To the Editor: In the January 30 issue, a laudable attempt wasmade to come to grips with the many issues surrounding terroristuse of variola. An essential point remains unclear, however.How easily is variola transmitted? In the model of Bozzetteet al.,1 no control measures are taken until 26 days after theinitial infection, 11 days after the expected development ofrash. Mack,2 however, argues persuasively that secondary spreadtakes place only after the characteristic rash is evident; thus,all infection takes place during those 11 days. Once the rashis evident, I presume that control procedures would be rapidlyinstituted, particularly in our era of heightened awarenessand instantaneous transcontinental communication. This woulddecrease the number of days after the initial infection (T)in the model of Bozzette et al. to a number closer to 16 daysand would drastically reduce the number of deaths expected froma smallpox attack predicted by their model. Can these viewsbe reconciled?
Anthony G. Letai, M.D., Ph.D. Dana–Farber Cancer Institute Boston, MA 02115 anthony_letai{at}dfci.harvard.edu
References
Bozzette SA, Boer R, Bhatnagar V, et al. A model for a smallpox-vaccination policy. N Engl J Med 2003;348:416-425. [Free Full Text]
Mack T. A different view of smallpox and vaccination. N Engl J Med 2003;348:460-463. [Free Full Text]
To the Editor: In their model for a smallpox-vaccination policy,Bozzette et al. make assumptions that decrease the perceivedvalue of pre-exposure vaccination. Successful pre-exposure vaccinationand post-exposure vaccination are assumed to provide equal benefit.This assumption is not supported by the literature. An expertworking group concluded, "Vaccination administered within 4days of first exposure has been shown to offer some protectionagainst acquiring infection and significant protection againsta fatal outcome."1
In the model of Bozzette et al., a death rate of 0.225 is assumedfor unvaccinated persons with smallpox. Historically, this ratehas varied widely, largely due to differences in virulence amongstrains of variola major.2 Mack's review of smallpox in Europebetween 1950 and 19713 showed a crude case fatality rate of52 percent among unvaccinated persons.
Through simple strain selection, or through use of recombinanttechnology,1 terrorists can control viral characteristics relatedto virulence and infectivity. The resulting epidemic would notresemble the "average" historical experience portrayed by thismodel, but rather — at a minimum — the worst historicalexperience. Credible alternative assumptions lower the thresholdfor pre-exposure vaccination.
Kim M. Snyder, M.D. 12222 Marine View Dr. Edmonds, WA 98026
References
Henderson DA, Inglesby TV, Bartlett JG, et al. Smallpox as a biological weapon: medical and public health management. JAMA 1999;281:2127-2137. [Free Full Text]
Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. Geneva: World Health Organization, 1988.
To the Editor: Having seen "natural" epidemics of smallpox duringmy work in the Democratic Republic of Congo,1,2,3 I believethe potential danger of disease and deaths associated with aterrorist attack far exceeds even the worst projections of Bozzetteet al. It is extremely important that we put in place a coreof persons who are protected (i.e., immunized) against smallpoxas soon as possible. You have made an excellent contributionto stimulating discussions and review of this terrorist threat.
James D. Fett, M.D., M.P.H. Hôpital Albert Schweitzer Deschapelles 98520-3343, Haiti jdftlsc{at}techline.com
References
Fett JD. Beyond "safe." N Engl J Med 1998;339:567-567. [Free Full Text]
Fett JD. Four dictators and one free man. Aberdeen, Wash.: Utterance Press, 1999.
Dr. James Fett: a passion for medicine. Daily World. January 25, 2003:24-31.
To the Editor: Since vaccination of health care workers withvaccinia virus may result in nosocomial transmission to immunocompromisedpatients, spread to family members, disseminated infections,and deaths, as discussed by Sepkowitz in the January 30 issue,1antiviral agents that are active against vaccinia are urgentlyneeded. Cidofovir is active in vitro against poxviruses andis recommended for serious vaccinia infections, but it may causerenal failure, neutropenia, metabolic acidosis, and uveitis.2
An older antiviral agent, vidarabine (adenine arabinoside),is a selective inhibitor of vaccinia DNA polymerase. Originallyapproved for the treatment of herpesvirus infections, vidarabineactually is 10 times as potent against vaccinia as it is againstherpes simplex virus type 1 or type 2.3 Vidarabine has beenshown to be beneficial in animal models of vaccinia infection.Treatment with vidarabine was highly effective in preventingdeath from disseminated vaccinia infection in mice with immunosuppressioninduced by the administration of antithymocyte globulin.4
The safety profile of vidarabine is excellent and was similarto that of acyclovir in clinical trials comparing the two drugs.5It is worthwhile to reevaluate vidarabine for the treatmentof severe vaccinia infection in humans and as a potential treatmentfor smallpox.
Michael G. Worthington, M.D. John J. Ross, M.D. Caritas Saint Elizabeth's Medical Center Boston, MA 02130 mworth{at}semc.org
References
Sepkowitz KA. How contagious is vaccinia? N Engl J Med 2003;348:439-446. [Free Full Text]
Smallpox vaccine. Med Lett Drugs Ther 2003;45:1-4. [Medline]
De Clercq E. Vaccinia virus inhibitors as a paradigm for the chemotherapy of poxvirus infections. Clin Microbiol Rev 2001;14:382-397. [Free Full Text]
Worthington M, Conliffe M. Treatment of fatal disseminated vaccinia virus infection in immunosuppressed mice. J Gen Virol 1977;36:329-333. [Free Full Text]
Whitley R, Arvin A, Prober C, et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. N Engl J Med 1991;324:444-449. [Abstract]
To the Editor: Sepkowitz's article may be misleading. He describes85 cases of nosocomial spread of vaccinia in 12 instances, allbut 1 before 1958. He states that little is known about therisk of transmission of vaccinia in a hospital and that vacciniamay be transmitted by aerosol. Two of us analyzed cases of adversereactions reported from a variety of sources, including allcases involving treatment with vaccinia immune globulin.1,2There were 462 patients with dermal vaccinia infections whowere hospitalized for an average of 7.5 days. There was oneinstance of nosocomial infection in a child with eczema whowas infected from a vaccinated licensed practical nurse.3 Therewere no cases of patient-to-patient spread. One of us (Dr. Fulginiti)hospitalized many patients with infectious cases of vacciniain the 1960s, with no instance of nosocomial spread. In allour collective experience, there was no aerosol spread, andnosocomial infection occurs possibly once in 3000 to 4000 hospitaldays.
John M. Neff, M.D. Children's Hospital Seattle, WA 98145-5020 john.neff{at}seattlechildrens.org
J. Michael Lane, M.D. Centers for Disease Control and Prevention Atlanta, GA 30307-1223
Vincent A. Fulginiti, M.D. University of Arizona School of Medicine Tucson, AZ 85718
Editor's note: Drs. Neff and Lane report having served as consultantsto Acambis and Dynport on the data and safety monitoring boardsfor their smallpox-vaccine trial, and Dr. Neff is chair of thedata and safety monitoring board for both companies. NeitherDr. Neff nor Dr. Lane has any financial interests in the vaccineproduct.
References
Neff JM, Lane JM, Pert JH, Moore R, Millar JD, Henderson DA. Complications of smallpox vaccination. I. National survey in the United States, 1963. N Engl J Med 1967;276:125-132. [Web of Science][Medline]
Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccinations, 1968: national surveillance in the United States. N Engl J Med 1969;281:1201-1208. [Web of Science][Medline]
Neff JM, Lane JM, Fulginiti VA, Henderson DA. Contact vaccinia -- transmission of vaccinia from smallpox vaccination. JAMA 2002;288:1901-1905. [Free Full Text]
To the Editor: Mack cites reports on two studies as evidencethat variola was not grown from exhaled air.1,2 The earlierstudy1 used inadequate methods of air sampling.2 The later studyrecovered virus in 5 of 47 attempts. Another study,3 in whichmore efficient sampling methods were used and patients werestudied late in the course of disease, when they were probablynot infectious, still found positive air samples. Thus, variolahas been grown from exhaled air. Airborne variola had an infectioushalf-life similar to that of vaccinia4,5 — about six hours,not a few minutes.
These reports suggest that, ordinarily, patients with smallpoxhave generated small numbers of infectious droplet nuclei. Suchpatients were too ill to go out in public when they were mostinfectious. Thus, the literature on airborne variola is consistentwith a risk of infection that is greatest at the bedside, exceptin rare cases of dissemination, and does not rule out frequentairborne transmission. The possibility of frequent airbornetransmission, however, reinforces the importance of Mack's recommendationthat plans to prevent in-hospital transmission not rely solelyon the vaccination of health care workers.
Donald K. Milton, M.D., Dr.P.H. Harvard School of Public Health Boston, MA 02115 dmilton{at}hsph.harvard.edu
References
Meiklejohn G, Kempe CH, Downie AW, Berge TO, St Vincent L, Rao AR. Air sampling to recover variola virus in the environment of a smallpox hospital. Bull World Health Organ 1961;25:63-67. [Medline]
Downie AW, Meikeljohn M, St Vincent L, Rao AR, Sundara Babu BV, Kempe CH. The recovery of smallpox virus from patients and their environment in a smallpox hospital. Bull World Health Organ 1965;33:615-622. [Medline]
Thomas G. Air sampling of smallpox virus. J Hyg (Lond) 1974;73:1-7.
Mayhew CJ, Hahon N. Assessment of aerosol mixtures of different viruses. Appl Microbiol 1970;20:313-316. [Medline]
Harper GJ. Airborne micro-organisms: survival test with four viruses. J Hyg (Lond) 1961;59:479-486.
Drs. Bozzette and Boer reply: Dr. Letai and Dr. Snyder identifysome of the key parameters of concern. We stand by our bestestimates of these parameters. We doubt that today's providerswill be better at quick recognition of smallpox than doctorsand nurses who had first-hand experience with the disease, especiallysince the number and geographic extent of exposures will notbe immediately apparent in any but the simplest attack. We donot make the assumption, attributed to us by Dr. Snyder, thatpre-exposure vaccination and post-exposure vaccination are equallyeffective. Rather, we assume that the overall efficacy of priorvaccination is considerably higher than that of ring vaccination.We are aware of Dr. Mack's estimate of the case fatality rate,but our best point estimate did not agree with it.
Nonetheless, Dr. Letai, Dr. Snyder, and, we suspect, othershave reasonable and legitimate concerns about the conditionsand parameters of our model. Our sensitivity analysis did includevariations in these parameters that were more extreme than thosesuggested here, with effects in the expected directions as describedin our article. None of the variations described would leadto a substantial change in the policy recommendations.
We certainly feel privileged that our sterile analyses haveearned the thanks of Dr. Fett, who has cared for "victims ofMobutu's massacres in the Congo," "unaccompanied minors" onCambodia's borders, and "peasants victimized by Baby Doc Duvalier."We believe that his interpretation is quite correct: raisingthe immune status of those in the population who are most likelyto become ill in an attack is a prudent policy, the implementationof which deserves a high priority and therefore full fundingas necessary.
Samuel A. Bozzette, M.D., Ph.D. Rob Boer, Ph.D. RAND Healthcare Santa Monica, CA 90407-2138 sam_bozzette{at}rand.org
Dr. Mack replies: Dr. Letai is correct; surveillance of contactswould start within days after the first evidence of rash, especiallyafter the initial report. Dr. Snyder is also correct; pre-exposurevaccination is highly effective, and post-exposure vaccinationis at best of limited effectiveness. Unfortunately the casefatality rate for variola major among unvaccinated persons islikely to be closer to 50 percent than 22.5 percent. Some historicalobservations were based on cases in smallpox hospitals —that is, cases in persons who made it to the hospital. Fieldinvestigators relied on the personal history and findings onphysical examination to infer vaccination status, thus misclassifyingsome surviving vaccinees.
Although recombinant technology might alter virulence, a morevirulent virus would probably lead to less contact with visitors,a more frightening appearance, and a shorter clinical course— a combination that would reduce transmission, not increaseit. Since infectivity is already maximal at the bedside, anincrease in this characteristic is more likely to occur as afunction of human, rather than viral, behavior.
Dr. Milton takes me to task for indicating that attempts togrow airborne variola virus were "unsuccessful," with viability"measured in minutes." Of course, person-to-person transmissionrequires that some virus be airborne, at least temporarily.Capture at the bedside in about 10 percent of attempts1 wasnot regarded as very successful, and the later success2 wasachieved only with equipment that screened very large volumesof air, captured droplets of variable size (unlikely to travelwell), and used an extremely sensitive two-stage culture protocol.Even so, success was limited to periods when infected personswere physically active, suggesting that airborne virus emanatedfrom clothing and bedclothes rather than directly from the enanthem.Moreover, infectiousness clearly is based on virion quantityas well as quality. Some virus can even be grown from the mouthof a healthy unvaccinated contact, who is not only unlikelyto transmit the virus but also unlikely even to become symptomatic.3Effective transmission probably requires a larger number ofvirions than a successful culture.
Vaccinia, not variola, survived for six hours, and it was ina small (75-liter), tightly regulated drum that rotated, possiblyrefreshing the aerosol.4 When variola virus itself was placedin a much larger (1500-liter) drum nine years later, no morethan 20 to 30 percent survived for 60 minutes under similarlywell-regulated conditions.5 The latter observation is consistentwith the epidemiologic evidence that suggests that this viruslives long enough when airborne near the bedside, but usuallydoes not live long when subjected to the changing conditionsof air currents.
Thomas Mack, M.D., M.P.H. University of Southern California Los Angeles, CA 90033 tmack{at}usc.edu
References
Downie AW, Meikeljohn M, St Vincent L, Rao AR, Sundara Babu BV, Kempe CH. The recovery of smallpox virus from patients and their environment in a smallpox hospital. Bull World Health Organ 1965;33:615-622. [Medline]
Thomas G. Air sampling of smallpox virus. J Hyg (Lond) 1974;73:1-7.
Sarkar JK, Mitra AC, Mukherjee MK, De SK. Virus excretion in smallpox. 2. Excretion in the throats of household contacts. Bull World Health Organ 1973;48:523-527. [Web of Science][Medline]
Harper GJ. Airborne micro-organisms: survival test with four viruses. J Hyg (Lond) 1961;59:479-486.
Mayhew C, Hahon N. Assessment of aerosol mixtures of different viruses. Appl Microbiol 1970;20:313-316. [Medline]
Dr. Sepkowitz replies: Letai asks if the contagiousness of variolais known. A table in the classic textbook by Fenner and colleaguessummarizes the available information (Table 1), demonstratingan incidence of secondary infection among nonimmune close contactsof about 58 percent.1
Table 1. Rates of Disease among Persons Exposed to Measles, Chickenpox, or Smallpox.
Worthington and Ross note that vidarabine has activity againstvaccinia and suggest that this drug may have a role in the managementof severe cases of vaccinia. I certainly agree that this andother compounds should be examined. Another nearly forgottendrug, methisazone (Marboran), a thiosemicarbazone, appearedto demonstrate activity against both viruses,2 but developmentwas not pursued, because the incidence of smallpox declinedworldwide. This oral medication may cause severe nausea andvomiting, possibly limiting its practical use. A recent reviewhas identified additional potentially active compounds.3
Neff et al. are correctly concerned that the older studies Icited will be misapplied to the current situation. My goal inthis review was not to take a stand on one side or the other,but rather to provide a dispassionate summary of a pertinentand difficult-to-obtain literature. The single cardinal rulefor those submerging themselves in the older literature is thatone must take the original authors at their word and not questiontheir observations, merely report them. In that spirit, I reportedthat several authors were concerned that vaccinia could be spreadby the airborne route. Certainly, Dr. Fulginiti's observation(previously unreported) that no nosocomial transmission occurredduring his years of caring for many patients with vaccinia,including eczema vaccinatum, is a very powerful indication ofhow unlikely airborne spread must be. This observation, coupledwith the current, most favorable experience with the vaccinein the United States and Israel, serves to endorse the new,admirably sane infection-control guidelines for smallpox vaccinationrecently released by the Centers for Disease Control and Prevention.4
Kent A. Sepkowitz, M.D. Memorial Sloan-Kettering Cancer Center New York, NY 10021 sepkowik{at}mskcc.org
References
Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. Geneva: World Health Organization, 1988.
Brainerd HD, Hanna L, Jawetz E. Methisazone in progressive vaccinia. N Engl J Med 1967;276:620-622. [Web of Science][Medline]
Smee DF, Sidwell RW. A review of compounds exhibiting anti-orthopoxvirus activity in animal models. Antiviral Res 2003;57:41-52. [CrossRef][Medline]
Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. MMWR Morb Mortal Wkly Rep 2001;50:1-25. [Medline]
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