from Medscape Infectious Diseases
Posted 10/17/2002

Smallpox is an abstraction, a specter of a forgotten era and irrelevant to medicine except in the guise of hypothetical scenarios and doomsday plots. Yet this apparition is real, due to the antipathy of variola's keepers toward its final destruction and our waning immunity. During the height of their biological weapons program, the former Soviet Union allegedly maintained weaponized smallpox in quantities measured in tons.^[1] Moreover, this production capacity was coupled with highly sophisticated mechanisms for widespread and even intercontinental dispersal. Whether additional stores currently survive outside of the United States and Russia is an open question. In 1969, Lane and Millar wrote, ". . . a lower proportion of immune persons in the population will raise our susceptibility to smallpox as a weapon of biological warfare."^[2] Against the backdrop of last year's intentional dispersal of anthrax spores, however, we face the prospect of mass vaccination to counter the threat of smallpox. Is smallpox -- to paraphrase Scrooge -- what is to come, or simply what may come to pass?

My connection to smallpox resides in the faint doughnut of a scar over my left deltoid. . . a reminder of the fear, respect, and competence of a now-gone generation of pediatricians. I was born 9 years after the last case of smallpox was reported in the United States. By the time I reached my teens, routine smallpox vaccination of children ceased.^[2] Like almost all other physicians in North America, I am part of a fully vaccinated generation. Despite this, I managed, as a child, to slip through the cracks and contract both mumps and measles prior to vaccination. In medical school I saw my first and only case of Haemophilus influenzae meningitis. As a resident on a rural rotation, I diagnosed my last case of H flu epiglottitis in a vaccine-avoidant 2-year old. Although I represented the American Academy of Family Physicians at the Centers for Disease Control and Prevention (CDC) Measles Elimination meeting in 2000, I have yet to see a case as a family physician. I have not seen diphtheria or tetanus. I have a handful of patients with postpolio syndrome, and it has been suggested -- by at least 1 specialist -- that our adopted daughter's partial paralysis stems from polio. The iron lung, like smallpox, is a curiosity from textbooks of medical history.

From what I have read, and from the words of older and wiser colleagues, I can appreciate the dread of most of the vaccine-preventable diseases. My recollection of my 1 case of epiglottitis serves as a potent reminder, which I frequently dredge up while explaining the benefits of H influenzae type b (Hib) vaccine to anxious parents. I have grown to embrace a great faith in the power and success of vaccines. Nevertheless, I have been witness to the demise of the oral polio vaccine (OPV) and the whole-cell pertussis vaccine due to their unfavorable adverse-effect profiles. The 0-10.5 cases per million of acute encephalopathy resulting from the whole-cell pertussis vaccine and the 0.4 cases of vaccine-associated paralytic poliomyelitis per million doses of OPV were felt to be unacceptably high.^[3] The well-intentioned but ill-fated swine flu vaccination campaign of 1976 is best remembered for the resulting "epidemic" of vaccine-related Guillain-Barré syndrome.^[4] Although family physicians were slow to embrace varicella vaccine, its use is now commonplace. Our reluctance was largely due to a sense of the risks potentially outweighing the benefits in preventing a common and relatively mild disease. Conversely, our hesitancy to adopt the rotavirus vaccine was unintentionally prophetic.

As a family physician providing care to an underserved community within a larger affluent metropolitan area, I see a highly diverse mix of patients. Our teaching clinic attracts African-Americans, Khmer and Hmong immigrants from Southeast Asia, Mexican-Americans, university professors and graduate students, patients from the local methadone clinic, and multiple other groups. Our childhood immunization successes are countered by the transient nature of many of our patient families, an inability to track down old records, and a small but increasingly proactive cohort of vaccine-avoidant parents. Safety concerns have been identified by 11% to 25% of parents across the nation as a barrier to immunization.^[5] I often receive comments from my more affluent and well-educated parents that they need to do more "research" on the safety of vaccines, particularly measles-mumps-rubella (MMR), before allowing their child to succumb. Many are well versed in the Internet-promoted claims of links to autism. Most are immune to my retort citing good epidemiologic evidence to the contrary.^[6,7] These concerns are raised rarely by my less affluent and less educated patients. I daily see the benefits of herd immunity borne on the backs of the less privileged.

Now we face vaccinia. Across the wide spectrum of opinion, there have been advocates for mass immunization of the entire US population, a daunting task at best.^[8] In response, like many other physicians, I have downloaded the 48-page "Smallpox Immunization Clinic Guide," paying particular attention to the screening and consent sections.^[9] In general, primary care physicians have relationships with and responsibilities to their communities. This stewardship involves not only providing appropriate medical care and preventive services, but also protecting patients through the avoidance of high-risk medical interventions. When it comes to the wide-scale introduction of smallpox vaccine, we are not so much afraid of liability issues as we are of genuinely hurting our patients.

To fully appreciate the smallpox vaccine, one needs to understand both the potential risks of administration and the spectrum of contraindications to the vaccine. The vaccinia vaccine is associated with a wide variety of mild and serious side effects. For example, 70% of children experienced at least 1 day of temperatures higher than 100^oF for 4 to 14 days after primary vaccination; 15% to 20% reached 102^oF or higher.^[3] These mild side effects, however, occurred within families that barely resemble those encountered today: 2-parent/1-income households with far less daycare use. Rates of more significant adverse effects reported in 1963 and 1968 were much lower (Table 1)^[10-12]:

Other adverse effects included erythema multiforme/Stevens-Johnson syndrome and superinfections of miscellaneous skin rashes and burns. Overall rates of severe complications for primary vaccination were age dependent. Rates of 112.4 adverse events per million were noted for children younger than 1 year; 79.0/million for 1- to 4-year-olds, 49.6/million for 5- to 9-year-olds, 32.0/million for 10- to 19-year-olds, and returning to 111.1/ million for adults.^[11] It is worthwhile to note that the estimates for adverse effects were conservative, due to probable underreporting^[2] and taken from a population 34-39 years ago. Furthermore, it should be noted that 20% of people with adverse effects in 1968 were not directly vaccinated, but had contact with recent vaccinees.^[11] In summary, significant adverse effects from vaccinia were rare, but also occurred at rates 2 to 3 orders of magnitude higher than those realized by vaccines that have since been deemed unacceptable.

Contraindications to vaccination include allergies to polymixin B, streptomycin, tetracycline, neomycin, and phenol, all of which are components of the vaccine in trace amounts. Live viral vaccines are generally avoided during pregnancy in nonemergency situations. Immunosuppression or contact with immunosuppressed household members are contraindications. Disorders including HIV, leukemia, lymphoma, generalized malignancy, and therapies that reduce immunity can lead to enhancement of vaccinia replication. Likewise, the use of prednisone at a dosage of 20 mg per day or higher for 14 or more days may also be a contraindication.^[3]

Beyond these rather clear contraindications are those related to eczema and atopic dermatitis. Currently having eczema, having had eczema in the past, or having household contact with someone meeting the above criteria are all considered contraindications. People with other chronic or acute or exfoliative skin disorders may also be at higher risk for developing eczema vaccinatum.^[3] In primary care practice, one enters a rather murky zone here. Eczema/atopic dermatitis (ICD-9: 692.9) is the 38th most commonly recorded ICD-9 code used for billing purposes at the 8 primary clinical training sites of the University of Wisconsin Department of Family Medicine (UW-DFM). It occurs in 0.58% of all visits. On closer examination, however, this rare presence is only the tip of the iceberg. We examined billing data through the UW-DFM clinical data warehouse and were able to identify 61,979 individuals seen at our clinical sites between January 1, 1999 and December 31, 2001. The percentage of patients at any one site who had been assigned to the ICD-9: 692.9 code ranged from 3.68% to 7.60%. Overall, 3298 (5.32%) individuals had been directly associated with this diagnostic code. The age and sex distribution of these patients are illustrated in the Figure. We did not attempt to identify the number of potential household contacts of these patients, nor did we attempt to verify the diagnosis. Regardless, the pool of patients with potential contraindications to smallpox vaccine, based simply on eczema/atopic dermatitis, is quite large.

Contraindications and risk factors for smallpox vaccination are broadcast to us from a different time and a different culture. To obtain copies of the original literature required a trip to the medical school library basement and the opening of dusty, long-shelved journals. Considering this, a number of questions come to my mind:

• How many of our patients diagnosed with eczema/atopic dermatitis know that they have this diagnosis? Do other family members have any idea? Would they recall this diagnosis at a smallpox vaccination clinic?
• How many of these patients have been accurately diagnosed?
• Are patients with chronic skin maceration from morbid obesity at higher risk?
• Is fungal dermatitis or acne a risk factor?
• Is there a maximum age cutoff for smallpox vaccination?
• Is the presence of severe chronic disease(s) a relative contraindication?
• Is the widespread use of contact lenses a potential problem for accidental vaccination of the eye?
• Does chronic hepatitis C infection increase one's risk for adverse effects?

These and other questions stem from my naiveté and my primary care practice, as well as from a medically transformed world. Many of the medical interventions and many of the chronic illnesses that we deal with on a daily basis simply did not exist during our last experience with widespread smallpox vaccination.

For physicians here, this may be the time to run the administrative data files and identify patients who have possible contraindications. These conditions need to be verified. This is also the time to provide this information to patients, so as to prophylax against the adverse effects of unintended immunization. In the face of threatened or actual release of smallpox and in the panic that will ensue, cool heads may become a very scarce resource.

Perhaps more of a concern is what really happens if the genie is let out of the bottle. I do not mean here in the United States where, despite our grumbling, we are blessed with the best of medical care, the best of rapid communication, and the resources to respond rapidly to mass catastrophe. What happens in a world in which 75 million subSaharan Africans suffer from HIV, and countless others endure the immunosuppressive effects of chronic malnutrition? What happens in the face of widespread poverty and overcrowding, and where natural and vaccine-induced immunity to smallpox no longer exists? What happens where resources, communication and transportation are insufficient to provide any ring vaccination to slow down transmission? It is with these questions that I am most troubled.