to about 10 million civilians, including all physicians, nurses, and fire and police department personnel.
By this summer, government officials plan to roll out a third phase: Members of the general public who want to be vaccinated will be allowed to enroll in vaccine trials. Administration officials have said, however, that general vaccinations are not being recommended for the public until a safer vaccine comes to market in 2004.
The first two phases of the new policy present monumental challenges to state health departments, acute care hospitals and medical practices. As hospital workers begin to get vaccinated, some internists will likely have to cope with temporary staffing disruptions as colleagues experience reactions to the vaccine.
The policy, however, also promises to affect the country's physicians on a much more personal level. Hundreds of thousands of hospital-based physicians and other providers are being asked to make a tough personal decision about whether to get inoculated for smallpox. And as early as March, office-based physicians may have to make the same daunting choice.
That decision is difficult because the smallpox vaccine carries higher risks than any other vaccine in use today. The risks are particularly high for people 30 or under, who have never been inoculated and could develop severe reactions. And because the vaccine uses live vaccinia virus, health care workers who get vaccinated can potentially transmit the virus to patients or family members.
The government's policy raises concerns for another reason. It calls for vaccinating large portions of the population much more quickly than some physicians are comfortable with. The new policy, in fact, goes far beyond the recommendations of the CDC's scientific advisors, raising concerns about its safety.
While there is nothing new about medical personnel serving on the front lines of vaccine research, the new vaccination policy is unique. "We've never faced a situation where a preventive measure, particularly one that carries these risks, is being adopted when the disease doesn't occur," explained infectious diseases specialist Marguerite A. Neill, FACP, associate professor of medicine at Brown University in Providence, R.I., and chair of the bioterrorism work group for the Infectious Diseases Society of America.
Formulating a vaccination policy
The anthrax attacks of 2001 made the prospect of bioterrorism a reality. National attention immediately focused on other potential bioterrorist agents including smallpox, which can kill up to 30% of its victims. Making matters worse, reports warned that the smallpox virus—which is transmitted in the air—has been produced in a version that can be aerosolized.
Last June, the Advisory Committee on Immunization Practices (ACIP), which advises the CDC, issued a recommendation that was strongly endorsed by the College and other groups, including the AMA. At that time, the ACIP recommended inoculating a small group of about 20,000 health care and public health professionals.
Last October, however, the committee issued more sweeping recommendations. It recommended that every acute care hospital in the country vaccinate up to 200 staff members in order to have an immunized team in-house to provide around-the-clock care to potential smallpox victims. (The October recommendations are online.)
The ACIP recommended vaccinating a long list of workers that included some members of emergency department and intensive care unit staff; specialists in infectious diseases, dermatology and possibly ophthalmology; general medical staff; and hospital transport, housekeeping and security personnel. Analysts at the time estimated that the committee's recommendations could encompass as many as 500,000 hospital workers nationwide—a policy informally endorsed by the College's Clinical Efficacy Assessment Subcommittee.
ACIP members said that two factors led them to expand their initial recommendation: possible war with Iraq, and complaints that individual hospitals did not want to be designated as their communities' sole smallpox treatment center.
While the Bush administration adopted some of the ACIP's recommendations, it went far beyond what the committee proposed in October. The administration will offer vaccine to as many as 440,000 hospital workers beginning in late January. The entire medical community, as well as emergency response personnel, will be offered the vaccine as early as March.
Some analysts applauded the government's resolve to vaccinate all health care workers. John A Mitas II, FACP, the College's Deputy Executive Vice President, for instance, helped develop vaccines for the military before he began working at the College last year. He pointed out that patients ill with smallpox—who would present with fever, backache and headache days before any telltale rash would appear—would probably go to a physician's office first.
"I think our policy should target all health care professionals, not just emergency department and hospital personnel," Dr. Mitas said. "Many people don't use hospitals for their initial care."
Others, however, say that any preemptive policy in the absence of disease is ill-advised. Paul A. Offit, MD, an ACIP member and chief of infectious diseases at Children's Hospital of Philadelphia, was the sole ACIP member who voted against vaccinating 400,000-plus hospital workers. In his mind, the risks of vaccination now outweigh any potential benefit.
"I argue that we should make the vaccine, distribute it to hospitals, identify those who should get it, show people how to give the vaccine—and then wait for one documented case of smallpox to appear anywhere in the world before we start vaccinating," Dr. Offit said. "I'm concerned that we will do more harm than good."
Other analysts are concerned about the policy's timetable. In October, the ACIP urged the government to gradually phase in any smallpox immunization policy, implementing it first in only a small number of hospitals. Because people with previous vaccinations have historically had fewer complications, the ACIP also recommended that they be vaccinated first.
And to minimize common reactions, the committee advised that hospitals stagger the number of workers they vaccinate in any given department. Walter Orenstein, MD, director of the CDC's national immunization program, said that up to 36% of vaccinees will experience "a nuisance kind of reaction" to the vaccine, ranging from sleep problems to a fever and a sore arm.
Typical primary injection site reactions over a three week period following immunization.
When the administration announced its plans in December, however, it called for hospital workers to be inoculated by March, giving officials at most only 60 days to implement it. Some public health experts say that timeframe doesn't give state health departments, hospitals and the CDC enough time to carefully monitor different approaches to vaccination management before expanding the policy to millions more.
"The emphasis here has to be on safety, and because we are a generation who has to re-learn this vaccine, health care workers and teams need to go slowly," said Kathleen M. Neuzil, FACP, an internist at the VA Puget Sound Health Care System in Seattle. She is also a member of the College's Adult Immunization Initiative Task Force and the College's representative to the ACIP. "In the absence of any threat, we have no incentive for meeting an arbitrary deadline."
Further, Dr. Neuzil continued, "Until we learn about this vaccine and make sure the first phase can be carried out safely, I don't think there's anything to be gained by even considering a phase two."
Other analysts say the policy raises major liability concerns. According to CDC officials, the Homeland Security Act that was passed in November included language indemnifying not only smallpox vaccine manufacturers, but any person or institution that distributes and administers the vaccine.
However, with the federal government now the sole defendant in any case involving smallpox vaccine, "It's just not clear to what degree people who are injured can seek compensation," said the CDC's Dr. Orenstein.
The vaccinia virus in smallpox vaccine is not as weakened as virus strains used in other "live" vaccines, such as for measles and chickenpox. As a result, experts say it is the riskiest vaccine currently licensed and can cause severe—and deadly—complications.
Further, the vaccination site can shed live virus for up to 19 days, making the risks of secondary transmission and accidental implantation small but real.
Officials project vaccine complication rates based on surveys from the 1960s. According to Dr. Orenstein, between 14 and 52 out of 1 million primary vaccinees would sustain severe or life-threatening complications of post-vaccinal encephalitis, progressive vaccinia or eczema vaccinatum. (For more adverse event data, see Smallpox Vaccine Adverse Event Rates, 1968.)
"Complications that are serious but not as severe may run as high as 1 in 1,000," Dr. Orenstein added. Those complications include autoinoculation, generalized vaccinia and other kinds of skin rashes such as erythema multiforme.
The problem is that no one is sure if those historic rates would still apply, or how many health care workers will be ineligible for the vaccine because of contraindications affecting themselves or family members.
For one, experts claim that the incidence of eczema—a major contraindication—has shot up in the United States. (See "Smallpox vaccine contraindications.") The authors of an article in the Oct. 16, 2002, Journal of the American Medical Association (JAMA), for instance, cited studies suggesting that the rate of atopic dermatitis among American children has jumped in the past 30 years from a range of 3%-6% to 6%-22%. (See Contact Vaccinia—Transmission of Vaccinia From Smallpox Vaccination.)
Further, dermatitis among health care workers is on the rise. The American Nurses Association (ANA) has pointed out that as many as 12% of health care workers are now sensitized to latex, which presents as dermatitis. That sensitivity, which has emerged since the onset of HIV/AIDS, was not a factor during the 1960s.
"I would argue that at least a third of the people in this country will say they've had some sort of skin condition or that someone in their family has a history of it," said the ACIP's Dr. Offit. "I would be curious to see who will really be eligible for this vaccine."
Other contraindications for both vaccinees and family members include pregnancy, immunosuppression problems or having a child under one year at home. According to Gregory A. Poland, FACP, Chair of the College's Adult Immunization Initiative Task Force and director of the vaccine research group at the Mayo Clinic in Rochester, Minn., he and his research group have no problems finding people willing to volunteer for the smallpox vaccine research trials the group has been conducting.
The problem? "We're lucky if half of them are eligible," he said.
According to the CDC's Dr. Orenstein, the risk of secondary transmission is also potentially much higher today than 40 years ago. "Then, the people you came into contact with were also vaccinated," he pointed out. "People getting vaccinated now are surrounded by fully susceptible people."
The potential for secondary transmission is certainly a concern in hospitals and medical practices, he continued: Hospitalized patients now suffer from more acute illness, while more patients now are immunocompromised because of AIDS, cancer, chemotherapy or organ transplants than during previous vaccination eras.
To reduce the risk of transmitting virus to patients, the ACIP considered recommending that vaccinated personnel be furloughed. But it decided against making that recommendation, the ACIP's Dr. Offit said, because furloughing thousands of hospital workers "would be incredibly disruptive to regular care"—particularly during a time of nationwide staffing shortages.
One other consideration led the ACIP to reject the notion of hospital furloughs. "The reality is that household contacts may be at even greater risk [of secondary transmission] than patients," said John F. Modlin, MD, chair of the ACIP and professor at Children's Hospital at Dartmouth, part of the Dartmouth-Hitchcock Medical Center in Lebanon, N.H.
According to data cited in the JAMA article, there were two to four cases per 100,000 immunizations in the 1950s and 1960s of contact vaccinia, most involving contact at home. However, the JAMA article concluded that in a society that now has close to zero immunity, "a higher incidence of contact vaccinia most likely would occur."
To curtail secondary transmission, the ACIP recommended using gauze bandaging as well as a semi-permeable, occlusive covering over the vaccination site. (See "The lost art of using bifurcated needles and other challenges of smallpox vaccine.") The ACIP also recommended against mandatory screening for pregnancy and HIV among health care workers who volunteer for the vaccine. Such screening could be, the CDC's Dr. Orenstein explained, "an invasion of privacy."
The committee did state, however, that testing for both conditions should be available, and that women of child-bearing age should be advised to abstain from sex or to use contraception for four weeks after being vaccinated. Forgoing mandatory screening raises the specter of persons who don't know they're infected with HIV or have other conditions like leukemia being vaccinated and developing progressive vaccinia.
Fallout of noncompliance?
Dr. Orenstein stressed that all phases of the newly-announced policy are voluntary. Some health care workers, however, worry about privacy issues. Do personnel who choose not to be vaccinated, for instance, have to disclose their reasons for not doing so?
Others are concerned that vaccination will become a prerequisite for holding positions in certain hospital departments or medical practices. "We think this policy has different implications, depending on where you're located," said Cheryl A. Peterson, RN, ANA's senior policy fellow. "Vaccination may not be mandated by the government, but it may become a condition of employment, say, if you work in an emergency room in Washington, D.C."
Some analysts are concerned that the highly publicized complications that would undoubtedly occur could hurt other, less risky immunization programs for conditions like influenza. And given the unknowns of vaccine complications, no one knows how eager medical professionals are to volunteer.
On one hand, pointed out James D. Bentley, PhD, senior vice president for strategic policy planning for the American Hospital Association, hospital personnel want to protect themselves against the possibility of unknowingly treating someone with smallpox. "When AIDS first emerged, people were scared to death that they might treat someone with AIDS and not know it," he said. "Unlike AIDS, we have something we can offer, which is the vaccine with its risks."
Others, however, disagree. "I think it will be a hard sell," said Larry M. Bush, FACP, the infectious diseases specialist who diagnosed the first case of inhalational anthrax in Florida in 2001. "I can't get some nurses to get a hepatitis B vaccine, which is much safer and the only vaccine out there that prevents cancer."
Dr. Bush, who is chief of staff at JFK Medical Center in Atlantis, Fla., said he sees another big challenge for implementing the policy: high staff turnover. "You're constantly going to be getting new people in these positions," he said.
The race is now on among researchers to find a safer vaccine. (See "The search for a safer vaccine.") And analysts agree that the discussion and planning that have gone into formulating a vaccination policy have been both important and educational.
"We're much more prepared than we were a year ago," said Dr. Neuzil of the College's Adult Immunization Initiative Task Force. "In my mind, all that preparation is more of a deterrent to using smallpox as a bioterrorist agent than getting 'x' number of vaccines into 'x' number of arms."
The CDC has identified several contraindications for prophylactic smallpox vaccination. There are no contraindications to vaccination, however, for patients who have been exposed to the smallpox virus.
Eczema and other skin conditions. The CDC recommends against vaccinating individuals with eczema or atopic dermatitis, even if the condition is not active. Likewise, people with family members who have ever been diagnosed with those conditions should not be vaccinated.
The following dermatological diagnoses in vaccinees or household members would also rule out preventive vaccination: herpes, severe acne, burns, zoster or psoriasis. Patients with Darier's disease should also not get vaccinated.
These diagnoses put vaccinees or family members at risk for eczema vaccinatum, a severe and sometimes fatal complication. Findings published in 1970 of a survey of physicians in 10 states claimed that more than 40 vaccinees per million over the age of one year contracted eczema vaccinatum. Experts today, however, say the rate of eczema may have increased dramatically in the last 30 years.
Conditions that cause immunodeficiencies. Individuals who have conditions that cause immunosuppression or have family members with those conditions should not be vaccinated. Those conditions include HIV/AIDS, cancer, autoimmune disease, leukemia, lymphoma or transplants.
These patients are at higher risk of developing progressive vaccinia. According to the CDC, the T-cell count that would put patients with immunosuppression problems at risk for the vaccine is not known.
Treatments that cause immunodeficiencies. Individuals or their family members who are undergoing radiation, chemotherapy, corticosteroid therapy or organ transplant medication treatment should not receive smallpox vaccine.
Pregnant women or women who want to become pregnant within a month of being vaccinated.
Anyone with moderate or severe illness.
Anyone under age 18.
Patients with a previous reaction to smallpox vaccine.
For more information, see Smallpox (Vaccinia) Vaccine Contraindications.
The ACP-ASIM Web site's section on smallpox. Later this month, you should be able to use that site to order a copy of the "Smallpox Vaccination: Vaccination Method & Reactions" brochure prepared by the CDC and the HHS Office of Public Health Emergency Preparedness.
The Infectious Diseases Society of America has a smallpox bioterrorism information and resources site.
The CDC offers comprehensive material on smallpox vaccination as well as smallpox identification and treatment.
The Agency for Healthcare Research and Quality sponsors a Web site to help primary care physicians learn how to diagnose and treat conditions caused by bioterrorist agents, including smallpox.
The Johns Hopkins Center for Civilian Biodefense Studies maintains a comprehensive Web site on bioterrorism agents.
Public health officials say the federal government's aggressive vaccination policy faces some very high hurdles. One is teaching a generation of nurses and physicians the lost art of inoculating patients against smallpox.
Instead of using a syringe to inject muscle, you administer the vaccine using a two-pronged needle to repeatedly jab the skin. "You can do it too vigorously, but you can do it too lightly too," explained John R. Lumpkin, MD, director of the Illinois State Health Department, who helped organize training sessions last fall for 1,000 infectious disease control nurses and paramedics. (They used bifurcated needles to practice on oranges.)
"You have to catch the skin just right so the vaccine gets at the right depth under the skin, Dr. Lumpkin said. "It's a matter of getting enough experience with the needle."
Not many people have been able to get that experience, however, because the CDC—which is the country's only source for bifurcated needles—will only now start to distribute them, along with smallpox vaccine and training material. State authorities are now deciding how to implement the immunization policy among hospital workers in each state.
At press time, many logistical details of the vaccination program had not yet been announced. For instance, will volunteer hospital personnel be vaccinated in the hospitals where they wor—a convenience that would probably increase the number willing to be vaccinated—or travel to a separate location set up by public health officials?
Because the vaccine is packaged in 100-dose vials that can be diluted five-fold and still be effective, a centralized location to service several different hospitals at the same time might make sense. (CDC officials say that once vaccine vials have been opened, they can be refrigerated for up to one month.)
The CDC had also not released recommendations for how vaccination sites should be checked and cared for, a crucial step in preventing secondary transmission. (Vaccination sites are traditionally checked daily until the scab separates to make sure a pustule forms, the sign that the vaccine has "taken.")
It is unclear, for example, whether public health officials will check workers' vaccinations or if other hospital staff will be designated to inspect vaccinees' arms. Nor had protocols yet been announced for medical professionals to follow in the event of complications.
"Who do we call if a patient appears to be developing a more severe side effect, and what process needs to be followed to get VIG [vaccine immune globulin]?" asked Marguerite A. Neill, FACP, chair of the bioterrorism work group for the Infectious Diseases Society of America. "That's a whole other piece that has to be worked out."
Because the current smallpox vaccine comes with high risks, researchers are working on two fronts: boosting the country's supply of drugs that can moderate vaccine complications and developing safer alternative vaccines.
Vaccine immune globulin (VIG) is the only treatment available for accidental autoinoculation, eczema vaccinatum and generalized and progressive vaccinia. The CDC now has 700 doses of VIG, said Walter Orenstein, MD, director of the CDC's national immunization program at press time.
"In the past, we needed one treatment [of VIG] for every 30,000 doses of vaccine," he said. "We think we would clearly have enough to cover complications from vaccinating the population of health care workers being targeted."
Manufacturers have also moved into high gear to produce more VIG. (The antiviral cidofovir may also mitigate vaccine reactions, but is now being tested for that purpose only in animals.)
The National Institutes of Health (NIH) is devoting a significant portion of its $2 billion biodefense research budget in fiscal year 2003 to testing smallpox vaccines. NIH-sponsored researchers, for instance, are now testing the effectiveness of an investigational smallpox vaccine grown in human tissue cells. The current vaccine, by contrast, was grown in calf lymph cells.
"We believe it will be less reactogenic because it won't have the impurities of an animal-based culture medium," said Gregory A. Poland, FACP, director of the vaccine research group at the Mayo Clinic in Rochester, Minn., who is involved in tissue-cell vaccine research.
Tissue-cell vaccine may produce fewer complications, and some lots could be available as early as this year. But it would probably not be tolerated by people with vaccine contraindications. One strain that potentially may be tolerated is modified vaccinia ankara (MVA), a mutated variation of vaccinia that is not as robust as the strain used in the current vaccine.
"Actually, several different types or mutations of MVA have been generated," said Carole A. Heilman, PhD, director of the division of microbiology and infectious diseases at the National Institute of Allergy and Infectious Diseases at NIH. "They all have several properties—including limited or absent replication in human cells—that make them of interest."
MVA is particularly promising, Dr. Heilman continued, as a replacement for the current vaccine for immunocompromised patients. But experts say that the availability of MVA is several years away.
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