--------------------------------------------------------------------------- Emerging Infectious Diseases * Volume 3 * Number 2 * April-June 1997 --------------------------------------------------------------------------- Perspective * The Economic Impact of a Bioterrorist Attack: Are Prevention and Postattack Intervention Programs Justifiable? A.F. Kaufmann, M.I. Meltzer, G.P. Schmid Synopses * Hantaviruses: A Global Disease Problem C. Schmaljohn and B. Hjelle * Japanese Spotted Fever: Report of 31 Cases and Review of the Literature * F. Mahara This article is also available in Japanese at http://www.cdc.gov/ncidod/EID/eid.htm * Polycystic Kidney Disease: An Unrecognized Emerging Infectious Disease? M.A. Miller-Hjelle, J.T. Hjelle, M. Jones, W.R. Mayberry, M.A. Dombrink-Kurtzman, S.W. Peterson, D.M. Nowak, and F.S. Darras * Borna Disease C.G.Hatalski,A.J.Lewis,and W.I. Lipkin * The Rickettsia: an Emerging Group of Pathogens in Fish J.L. Fryer and M.J. Mauel * Rhodococcus equi and Arcanobacterium haemolyticum: Two "Coryneform"Bacteria Increasingly Recognized as Agents of Human Infection R. Linder * Is Creutzfeldt-Jakob Disease Transmitted in Blood? M.N. Ricketts, N.R. Cashman, E.E. Stratton, S. ElSaadany Dispatches * A New Tick-borne Encephalitis-like Virus Infecting New England Deer Ticks, Ixodes dammini S.R. Telford III, P.M. Armstrong, P. Katavolos, I. Foppa, A.S.O. Garcia, M.L. Wilson, A. Spielman * An Unusual Hantavirus Outbreak in Southern Argentina: Person-to-Person Transmission? R.M. Wells, S.S. Estani, Z.E. Yadon, D. Enria, P. Padula, N. Pini, J.N. Mills, C.J. Peters, E.L. Segura, and the Hantavirus Pulmonary Syndrome Study Group for Patagonia * Pertussis in the Netherlands: an Outbreak Despite High Levels of Immunization with Whole-Cell Vaccine H.E. de Melker, M.A.E. Conyn-van Spaendonck, H.C. Rümke, J.K. van Wijngaarden, F.R. Mooi, and J.F.P. Schellekens * Invasive Haemophilus influenzae type b Disease in Elderly Nursing Home Residents: Two Related Cases T.C. Heath, M.C. Hewitt, B. Jalaludin, C. Roberts, A.G. Capon, P. Jelfs, and G.L. Gilbert * Seroepidemiologic Studies of Hantavirus Infection Among Wild Rodents in California M. Jay, M.S. Ascher, B.B. Chomel, M. Madon, D. Sesline, B.A. Enge, B. Hjelle, T.G. Ksiazek, P. E. Rollin, P.H. Kass, and K. Reilly * Gestational Psittacosis in a Montana Sheep Rancher D.M. Jorgensen * Lack of Serologic Evidence for an Association between Cache Valley Virus Infection and Anencephaly and Other Neural Tube Defects in Texas J.F. Edwards and K. Hendricks * Rabies Postexposure Prophylaxis Survey Kentucky M. Auslander and C. Kaelin Commentary * Biologic Terrorism Responding to the Threat P.K. Russell From the 1st International Conference on Emerging Zoonoses The articles in this section were originally presented at the 1st International Conference on Emerging Zoonoses, Jerusalem, Israel, November 24-28, 1996. The conference was cosponsored by the Centers for Disease Control and Prevention and the Israel Center for Disease Control. * The Hantaviruses of Europe: from the Bedside to the Bench J. Clement, P. Heyman, P. McKenna, P. Colson, and T. Avsic-Zupanc * Brucellosis: an Overview M.J. Corbel * Global Aspects of Emerging and Potential Zoonoses: a WHO Perspective F.-X. Meslin * Epidemiology of Emerging Zoonoses in Israel A. Shimshony * Electronic Media and Emerging Zoonoses S.A. Berger Letters * The Reemergence of Aedes aegypti in Arizona D.M. Engelthaler, T.M. Fink, C.E. Levy and M.J. Leslie * Treatment of Exudative Pharyngitis P.D. Ellner * Reply to P.D. Ellner H.S. Izurieta, P.M. Strebel, T. Youngblood, D.G. Hollis, and T. Popovic News and Notes * Molecular Epidemiology and Evolutionary Genetics of Pathogenic Microorganisms * Simian Virus 40 (SV40) * Foodborne Pathogens: Implications and Control * Emerging Infectious Diseases in the Pacific Rim * Emerging Zoonotic Infectious Diseases * Hantavirus Conference * International Conference on Emerging Infectious Diseases * Emerging Infectious Diseases Laboratory Fellowship Program * Emerging Infections: Clinical and Pathologic Update II * Rabies Conference * Erratum --------------------------------------------------------------------------- About EID Emerging Infectious Diseases is indexed in Index Medicus/Medline, Current Contents, and several other electronic databases. Emerging Infectious Diseases is part of CDC's plan for combatting emerging infectious diseases; the plan is outlined in a recently published document, Addressing Emerging Infectious Disease Threats--A Prevention Strategy for the United States. One of the main goals of CDC's plan is to enhance communication of public health information about emerging diseases so that prevention measures can be implemented without delay. Emerging Infectious Diseases is peer reviewed and will be providing information on emerging infections in three broad categories: 1) Perspectives, a section addressing factors that underlie disease emergence including microbial adaptation and change, human demographics and behavior, technology and industry, economic development and land use, international travel and commerce, and breakdown of public health measures; 2) Synopses, concise, state-of-the-art summaries of specific diseases or syndromes and related emerging infectious disease issues; 3) Dispatches, brief laboratory or epidemiologic reports with an international scope. --------------------------------------------------------------------------- Editors Editor Joseph E. McDade, Ph.D., National Center for Infectious Diseases Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA Perspectives Editor Stephen S. Morse, Ph.D.,The Rockefeller University, New York, New York, USA Synopses Editor Phillip J. Baker, Ph.D., Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA Dispatches Editor Stephen Ostroff, M.D., National Center for Infectious Diseases, CDC, Atlanta, Georgia, USA Managing Editor Polyxeni Potter, M.A., National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA --------------------------------------------------------------------------- Liaison Representatives Anthony I. 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As soon as the full issue is completed, these dispatches become part of the issue. --------------------------------------------------------------------------- [Emerging Infectious Diseases * Volume 3 * Number 2 * April-June 1997] Perspective The Economic Impact of a Bioterrorist Attack: Are Prevention and Postattack Intervention Programs Justifiable? Arnold F. Kaufmann, Martin I. Meltzer, and George P. Schmid Centers for Disease Control and Prevention, Atlanta, Georgia, USA --------------------------------------------------------------------------- Understanding and quantifying the impact of a bioterrorist attack are essential in developing public health preparedness for such an attack. We constructed a model that compares the impact of three classic agents of biologic warfare (Bacillus anthracis, Brucella melitensis, and Francisella tularensis) when released as aerosols in the suburb of a major city. The model shows that the economic impact of a bioterrorist attack can range from an estimated $477.7 million per 100,000 persons exposed (brucellosis scenario) to $26.2 billion per 100,000 persons exposed (anthrax scenario). Rapid implementation of a postattack prophylaxis program is the single most important means of reducing these losses. By using an insurance analogy, our model provides economic justification for preparedness measures. Bioterrorism and its potential for mass destruction have been subjects of increasing international concern. Approximately 17 countries (including five implicated as sponsors of international terrorism) may have active research and development programs for biologic weapons (1). Moreover, groups and individuals with grievances against the government or society have been known to use or plan to use biologic weapons to further personal causes. Only modest microbiologic skills are needed to produce and effectively use biologic weapons. The greatest, but not insurmountable, hurdle in such an endeavor may be gaining access to a virulent strain of the desired agent. Production costs are low, and aerosol dispersal equipment from commercial sources can be adapted for biologic weapon dissemination. Bioterrorists operating in a civilian environment have relative freedom of movement, which could allow them to use freshly grown microbial suspensions (storage reduces viability and virulence). Moreover, bioterrorists may not be constrained by the need for precise targeting or predictable results. The impact of a bioterrorist attack depends on the specific agent or toxin used, the method and efficiency of dispersal, the population exposed, the level of immunity in the population, the availability of effective postexposure and/or therapeutic regimens, and the potential for secondary transmission. Understanding and quantifying the impact of a bioterrorist attack are essential to developing an effective response. Therefore, we have analyzed the comparative impact of three classic biologic warfare agents (Bacillus anthracis, Brucella melitensis, and Francisella tularensis) when released as aerosols in the suburbs of a major city and compared the benefits of systematic intervention with the costs of increased disease incidence (from the economic point of view used in society). Analytic Approach Scenario Assumptions We compared the impact of a theoretical bioterrorist attack on a suburb of a major city, with 100,000 population exposed in the target area. The attack was made by generating an aerosol of an agent (B. anthracis spores, B. melitensis, or F. tularensis) along a line across the direction of the prevailing wind. The meteorologic conditions (thermal stability, relative humidity, wind direction and speed) were assumed to be optimal (2), and the aerosol cloud passed over the target area within 2 hours. We projected impact on the basis of 10% and 100% of the target population being exposed to the aerosol cloud. We assumed that, when inhaled, the infectious dose50 (ID50) was 20,000 spores for B. anthracis and 1,000 vegetative cells for B. melitensis and F. tularensis. The rate of physical decay for airborne particles 5 mm or less in diameter was estimated to be negligible during the 2-hour transit time. The rate of biologic decay of the particulate agents was estimated to be negligible for the B. anthracis spores and 2% per minute for the B. melitensis and F. tularensis vegetative cells. Viability and virulence did not dissociate. Persons who were exposed to the B. anthracis cloud at any point during the 2-hour transit time inhaled one ID50 dose, and persons who were exposed to either the B. melitensis or F. tularensis cloud inhaled one to 10 ID50 doses, depending on their proximity to the origination point of the aerosol cloud. The epidemic curve for anthrax by days after exposure was assumed to be <1 day, 0% of cases; 1 day, 5%; 2 days, 20%; 3 days, 35%; 4 days, 20%; 5 days, 10%; 6 days, 5%; and 7 or more days, 5% (3-5). Case-fatality rates were also assumed to vary by the day symptoms were first noted. The case-fatality rate was estimated as 85% for patients with symptoms on day 1; 80% for patients with symptoms on day 2; 70% for those with symptoms on day 3; 50% for those with symptoms on days 4, 5, and 6; and 70% for those with symptoms on and after day 7. The increased death rate in persons with an incubation period of 7 or more days is calculated on an assumption of delayed diagnosis, with resultant delayed therapy. When estimating days in hospital and outpatient visits due to infection, we assumed that 95% of anthrax patients were hospitalized, with a mean stay of 7 days. Patients not admitted to a hospital had an average of seven outpatient visits, and surviving hospitalized patients had two outpatient visits after discharge from the hospital. Persons who received only outpatient care were treated for 28 days with either oral ciprofloxacin or doxycycline. No significant long-term sequelae resulted from the primary infection, and no relapses occurred. The epidemic curve for brucellosis by days after exposure was assumed to be 0 to 7 days, 4% of cases; 8 to 14 days, 6%; 15 to 28 days, 14%; 29 to 56 days, 40%; 57 to 112 days, 26%, and 113 or more days, 10% (4, 6-9). The case-fatality rate was estimated to be 0.5%. Fifty percent of patients were hospitalized, with an average stay of 7 days. Nonhospitalized patients had an average of 14 outpatient visits, and hospitalized patients had seven outpatient visits after discharge from the hospital. Outpatients received a combination of oral doxycycline for 42 days and parenteral gentamicin for the first 7 days of therapy. Five percent of patients had a relapse or long-term sequelae, and required 14 outpatient visits within 1 year. The epidemic curve for tularemia by days after exposure was assumed to be: <1 day, 0% of cases; 1 day, 1%; 2 days, 15%; 3 days, 45%; 4 days, 25%; 5 days, 10%; 6 days, 3%; and 7 or more days, 1% (4,10-11). The estimated case-fatality rate was 7.5%; and 95% of patients were hospitalized, with an average stay of 10 days. Nonhospitalized patients had an average of 12 outpatient visits, and hospitalized patients who survived the acute illness had two outpatient visits after discharge from the hospital. Outpatients received oral doxycycline for 14 days and parenteral gentamicin for 7 days. Five percent of patients had a relapse or long-term sequelae and required an average of 12 outpatient visits. The efficacy of intervention strategies is unknown; our projections are our best estimates based on published clinical and experimental data (4,12-14). For anthrax, the projected intervention program was either a 28-day course of oral ciprofloxacin or doxycycline (assumed to be 90% effective), or a 28-day course of oral ciprofloxacin or doxycycline plus three doses of the human anthrax vaccine (assumed to be 95% effective); for brucellosis, a 42-day course of oral doxycycline and rifampin (assumed to be 80% effective), or a 42-day course of oral doxycycline, plus 7 days of parenteral gentamicin (assumed to be 95% effective); for tularemia, the intervention program was a 14-day course of oral doxycycline (assumed to be 80% effective), or a 14-day course of oral doxycycline plus 7 days of parenteral gentamicin (assumed to be 95% effective). Only 90% of persons exposed in the target area were assumed to effectively participate in any intervention program. Because the target area cannot be precisely defined, we estimated that for every exposed person participating in the intervention program, an additional 5, 10, or 15 nonexposed persons would also participate. Economic Analyses of Postattack Intervention To analyze the economic factors involved in establishing an intervention program, we compared the costs to the potential savings from such an intervention. Following the recommendation of the Panel of Cost-Effectiveness in Health and Medicine (PCEHM), we used estimates of actual costs rather than financial charges or market prices, which usually incorporate profit (15). We calculated the net savings (cost reductions) by using the following formula: Net savings = (number of deaths averted x present value of expected future earnings) + (number of days of hospitalization averted x cost of hospitalization) + (number of outpatient visits averted x cost of outpatient visits) - cost of intervention. When we calculated the costs of hospitalization and outpatient visits, we assumed that only persons with symptoms (i.e., case-patients) would use medical facilities. The remainder of the exposed and potentially exposed populace would receive postexposure prophylaxis. Present Value of Expected Future Earnings The cost of a premature human death was nominally valued at the present value of expected future earnings and housekeeping services, weighted by the age and sex composition of the work force in the United States (16). The undiscounted average of future earnings is $1,688,595. As recommended by PCEHM (17), the stream of future earnings was discounted at 3% and 5%, to give values of $790,440 and $544,160, respectively. The present value of expected future earnings was estimated with 1990 dollars, adjusted for a 1% annual growth in productivity (16). However, in constant terms (1982 dollars), the average hourly earnings in private industry fell from $7.52 in 1990 to $7.40 in 1994 (18); therefore, the estimate of future earnings was not adjusted upwards. Cost of Hospitalization In 1993, the average charge for a single day of hospitalization was $875 (19). To derive true cost, we multiplied the average charge by the cost-to-charge ratio of 0.635, (the April 1994 statewide average cost-to-charge ratio for urban hospitals in New York state) (16). On this basis, we estimated true hospitalization costs at $556/day (Table 1). Hospital costs included all professional services, drugs, x-rays, and laboratory tests. Lost productivity during hospital stay was valued at $65/day (the value of an "unspecified" day's earnings, weighted for age and sex composition of the U.S. work force) (16). Table 1. Costs of hospitalization and outpatient visits (OPVs) following a bioterrorist attack --------------------------------------------------------------------------- Anthrax Tularemia Brucellosis Base Upper Base Upper Base Upper --------------------------------------------------------------------------- Hospitalized patient Days in hospital 7 7 10 10 7 7 Cost per day ($)(a) 556 669 556 669 556 669 Lost productivity ($/day) 65 65 65 65 65 65 Follow-up OPVs (no.) 2 2 2 2 7 7 Cost 1st OPV ($) 28 44 28 44 28 44 Cost other OPVs, ea. ($) 13 24 13 24 13 24 OPV laboratory ($)(b,c) 87 174 87 174 131 261 OPV x-rays costs ($)(d) 66 66 0 0 0 0 Lost productivity ($/OPV)(e) 16 16 16 16 16 16 Total costs ($) 4,541 5,380 6,338 7,582 4,584 5,587 Avg. costs/day ($/day) 649 769 634 758 655 798 % increase: Base to upper estimate 18 20 22 Nonhospitalized patient Number of OPVs 7 7 12 12 14 14 Cost 1st OPV ($) 28 44 28 44 28 44 Cost other OPVs, ea. ($) 13 24 13 24 13 24 Lost productivity ($/OPV)(e) 16 16 16 16 16 16 Laboratory costs ($)(b,f) 131 174 261 522 261 522 X-ray costs ($)(d) 66 66 66 66 66 66 Drugs used(g) D C D+G D+G D+R D+R+G Cost of drugs ($) 6 181 29 29 220 246 Total costs ($) 422 810 722 1,120 972 1,418 Avg. costs/day ($/day) 60 116 60 93 69 101 % increase: Base to upper estimate 93 55 46 --------------------------------------------------------------------------- Notes: All costs rounded to the nearest whole dollar. (a)Hospital costs assumed to include all costs such as drugs, laboratory tests, and x-rays. (b)Laboratory tests consists of general health panel (CPT code 80050) and an antigen or antibody test (modeled on the cost of a Streptococcus screen, CPT code 86588). (c)Follow-up OPVs for hospitalized patients included two laboratory test sets for anthrax and tularemia patients and three laboratory test sets for brucellosis patients. (d)X-ray costs (CPT code 71021), included two sets taken at different OPVs. (e)Productivity lost due to an OPV was assumed to be one-quarter of an unspecified day's value. (f)For OPVs of nonhospitalized patients, one set of laboratory tests is assumed for every two visits. (g)Drugs used: D = doxycycline; C = ciprofloxacin; R = rifampin. Sources: See text for explanation of sources of cost estimates. Cost of Posthospitalization Outpatient Visits After discharge from the hospital, a patient was assumed to have follow-up outpatient visits, the number of which varied by disease (Table 1). Outpatient visit costs were valued by using the Medicare National Average Allowance (20), which was chosen to represent the equivalent of bulk purchase discounted costs (i.e., actual costs) (Table 1). The first visit has a Current Procedural Terminology (CPT) code of 99201, which is classified as a "level 1" visit, requiring a physician to spend an average of 10 minutes with a patient (20). Subsequent level 1 visits, with the physician spending an average of 5 minutes with each patient, have a CPT code of 99211 (20). During outpatient visits, a general health panel test incorporating clinical chemistry tests and complete blood counts (CPT code 80050) and a single antigen or antibody detection test (e.g., CPT code 86558) were assumed to be ordered (20). Although data on Medicare allowances for office visits and many other procedures were available, data on Medicare allowances for laboratory tests were not. Thus, to establish the costs of the tests, we arbitrarily divided the lowest allowable charge for each test in half. X-rays (CPT code 71021) were valued according to the Medicare National Average Allowance (Table 1). In terms of lost productivity, we assumed that each outpatient visit cost the equivalent of 2 hours, or one-quarter, of the value of an unspecified day (16). Cost of Outpatient Visits of Nonhospitalized Patients For nonhospitalized outpatients, the cost of each visit, laboratory test, x-ray, and lost productivity was the same as an outpatient visit for discharged hospital patients and varied by disease (Table 1). We assumed that one set of laboratory tests would be ordered every other visit and that two sets of x-rays (CPT code 71021) would be ordered during the therapeutic course. Drug costs are discussed below. Cost of an Intervention The costs of an intervention can be expressed as follows: Cost of intervention = (cost of drugs used) x ([number of people exposed x multiplication factor] - number killed - number hospitalized - number of persons who require outpatient visits). The intervention costs per person depend directly on the costs of the antimicrobial agents and vaccines used in a prophylaxis program (Table 2). We obtained drug prices from the 1996 Drug Topics Red Book and used the lowest cost available for each drug (21). The cost of doxycycline ($0.22 per 200 mg total daily dose) was the Health Care Financing Administration cost, whereas the cost of gentamicin ($3.76 per 160 mg total daily dose), ciprofloxacin ($3.70 per 1,000 mg total daily dose), and rifampin ($5.01 per 900 mg total daily dose) were wholesale costs from pharmaceutical companies. The cost of anthrax vaccine was $3.70 per dose (Helen Miller-Scott, pers. comm., 1996). The cost of administering one vaccine dose or gentamicin injection was estimated at $10.00, on the basis of the 1992 cost of administering a vaccine in a clinical setting (Valerie Kokor, pers. comm., 1996). In estimating the cost of administering oral antimicrobial agents, we assumed weekly visits, during which the drug would be distributed and counseling would be given ($15.00 for the first visit and $10.00 for each subsequent visit). Table 2. Costs of prophylaxis following a bioterrorist attack --------------------------------------------------------------------------- Level of effectiveness Anthrax Tularemia Brucellosis --------------------------------------------------------------------------- Lower Effectiveness (%) 90 80 80 Drugs used(a) D or C D D+R Cost of drugs ($)(b) 6 or 181 3 220 No. of visits(c) 4 2 6 Total cost/ person ($) 51 or 226 28 285 Upper Effectiveness (%) 95 95 95 Drugs used(a) D+V or D+G D+G C+V Cost of drugs ($)(b ) 17 or 193 29 36 No. of visits(c) 4 7 12 Total cost/ person ($) 62 or 238 104 161 Minimum No. participants(d) 451,912 418,094 423,440 Maximum No. participants(e) 1,492,750 1,488,037 1,488,037 --------------------------------------------------------------------------- Notes: All costs are rounded to the nearest whole dollar. (a)Drugs used: D = doxycycline; C = ciprofloxacin; V = anthrax vaccine; G = gentamicin; R = rifampin. (b)See text for explanation of drug costs. (c)Cost of visit to drug-dispensing site: 1st visit = $15/person; follow-up visits = $10/person/visit. (d)Estimate assumed that the prophylaxis program was initiated on postattack day 6 for anthrax and tularemia and postattack day 113 for brucellosis, that the prophylaxis program had the lower effectiveness level, and that the multiplication factor for unnecessary prophylaxis given to unexposed persons was 5. (e)Estimate assumed that prophylaxis was initiated on postattack day 0 (day of release), that prophylaxis had the upper effectiveness level, and that the multiplication factor for unnecessary prophylaxis given to unexposed persons was 15. We assumed that more people would receive prophylaxis than were actually exposed because of general anxiety and uncertainty about the boundaries of the attack, the timing of the attack, and the time it would take nonresidents to travel through the attack area. Three different multiplication factors (5, 10, and 15) were used to construct within the population. Finally, ongoing intelligence gathering would detect possible bioterrorist threats. The cost of these prerequisite activities can be calculated if they are seen as a form of insurance, the goal of which is to "purchase" the maximum net savings through preparedness to manage the consequences of an attack and reduce the probability of an attack. The "actuarially fair premium" for the "insurance" can be defined as follows (22): Actuarially fair premium = reduction of loss probability x value of avoidable loss. The term "reduction of loss probability" indicates that, although increased surveillance and related activities can reduce the odds of an attack, they cannot guarantee absolute protection. The term "avoidable loss" refers to the fact that, even if a postexposure prophylaxis program were implemented on the day of release (day zero), some deaths, hospitalizations, and outpatient visits would be unavoidable. Various reductions of attack probability illustrated the impact of these estimates on the calculation of actuarially fair premiums. Such reductions included reducing the probability from 1 in 100 years (0.01) to 1 in 1,000 years (0.001), a reduction of 0.009, and reducing a probability from 1 in a 100 years (0.01) to 1 in 10,000 years (0.0001), and from 1 in 100 years (0.01) to 1 in 100,000 years (0.00001). The attack probability of 0.01 in the absence of enhanced preventive actions was selected for illustrative purposes and does not represent an official estimate. A range of minimum and maximum values of avoidable loss was derived from the net savings calculations. The values reflect differences in effectiveness of the various prophylaxis regimens, the reduced impact of delayed prophylaxis on illness and death, and the two discount rates used to calculate the present value of earnings lost because of death. Sensitivity Analyses In addition to the scenarios discussed above, three sensitivity analyses were conducted. First, the impact of increasing the cost of hospitalization and outpatient visits was assessed by using a set of upper estimates (Table 1). The cost of a hospital day was increased to $669 by increasing the cost-to-charge ratio from 0.634 to 0.764 (the ratio for Maryland) (16). The costs of outpatient visits (first and follow-up) were increased by assuming each visit was a "level 2" visit, doubling the average time a physician spends with each patient. The alternative cost-of-intervention scenarios that take into account persons who were not at risk but participated in the prophylaxis program. Thus, if 100,000 people were exposed, we assumed that the maximum number seeking prophylaxis was 500,000, 1,000,000, or 1,500,000. Economic Analysis of Preparedness: Insurance The analyses outlined above consider only the economics of an intervention after an attack and include several assumptions: First, stockpiles of drugs, vaccines, and other medical supplies would be available and could be rapidly moved to points of need. Second, civil, military, and other organizations would be in place and have the capability to rapidly identify the agent, dispense drugs, treat patients, and keep order costs of laboratory tests were increased to the full amount of the allowable charge (20). The second sensitivity analysis considered a reduced impact, in which only 10% of the original 100,000 target population were considered exposed. All other estimates were held constant. The third sensitivity analysis considered the threshold cost of an intervention, given differences due to the effectiveness of various drug regimens, and discount rates used to calculate the present value of expected lifetime earnings lost to a death. The threshold cost occurs when net savings equal $0. Thus, the threshold value represents the maximum that could be spent per person on an intervention without having the intervention cost more than the loss from no intervention. Findings Postattack Illness and Death In our model, all three biologic agents would cause high rates of illness and death. In the absence of an intervention program for the 100,000 persons exposed, the B. anthracis cloud would result in 50,000 cases of inhalation anthrax, with 32,875 deaths; the F. tularensis cloud in 82,500 cases of pneumonic or typhoidal tularemia, with 6,188 deaths; and the B. melitensis cloud in 82,500 cases of brucellosis requiring extended therapy, with 413 deaths. The speed with which a postattack intervention program can be effectively implemented is critical to its success (Figure 1). For diseases with short incubation periods such as anthrax and tularemia, a prophylaxis program must be instituted within 72 hours of exposure to prevent the maximum number of deaths, hospital days, and outpatient visits (Figure 1). Some benefit, however, can be obtained even if prophylaxis is begun as late as day 6 after exposure. The relative clinical efficacy of the intervention regimen has a lesser but definite impact on observed illness and death rates (Figure 1). [Figure 1] [Figures not available in ASCII version] Figure 1. Total deaths, hospital days, and outpatient visits associated with aerosol releases of B. anthracis, B. melitensis, and F. tularensis by the postattack day of prophylaxis initiation and level of prophylaxis effectiveness. A disease with a long incubation period such as brucellosis has a similar pattern (Figure 1); an important difference is the time available to implement an intervention program. Having more time available to implement an intervention program can make a marked difference in its effectiveness. However, the prolonged incubation period creates a greater potential for panic in potentially exposed persons because of the uncertainty about their health status. Economic Analyses of Postattack Intervention: No Program Without a postexposure prophylaxis program, an attack with B. anthracis is far costlier than attacks with F. tularensis or B. melitensis (Table 3). The differences between agents in medical costs as a percentage of total estimated costs are due to the large differences in death rates attributed to each agent (Figure 1). Table 3. Costs(a)($ millions) of a bioterrorist attack with no postexposure prophylaxis program --------------------------------------------------------------------------- Anthrax Tularemia Brucellosis --------------------------------------------------------------------------- Direct costs Medical: Base estimates(b) Hospital 194.1 445.8 170.3 OPV(c) 2.0 10.5 48.9 Medical: Upper estimates(d) Hospital 237.1 543.3 211.7 OPV(c) 4.4 18.5 78.3 Lost productivity Illness(e) Hospital 21.6 50.9 18.8 OPV(c) 0.7 3.9 15.0 Death 3% discount(f) 25,985.7 4,891.2 326.5 5% discount(f) 17,889.3 3,367.3 224.7 Total costs Base estimates 3% discount(f) 26,204.1 5,402.4 579.4 5% discount(f) 18,107.7 3,878.4 477.7 Upper estimates 3% discount(f) 26,249.7 5,507.9 650.1 5% discount(f) 18,153.1 3,983.9 548.4 --------------------------------------------------------------------------- (a)Assuming 100,000 exposed. (b)Medical costs are the costs of hospitalization (which include follow-up outpatient visits) and outpatient visits (Table 1). (c)OPV = outpatient visits. (d)Upper estimates calculated with data in Table 1. (e)Lost productivity due to illness is the value of time spent in hospital and during OPVs (Table 1). (f)Discount rate applied to calculate the present value of expected future earnings and housekeeping services, weighted by age and sex composition of the United States workforce (16), lost due to premature death. Net Savings Due to a Postexposure Prophylaxis Program If the postexposure prophylaxis program is initiated early, it reduces the economic impact of all three diseases, especially anthrax (Figure 2). Regardless of drug costs, the largest cost reductions are obtained through a combination of the most effective prophylaxis regimen (i.e., 95% effective, Table 2), the smallest multiplication factor to adjust for persons who unnecessarily receive prophylaxis, and a 3% discount rate to calculate the present value of the expected value of lifetime earnings. In the case of anthrax, either doxycycline or ciprofloxacin could be used in the intervention program (Table 2), but the use of doxycycline generated the largest savings. The largest difference in net savings between the two drugs was approximately $261.6 million. This difference occurred when it was assumed that the program began on day zero (day of release), each drug was used in combination with the anthrax vaccine, a 3% discount rate was used, and a multiplication factor of 15 for unnecessary prophylaxis was used. This amount is equal to approximately 1.2% of the maximum total net savings generated by using a regimen of doxycycline plus the anthrax vaccine. Some scenarios, particularly those in which prophylaxis programs were started late, generated negative net savings (i.e., net losses). In the case of tularemia, at a 5% discount rate, net losses of $10.7 to $115.1 million occurred when a post-exposure program was delayed until day 6 after exposure, and a prophylaxis regimen of doxycycline and gentamicin (estimated 95% efficacy) was used. For the same scenario, but with a 3% discount, a net savings of $1,513.3 million was observed when a multiplication factor of five for unnecessary prophylaxis was used. However, multiplication factors of 10 and 15 generated net losses of $49.8 and $102.0 million, respectively. With the same drug combination, beginning the program 1 day earlier (day 5 after exposure) resulted in net savings in all scenarios except when a multiplication factor of 15 and a discount rate of 5% were used. Under the latter two assumptions, net savings result only for prophylaxis initiated by day 4 after exposure. In the case of brucellosis, the use of a doxycycline-rifampin regimen (estimated 80% efficacy), a multiplication factor of 15 for unnecessary prophylaxis, and a discount rate of either 3% or 5% generated net losses regardless of when intervention began (Figure 2). The doxycycline-gentamicin regimen (estimated 95% efficacy) generated net losses only when it was assumed that the start of a program was delayed until 113 or more days after exposure. [Figure 2] [Figures not available in ASCII version] Figure 2. Ranges(a) of net savings due to postattack prophylaxis by disease and day of prophylaxis program initiation. (a)Maximum savings (l) were calculated by assuming a 95% effectiveness prophylaxis regimen and a 3% discount rate in determining the present value of expected lifetime earnings lost due to premature death (16) and a multiplication factor of 5 to adjust for unnecessary prophylaxis. Minimum savings (n) were calculated by assuming an 80% to 90% effectiveness regimen and a 5% discount rate and a multiplication factor of 15. In tularemia prophylaxis programs initiated on days 4-7 postattack, the minimum savings were calculated by assuming a 95% prophylaxis regimen effectiveness rather than an effectiveness of 80% to 90%. Preparedness: Insurance The annual actuarially fair premium that can be justifiably spent on intelligence gathering and other attack prevention measures increases with the probability that a bioterrorist attack can be decreased by such measures (Table 4). However, the potential net savings attributed to reduced probability are minor compared with the potential net savings from implementing a prophylaxis program. Depending on the level of protection that can be achieved, the annual actuarially fair premium in an anthrax scenario would be $3.2 million to $223.5 million (Table 4). The lower premium would be justifiable for measures that could reduce the risk for an attack from 0.01 to 0.001 and provide the ability to mount an intervention program within 6 days of the attack. The higher premium would be justifiable for measures that could reduce the risk from 0.01 to 0.00001 and allow immediate intervention if an attack occurred. Table 4. The maximum annual actuarially fair premium(a) by reduction in probability of event and size of avoided loss: Anthrax --------------------------------------------------------------------------- Actuarially fair annual premium ($ millions) ------------------------------------- Days Preventable 0.01 0.01 0.01 post- loss tp to to attack(b) ($millions) 0.001 0.0001 0.00001 --------------------------------------------------------------------------- Maximum loss estimate(c) 0 22,370.5 201.3 221.5 223.5 1 20,129.4 181.2 199.3 201.1 2 15,881.5 142.9 157.2 158.7 3 8,448.0 76.0 83.6 84.4 4 4,200.1 37.8 41.6 42.0 5 2,076.1 18.7 20.6 20.7 6 1,013.8 9.1 10.0 10.1 Minimum loss estimate(d) 0 14,372.4 128.9 141.8 143.1 1 12,820.1 115.4 126.9 128.1 2 10,049.1 90.4 99.5 100.4 3 5,200.1 46.8 51.5 51.9 4 2,429.7 21.9 24.1 24.3 5 1,004.2 9.4 10.3 10.4 6 351.2 3.2 3.5 3.5 --------------------------------------------------------------------------- (a)See text for definition. (b)No. of days from attack to effective initiation of prophylaxis. (c)Maximum loss preventable (potential net savings) occurs with the doxycycline-anthrax vaccine prophylaxis regimen, a multiplication factor of 5 for unnecessary prophylaxis, and a discount rate of 3% (Table 2). (d)Minimum loss preventable (potential net savings) occurs with the ciprofloxacin prophylaxis regimen, a multiplication factor of 15 for unnecessary prophylaxis, and a discount rate of 5% (Table 2). Sensitivity Analyses The upper estimates of the cost of hospitalization increased average costs per day by 18% to 22%, and upper estimates of the cost of outpatient visits increased average costs per day by 46% to 93% (Table 1). However, the upper estimates only increased medical costs by 1% to 6% of the total medical costs associated with a bioterrorist attack (Table 3). The largest increase was for brucellosis, for which upper estimates increased medical costs from 38% to 44% of total costs (Table 3). When the number of persons infected during an attack was reduced tenfold, the patient-related costs were reduced proportionately (Table 3). In most cases, however, the net savings in total costs are less than 10% of the net savings when 100% of the target population was presumed infected. The shortfall in savings is caused by an increase in the number of unexposed persons receiving prophylaxis. In the case of anthrax, when intervention programs are initiated within 3 days of exposure, savings are 4.1% to 10% of those in the original scenario (Figure 2). Delaying initiation of prophylaxis until days 4, 5, or 6 after exposure, however, results in net losses of $13.4 to $283.1 million. Losses occur regardless of prophylaxis regimen, discount rate, or multiplication factor used to adjust for unnecessary prophylaxis by unexposed persons. In scenarios in which a multiplication factor of 15 was used to adjust for unnecessary prophylaxis, the threshold value of intervention was always above the prophylaxis cost for anthrax but not above the prophylaxis costs for tularemia and brucellosis (Table 5). For tularemia, the threshold intervention costs exceeded disease costs up to day 5 in the scenario with 95% effectiveness and a 5% discount, and for brucellosis, at all levels in the scenarios with 80% effectiveness and up to day 56 in the scenarios with 95% effectiveness. This is consistent with the lower range of estimated net savings (net losses) given in Figure 2. Reducing the number of unexposed persons receiving prophylaxis increases the cost thresholds, making the program cost beneficial. For example, changing the multiplication factors for unnecessary prophylaxis to 5 and 10 increases the cost thresholds to $659 and $319, respectively, for a brucellosis prophylaxis program initiated 15 to 28 days after exposure, with a 5% discount rate. If a discount rate of 3% is used instead of 5%, the cost thresholds increase to $799 and $387. All these cost thresholds are above the estimated prophylaxis cost of $285 per person for the doxycycline-rifampin regimen and $161 per person for the doxycycline-gentamicin regimen (Table 2). Table 5. Cost thresholds(a) of interventions ($/person) by day of intervention initiation, prophylaxis effectiveness, and discount rates. -------------------------------------------------------------------------- Threshold costs for intervention ($/person, multiplication factor of 15(b)) Anthrax Tularemia Brucellosis Post- Disc. rate(c) Post- Disc. rate Post- Disc. rate attack attack attack day(d) 5% 3% day 5% 3% day 5% 3% -------------------------------------------------------------------------- 90% effectiveness(e) 80% effectiveness(e) 80% effectiveness(e) 0 9,838 14,238 0 1,891 2,633 0-7 233* 282* 1 8,851 12,809 1 1,873 2,609 8-14 224* 272* 2 7,022 10,162 2 1,599 2,227 15-28 211* 255* 3 3,775 5,463 3 756 1,053 29-56 179* 217* 4 1,893 2,739 4 258 366 57-112 86* 104* 5 944 1,366 5 79 110 113+ 24* 30* 6 468 677 6 20* 28 Prophylaxis cost(c) $226 $28 $285 95% effectiveness(e) 95% effectiveness(e) 95% effectiveness(e) 0 10,370 15,007 0 2,229 3,104 0-7 274 333 1 9,359 13,544 1 2,207 3,074 8-14 264 320 2 7,427 10,948 2 1,898 2,644 15-28 248 301 3 3,995 5,782 3 898 1,251 29-56 211 256 4 2,004 2,900 4 328 457 57-112 102* 124* 5 1,000 1,447 5 93* 131 113+ 29* 35* 6 496 718 6 23* 32* Prophylaxis cost(e) $238 $104 $161 -------------------------------------------------------------------------- *Threshold value is below estimated cost of prophylaxis. (a)Cost threshold is the point where cost of intervention and net savings due to the intervention are equal. (b)Multiplication factor to adjust for persons who participated in the prophylaxis program but were unexposed. (c)Applied to present value of expected future earnings and housekeeping services (weighted average for age and sex). (d)Postattack day on which prophylaxis was effecively implemented. (e)See Table 2 for prophylaxis regimens assumed to give the stated levels of effectiveness and cost/person of prophylaxis. Conclusions The economic impact of a bioterrorist attack can range from $477.7 million per 100,000 persons exposed in the brucellosis scenario to $26.2 billion per 100,000 persons exposed in the anthrax scenario (Table 3). These are minimum estimates. In our analyses, we consistently used low estimates for all factors directly affecting costs. The ID50 estimates for the three agents are twofold to 50-fold higher than previously published estimates (5,6,10,11), resulting in a possible understatement of attack rates. Also, in our analyses we did not include a number of other factors (e.g., long-term human illness or animal illnesses) (Table 6) whose cumulative effect would likely increase the economic impact of an attack. Our model shows that early implementation of a prophylaxis program after an attack is essential. Although the savings achieved by initiating a prophylaxis program on any given day after exposure has a wide range, a clear trend of markedly reduced savings is associated with delay in starting prophylaxis (Figure 2). This trend was found in the analysis of all three agents studied. Table 6. Potential factors affecting the economic impact of a bioterrorist attack --------------------------------------------------------------------------- Potential Relative impact on magnitude Factor net savings of impact --------------------------------------------------------------------------- Higher than projected Increase ++++ case-fatality rate Long term illness (physical Increase ++ and psychological) Decontamination and disposal Increase ++ of biohazardous waste Disruptions in commerce Increase ++ (local, national, and international) Animal illness and death Increase + Lower than projected Decrease - - - effectiveness of prophylaxis Adverse drug reactions due Decrease - to prophylaxis Postattack prophylaxis Decrease - distribution costs, including crowd control and security Training and other skill Decrease - maintenance costs Procurement and storage of Decrease - antimicrobial drugs and vaccines before attack Criminal investigations Variable +/- and court costs --------------------------------------------------------------------------- Delay in starting a prophylaxis program is the single most important factor for increased losses (reduced net savings). This observation was supported by the actuarially fair premium for preparedness analysis (Table 4). Reductions in preventable loss due to early intervention had significantly greater impact on the amount of an actuarially fair premium than reductions in probability of an attack through intelligence gathering and related activities. Although implemented at different times in a threat-attack continuum, both attack prevention measures and prophylaxis programs are forms of preventive medicine. Attack prevention measures seek to prevent infection, while prophylaxis programs prevent disease after infection has occurred. Using an actuarially fair premium analogy in which cost and benefit are required to be equal, we find that the incremental rate of increasing prevention effectiveness (the marginal increase) declines rapidly as probability reduction targets go from 0.001 to 0.0001 to 0.00001. Because the loss probability is decreasing on a logarithmic scale, the potential increment in marginal benefit drops comparably, resulting in ever smaller increments in the protection above the preceding base level. Conversely, delaying a prophylaxis program for anthrax, a disease with a short incubation period and a high death rate, increases the risk for loss in a manner akin to a semilogarithmic scale. Arithmetic increases in response time buy disproportionate increases in benefit (prevented losses.) The potential for reducing loss is great because an attack is assumed, thus increasing the actuarially fair premium available to prepare for and implement a rapid response. Large differences between prophylaxis costs and the threshold costs for most scenarios, particularly if prophylaxis is early (Table 5), suggest that the estimates of savings from prophylaxis programs are robust. Even with large increases in prophylaxis cost, net savings would still be achieved. The ability to rapidly identify persons at risk would also have significant impact on costs. For example, the threshold costs for brucellosis prophylaxis are often lower than intervention costs when the ratio of unexposed to exposed persons in the prophylaxis program is 15:1 (Table 5). This finding provides an economic rationale for preparedness to rapidly and accurately identify the population at risk and reduce unnecessary prophylaxis costs. The maximum amount of the annual actuarially fair premium varies directly with the level of risk reduction and the rapidity of postattack response (Table 4). The calculated amount of actuarially fair premiums, however, should be considered a lower bound estimate. A higher estimate (called the certainty equivalent) can also be calculated; however, this requires the determination of a social welfare function (22), and such complexity is beyond the scope of this study. Our model provides an economic rationale for preparedness measures to both reduce the probability of an attack and increase the capability to rapidly respond in the event of an attack. The larger portion of this preparedness budget (insurance premium) should be allocated to measures that enhance rapid response to an attack. These measures would include developing and maintaining laboratory capabilities for both clinical diagnostic testing and environmental sampling, developing and maintaining drug stockpiles, and developing and practicing response plans at the local level. These measures should be developed with a value-added approach. For example, the laboratory capability could be used for other public health activities in addition to preparedness, and drugs nearing their potency expiration date could be used in government-funded health care programs. However, these secondary uses should not undermine the preparedness program's effectiveness. Arnold Kaufmann is a retired Public Health Service officer, formerly assigned to the National Center for Infectious Diseases. Address for correspondence: Martin I. Meltzer, Mail Stop C-12, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333; fax: 404-639-3039; e-mail: qzm4@cdc.gov. References 1. Cole LA. The specter of biological weapons. Sci Am 1996;275:60-5. 2. Gochenour WS. Aerobiology. Mil Med 1963;128:86-9. 3. Abramova FAN, Grinberg LM, Yampolskaya OV, Walker DH. Pathology of inhalational anthrax in 42 cases from the Sverdlovsk outbreak of 1979. Proc Natl Acad Sci 1993;90:2291-4. 4. Benenson AS, editor. Control of communicable diseases manual. 16th ed. Washington (DC): American Public Health Association, 1995. 5. Messelson M, Guillemin J, Hugh-Jones M, Langmuir A, Popova I, Shelokov A, et al. The Sverdlosvsk anthrax outbreak of 1979. Science 1994;266:1202-8. 6. Kaufmann AF, Fox MD, Boyce JM, Anderson DC, Potter ME, Martone WJ, et al. Airborne spread of brucellosis. Ann NY Acad Sci 1980;335:105-14. 7. Olle-Goig JE, Canela-Soler J. An outbreak of Brucella melitensis infection by airborne transmission among laboratory workers. Am J Public Health 1987;77:335-8. 8. Staszkiewicz J, Lewis CM, Colville J, Zervos M, Band J. Outbreak of Brucella melitensis among microbiology laboratory workers in a community hospital. J Clin Microbiol 1991;29:287-90. 9. Trever RW, Cluff LE, Peeler RN, Bennett IL. Brucellosis I. laboratory-acquired acute infection. Arch Intern Med 1959;103:381-97. 10. McCrumb FR. Aerosol infection of man with Pasteurella tularensis. Bacteriolical Reviews 1961;25:262-7. 11. Saslaw S, Eigelsbach HT, Wilson HR, Prior JA, Carhart S. Tularemia vaccine study II. respiratory challenge. Arch Intern Med 1961;107:689-701. 12. Friedlander AM, Welkos SL, Pitt MLM, Ezzell JW, Worsham PL, Rose, KJ, et al. Postexposure prophylaxis against experimental inhalation anthrax. J Infect Dis 1993;167:1239-42. 13. Sawyer WD, Dangerfield HG, Hogge AL, Crozier D. Antibiotic prophylaxis and therapy of airborne tularemia. Bacteriolical Reviews 1966;30:542-8. 14. Solera J, Rodriguez-Zapata M, Geijo P, Largo J, Paulino J, Saez L, et al. Doxycycline-rifampin versus doxycycline-streptomycin in treatment of human brucellosis due to Brucella melitensis. Antimicrob Agents Chemother 1995;39:2061-7. 15. Luce BR, Manning WG, Siegel JE, Lipscomb J. Estimating costs in cost-effectiveness analysis. In: Gold MR, Siegel JE, Russell LB, Weinstein MC, editors. Cost-effectiveness in health and medicine. New York: Oxford University Press, 1966:176-213. 16. Haddix AC, Teutsch SM, Shaffer PA, Dunet DO, editors. Prevention effectiveness: a guide to decision analysis and economic evaluation. New York: Oxford University Press, 1996. 17. Lipscomb J, Weinstein MC, Torrance GW. Time preference. In: Gold MR, Siegel JE, Russell LB, Weinstein MC, editors. Cost-effectiveness in health and medicine. New York: Oxford University Press, 1966:214-35. 18. U.S. Bureau of the Census. Statistical abstract of the United States: 1995. 115th ed. Washington (DC): U.S. Government Printing Office, 1996. 19. National Center for Health Statistics. Health, United States, 1995. Hyattsville (MD):U.S.Departmentof Health and Human Services, Public Health Service, 1996. 20. HealthCare Consultants of America, Inc. HealthCare Consultants' 1996 physicians fee and coding guide. 6th ed. Augusta (GA): HealthCare Consultants of America, Inc. 1996. 21. Cardinale V, editor. 1996 Drug Topics Red Book. Montvale (NJ): Medical Economics Company, Inc., 1996. 22. Robison LJ, Barry PJ. The competitive firm's response to risk. New York: Macmillan, 1987. --------------------------------------------------------------------------- [Emerging Infectious Diseases * Volume 3 * Number 2 * April-June 1997] Synopses Hantaviruses: A Global Disease Problem Connie Schmaljohn* and Brian Hjelle† *United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, USA; and †University of New Mexico, Albuquerque, New Mexico, USA --------------------------------------------------------------------------- Hantaviruses are carried by numerous rodent species throughout the world. In 1993, a previously unknown group of hantaviruses emerged in the United States as the cause of an acute respiratory disease now termed hantavirus pulmonary syndrome (HPS). Before then, hantaviruses were known as the etiologic agents of hemorrhagic fever with renal syndrome, a disease that occurs almost entirely in the Eastern Hemisphere. Since the discovery of the HPS-causing hantaviruses, intense investigation of the ecology and epidemiology of hantaviruses has led to the discovery of many other novel hantaviruses. Their ubiquity and potential for causing severe human illness make these viruses an important public health concern; we reviewed the distribution, ecology, disease potential, and genetic spectrum. The genus Hantavirus, family Bunyaviridae, comprises at least 14 viruses, including those that cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) (Table 1). Several tentative members of the genus are known, and others will surely emerge as their natural ecology is further explored. Hantaviruses are primarily rodent-borne, although other animal species harboring hantaviruses have been reported. Unlike all other viruses in the family, hantaviruses are not transmitted by arthropod vectors but (most frequently) from inhalation of virus-contaminated aerosols of rodent excreta (1). Human-to-human transmission of hantaviruses has not been documented, except as noted below. Table 1. Members of the genus Hantavirus, family Bunyaviridae -------------------------------------------------------------------------- Species Disease Principal Distribution Distribution of Reservoir of Virus Reservoir -------------------------------------------------------------------------- Hantaan (HTN) HFRS(a) Apodemus China, C Europe south to agrarius Russia, Thrace, Caucasus, (striped field Korea & Tien Shan Mtns; mouse) Amur River through Korea to E Xizang & E Yunnan, W Sichuan, Fujiau, & Taiwan(China) Dobrava-Belgrade HFRS Apodemus Balkans England & Wales, (DOB) flavicollis from NW Spain, (yellow-neck France, S mouse) Scandinavia through European Russia to Urals, S Italy, the Balkans, Syria, Lebanon, & Israel Seoul (SEO) HFRS Rattus Worldwide Worldwide norvegicus (Norway rat) Puumala (PUU) HFRS Clethrionomys Europe, W Palearctic from glareolus Russia, France and (bank vole) Scandinavia Scandinavia to Lake Baikai, south to N Spain, N Italy, Balkans,W Turkey, N Kazakhstan, Altai & Sayan Mtns; Britain & SW Ireland Thailand (THAI) nd(b) Bandicota Thailand Sri Lanka, indica peninsular India (bandicoot rat) to Nepal, Burma, NE India, S China, Laos, Taiwan, Thailand, Vietnam Prospect Hill nd Microtus U.S., Canada C Alaska to (PH) pennsylvanicus Labrador, (meadow vole) including Newfoundland & Prince Edward Island, Canada; Rocky Mountains to N New Mexico, in Great Plains to N Kansas, & in Appalachians to N Georgia, U.S. Khabarovsk (KHB) nd Microtus fortis Russia Transbaikalia Amur (reed vole) region; E China Thottapalayam nd Suncus murinus India Afghanistan, (TPM) (musk shrew) Pakistan, India, Sri Lanka, Nepal, Bhutan, Burma, China, Taiwan, Japan, Indomalayan Region Tula (TUL) nd Microtus Europe Throughout Europe arvalis to Black Sea & NE (European to Kirov region, common Russia vole) Sin Nombre (SN) HPS(c) Peromyscus U.S., Alaska Panhandle maniculatus Canada, across N Mexico (deer mouse) Canada, south through most of continental U.S., excluding SE & E seaboard, to southernmost Baja California Sur and to NC Oaxaca, Mexico New York (NY) HPS Peromyscus U.S. C and E U.S. to S leucopus Alberta & S (white-footed Ontario, Quebec & mouse) Nova Scotia, Canada; to N Durango & along Caribbean coast to Isthmus of Tehuantepec & Yucatan Peninsula, Mexico Black Creek HPS Sigmodon U.S. SE U.S., from S Canal hispidus Nebraska to C (BCC) (cotton rat) Virginia south to SE Arizona & peninsular Florida; interior & E Mexico through Middle America to C Panama; in South Amer ica to N Colombia & N Venezuela El Moro Canyon nd Reithrodontomys U.S., Mexico British Columbia & (ELMC)(d) SE Alberta, megalotis Canada; W and NC (Western U.S., S to N Baja harvest mouse) California & interior Mexico to central Oaxaca Bayou (BAY)(d) HPS Oryzomys U.S. SE Kansas to E palustris Texas, eastward to (rice rat) S New Jersey & peninsular Florida -------------------------------------------------------------------------- Probable species:(e) -------------------------------------------------------------------------- Topografov (TOP) nd Lemmus Siberia Palearctic, from sibiricus White Sea, W (Siberian Russia, to lemming) Chukotski Peninsula, NE Siberia, & Kamchatka; Nearctic, from W Alaska E to Baffin Island & Hudson Bay, S Rocky Mtns to C B.C., Canada Andes (AND)(d) HPS Oligoryzomys Argentina NC to S Andes, longicaudatus(f) approximately to 50 deg S latitude, (long-tailed in Chile & pygmy Argentina rice rat) To be named(d) HPS Calomys laucha Paraguay N Argentina & vesper mouse Uruguay, SE Bolivia, W Paraguay, and WC Brazil Isla Vista nd Microtus U.S. Pacific coast, (ISLA)(d) californicus from SW Oregon (California through vole) California, U.S., to N Baja California, Mexico Bloodland Lake nd Microtus U.S. N & C Great (BLL)(d) ochrogaster Plains, EC Alberta (prairie vole) to S Manitoba, Canada, S to N Oklahoma & Arkansas, E to C Tennessee & W West Virginia, U.S.; relic populations elsewhere in U.S. & Mexico Muleshoe nd Sigmodon U.S. See Black Creek (MUL)(d) hipidus Canal (cotton rat) Rio Segundo nd Reithrodontomys Costa Rica S Tamaulipas & WC (RIOS)(d) Michoacan, Mexico, mexicanus S through Middle (Mexican American highlands harvest mouse) to W Panama; Andes of W Colombia & N Ecuador Rio Mamore nd Oligoryzomys Bolivia C Brazil south of (RIOM)(d) microtis Rios Solimoes- (small-eared Amazon & pygmy contiguous low rice rat) lands of Peru, Bolivia, Paraguay, & Argentina. -------------------------------------------------------------------------- (a)HFRS, hemorrhagic fever with renal syndrome (b)nd, none documented (c)HPS, hantavirus pulmonary syndrome (d) not yet isolated in cell culture (e) viruses for which incomplete characterization is available, but for which there is clear evidence indicating that they are unique (f) suspected host, but not confirmed Adapted from (57,72) and from (9,13,23,38,42,43,50-71) The recognition of a previously unknown group of hantaviruses as the cause of HPS in 1993 is an example of virus emergence due to environmental factors favoring of the natural reservoir; a larger reservoir increases opportunities for human infection. We reviewed the global distribution of hantaviruses, their potential to cause disease, and their relationships to each other and to their rodent hosts. History of HFRS and HPS "Hemorrhagic fever with renal syndrome" denotes a group of clinically similar illnesses that occur throughout the Eurasian landmass and adjoining areas (2,3). HFRS includes diseases previously known as Korean hemorrhagic fever, epidemic hemorrhagic fever, and nephropathia epidemica (4). Although these diseases were recognized in Asia perhaps for centuries, HFRS first came to the attention of western physicians when approximately 3,200 cases occurred from 1951 to 1954 among United Nations forces in Korea (2,5). Other outbreaks of what is believed to have been HFRS were reported in Russia in 1913 and 1932, among Japanese troops in Manchuria in 1932 (2,6), and in Sweden in 1934 (7,8). In the early 1940s, a viral etiology for HFRS was suggested by Russian and Japanese investigators who injected persons with filtered urine or serum from patients with naturally acquired disease (2). These studies also provided the first clues to the natural reservoir of hantaviruses: the Japanese investigators claimed to produce disease in humans by injecting bacteria-free filtrates of tissues from Apodemus agrarius or mites that fed on the Apodemus mice. Mite transmission was never conclusively demonstrated by other investigators, and it was not until 1978 that a rodent reservoir for HFRS-causing viruses was confirmed by investigators who demonstrated that patient sera reacted with antigen in lung sections of wild-caught Apodemus agrarius and that the virus could be passed from rodent to rodent (9). The successful propagation of Hantaan (HTN) virus in cell culture in 1981 provided the first opportunity to study this pathogen systematically (10). The history of HFRS has been explored (2,11,12). HPS was first described in 1993 when a cluster of cases of adult fatal respiratory distress of unknown origin occurred in the Four Corners region of the United States (New Mexico, Arizona, Colorado, and Utah). The unexpected finding that sera from patients reacted with hantaviral antigens was quickly followed by the genetic identification of a novel hantavirus in patients' tissues and in rodents trapped near patients' homes (13-15). Prevalence and Clinical Course Approximately 150,000 to 200,000 cases of HFRS involving hospitalization are reported each year throughout the world, with more than half in China (16). Russia and Korea also report hundreds to thousands of HFRS cases each year. Most remaining cases (hundreds per year) are found in Japan, Finland, Sweden, Bulgaria, Greece, Hungary, France, and the Balkan countries formerly constituting Yugoslavia (16). Depending in part on which hantavirus is responsible for the illness, HFRS can appear as a mild, moderate, or severe disease (Table 2). Death rates range from less than 0.1% for HFRS caused by Puumala (PUU) virus to approximately 5% to 10% for HFRS caused by HTN virus (16). The clinical course of severe HFRS involves five overlapping stages: febrile, hypotensive, oliguric, diuretic, and convalescent; it is not uncommon, however, for one or more of these stages to be inapparent or absent. The onset of the disease is usually sudden with intense headache, backache, fever, and chills. Hemorrhage, if it occurs, is manifested during the febrile phase as a flushing of the face or injection of the conjunctiva and mucous membranes. A petechial rash may also appear, commonly on the palate and axillary skin folds. Sudden and extreme albuminuria, around day 4, is characteristic of severe HFRS. As the febrile stage ends, hypotension can abruptly develop and last for hours or days, during which nausea and vomiting are common. One-third of deaths occur during this phase because of vascular leakage and acute shock. Almost half of all deaths occur during the subsequent (oliguric) phase because of hypervolemia. Patients who survive and progress to the diuretic phase show improved renal function but may still die of shock or pulmonary complications. The final (convalescent) phase can last weeks to months before recovery is complete (3,5,12). Table 2. Distinguishing clinical characteristics for HFRS and HPS -------------------------------------------------------------------------- Disease Pathogens Distinguishing Characteristics* -------------------------------------------------------------------------- HFRS (moderate-severe) HTN, SEO, hemorrhage +++ Death rate DOB azotemia/ 1%-15% proteinuria +++/++++ pulmonary capillary leak +/++ myositis +/+++ conjunctival injection ++/++++ eye pain/myopia ++/++++ HFRS (mild) PUU hemorrhage + Death rate <1% azotemia/ proteinuria +/++++ pulmonary capillary leak -/+ myositis + conjunctival injection + eye pain/myopia ++/++++ HPS (prototype) SN, NY hemorrhage + Death rate >40% zotemia/ proteinuria + pulmonary capillary leak ++++ myositis - conjunctival injection -/+ eye pain/myopia - HPS (renal BAY, BCC, hemorrhage + variant) Andes azotemia/ Death rate>40% proteinuria ++/+++ pulmonary capillary leak +++/++++ myositis ++/++++ conjunctival injection -/++ eye pain/myopia - -------------------------------------------------------------------------- *Minimum/maximum occurrence of the characteristic: - rarely reported; + infrequent or mild manifestation; ++, +++, ++++ more frequent and severe manifestation. More than 250 cases of HPS have been reported throughout North and South America. Although the disease has many features (e.g., a febrile prodrome, thrombocytopenia, and leukocytosis) in common with HFRS (Table 2), in HPS capillary leakage is localized exclusively in the lungs, rather than in the retroperitoneal space, and the kidneys are largely unaffected. Most of the 174 cases of HPS in the United States and Canada have been caused by Sin Nombre (SN) virus. In HPS, death occurs from shock and cardiac complications, even with adequate tissue oxygenation. Cases of HPS in the southeastern United States, as well as many in South America, are caused by a newly recognized clade (a group that shares a common ancestor) of viruses that includes Bayou (BAY), Black Creek Canal (BCC), and Andes viruses. As with HFRS, clinical differences can be observed among patients with HPS caused by different hantaviruses. For example, although HPS due to SN virus infection can sometimes be associated with renal insufficiency after prolonged hypoperfusion, renal impairment is only rarely observed early in disease, and chemical evidence of skeletal muscle inflammation (increased serum levels of the muscle enzyme creatine kinase) is rare (17). In contrast, both renal insufficiency and elevated creatine kinase levels are observed at much higher frequency, although not universally, with Andes, BAY, and BCC virus infections (18-20; J. Davis, J. Cortes, and C. Barclay, pers. comm.). In an outbreak of HPS recently described in Paraguay, a novel hantavirus, carried by Calomys laucha, was identified as the etiologic agent (21). The relationship of this virus to other HPS-causing hantaviruses remains to be established. Ecology and Epidemiology Hantavirus infection is apparently not deleterious to its rodent reservoir host and is associated with a brisk antibody response against the virion envelope and core proteins and chronic, probably lifelong infection. In natural populations, most infections occur through age-dependent horizontal route(s). The highest antibody prevalence is observed in large (mature) animals. A striking male predilection for hantavirus infection is observed in some rodent species such as harvest mice and deer mice, but not in urban rats (Rattus norvegicus) (22-24). Horizontal transmission among cage-mates was experimentally demonstrated (25), but vertical transmission from dam to pup is negligible or absent both in wild and experimental settings (22,24,25). Outbreaks of hantaviral disease have been associated with changes in rodent population densities, which may vary greatly across time, both seasonally and from year to year. Cycles respond to such extrinsic factors as interspecific competition, climatic changes, and predation. Spring and summer outbreaks of HFRS in agricultural settings in Asia and Europe are linked to human contact with field rodents through the planting and harvesting of crops (16,26). PUU outbreaks in Scandinavia and the HPS outbreak in the Four Corners region of the United States were associated with natural rodent population increases, followed by invasion of buildings by rodents (27,28). The ecologic events that led to 1994 and 1996 outbreaks of Andes virus-HPS in Patagonia, a region in southern South America, are being investigated. Human interventions, such as the introduction of Old World plant species (e.g., rosas mosquetas and Scottish brougham) to Patagonia, with associated alteration in rodent population dynamics, have been suggested as possible factors. Recent fires and a mild winter in Argentina's Rio Negro and Chubut Provinces may also have had a positive effect on the carrier rodent, the colilargo, Oligoryzomys longicaudatus (M. Christie and O. Pearson, pers. comm.). Although the aerosol route of infection is undoubtedly the most common means of transmission among rodents and to humans, virus transmission by bite may occur among certain rodents (29) and may also occasionally result in human infection (30) (often inside a closed space, such as a rodent-infested grain silo, garage, or outbuilding used for food storage). Epidemiologic investigations have linked virus exposure to such activities as heavy farm work, threshing, sleeping on the ground, and military exercises. Indoor exposure was linked to invasion of homes by field rodents during cold weather or to nesting of rodents in or near dwellings (16,31). Genetic sequencing of rodent- and patient-associated viruses has been used to pinpoint the precise locations of human infections, which has supported the role of indoor exposure in hantavirus transmission (32,33). Many hantavirus infections have occurred in persons of lower socioeconomic status because poorer housing conditions and agricultural activities favor closer contact between humans and rodents. However, suburbanization, wilderness camping, and other outdoor recreational activities have spread infection to persons of middle and upper incomes. Nosocomial transmission of hantaviruses has not been documented until very recently (34) and must be regarded as rare. However, viruses have been isolated from blood and urine of HFRS patients, so exposure to bodily fluids of infected persons could result in secondary transmission. Only rarely have multiple North American HPS cases been associated with particular households or buildings. During recent outbreaks of HPS in South America, however, clustering of cases in households and among personal contacts appeared to be more common (M. Christie, pers. comm.). During a recent outbreak of Andes-virus-associated HPS in Patagonia, a Buenos Aires physician apparently contracted the infection after minimal exposure to infected patient blood (34; D.A. Pirola, pers. comm.). An adolescent patient in Buenos Aires apparently contracted hantavirus infection from her parents, who were infected in Patagonia. This unprecedented observation of apparent person-to-person spread of a hantavirus clearly requires laboratory confirmation, especially by careful comparative analysis of the viral sequences (32,33). Hantaviruses have also caused several laboratory-associated outbreaks of HFRS. Laboratory-acquired infections were traced to persistently infected rats obtained from breeders (35-37), to wild-caught, naturally infected rodents (38-40), or to experimentally infected rodents (39). No illnesses due to laboratory infections have been reported among workers using cell-culture adapted viruses, although asymptomatic seroconversions have been documented (40). Hantavirus Distribution and Disease-causing Potential The worldwide distribution of rodents known to harbor hantaviruses (Table 1) suggests great disease-causing potential. Each hantavirus appears to have a single predominant natural reservoir. With rare exception, the phylogenetic interrelationships among the viruses and those of their predominant host show remarkable concordance (Figure; 41). These observations suggest that hantaviruses do not adapt readily to new hosts and that they are closely adapted for success in their host, possibly because of thousands of years of coexistence. As many as three hantaviruses can be found in a particular geographic site, each circulating in its own rodent reservoir, with no apparent evolutionary influence on one another (42). [Figure 1] [Figures not available in ASCII version] Figure. Phylogeny of hantaviruses and their relationships to natural reservoirs. The trees were constructed by comparing the complete coding regions of the S segments of hantaviruses or of 330 nucleotides corresponding to those of the M segment of Hantaan virus (strain 76118) from nucleotides 1987 to 2315. Abrreviations for viruses are as in Table 1. For each analysis, a single most parsimonious tree was derived by using PAUP 3.1.1 software. For the S segment tree, boostrap values resulting from 100 replications were all greater than 87% except for the branch leading to BCC (78%) and the branch leading to DOB (52%). The next most common placing of DOB was on a branch with HTN. All known hantaviruses, except Thotta-palayam (TPM) virus, have been isolated or detected in murid rodents. Because only one isolate of TPM virus was made from a shrew (Order Insectivora), it is not clear if Suncus is the true primary reservoir or an example of a "spillover" host, i.e., a secondary host infected through contact with the primary host. Spillover is common in sympatric murid rodents, including those identified as the predominant carrier of another hantavirus; thus, the opportunity for genetic exchange among hantaviruses is present in nature. Spillover hosts are believed to have little or no impact on hantaviral distribution or associated disease. However, rodents other than the primary reservoirs can play an important carrier role. For example, Microtus rossiaemeri-dionalis may play a role in maintenance of Tula virus in some settings (43), and Peromyscus leucopus and Peromyscus boylii can be important reservoirs for SN virus in the western United States (T. Yates and B. Hjelle, unpub. data). Apparent spillover may also be the result of laboratory errors such as polymerase chain reaction (PCR) contamination or misidentification of rodent species. However, spillover is probably under-appreciated in many studies that rely on reverse transcriptase PCR for identifying specific viruses because many primer pairs may not detect an unexpected spillover virus. In either case, because mistaken identities and cell culture contaminations with other hantaviruses have occasionally been reported, investigators should verify unusual findings to prevent further confusion. Antigenic and Genetic Diversity among Hantaviruses Hantaviruses have been characterized by a combination of antigenic and genetic methods. For viruses propagated in cell culture, the plaque-reduction neutralization test is the most sensitive serologic assay for differentiation (44,45); nine hantaviruses have been defined by this test: HTN, Seoul (SEO), PUU, Prospect Hill, Dobrava-Belgrade (DOB), Thailand, TPM, SN, and BCC viruses (44-48). Genetic relationships among hantaviruses are mirrored in their antigenic properties. A direct correlation between genetic and antigenic relationships is difficult; however, it can be assumed that the plaque-reduction neutralization test measures differences in the M segment gene products, i.e., the G1 and G2 envelope glycoproteins. Comparing the deduced G1 and G2 amino acid sequences, therefore, may provide clues to the antigenic as well as genetic diversity among hantaviruses. Of characterized hantavirus isolates, SEO virus is the most genetically homogeneous. Isolates of SEO virus, regardless of their geographic origin, display M segment nucleotide and deduced amino acid sequence homologies of approximately 95%, and 99%, respectively (41,47). A reported exception, the R22 isolate from China, had a slightly lower homology; however, the original data suggest that an error in the nucleotide sequence, resulting in a frame shift reading error, may account for almost all of the additional changes. PUU virus isolates vary the most, with M segment nucleotide and amino acid sequence homologies of 83% and 94% observed between a Finnish and Russian isolate. HTN virus also appears to be quite stable in nature. Comparing the M segment sequences of prototype HTN virus (from Apodemus) and those of two human isolates obtained at a 6-year interval from HFRS patients in Korea produced nucleotide and deduced amino acid sequence homologies of 94% and 97%, respectively (48). For SN virus, comparing the complete M or S segment sequences of three strains from California or New Mexico produced homologies of 87% to 99%. Partial nucleotide sequence comparisons of the M or S segments of SN viruses from adjacent counties in California, detected in deer mice captured 19 years apart, were 97.5% homologous (49). Similarly, a retrospective analysis of archived tissue samples collected in Mono County, California, in 1983 showed viruses with partial M and S segment nucleotide sequence homologies of about 87% with SN from an 1993 HPS patient from New Mexico (50). In all cases, the amino acid sequences encoded by these genes differed between cognate proteins by much less than 5%. These values are similar to those observed among strains of HTN virus. Studies have just begun to appear in which the nature of quasispecies in natural rodent hosts is defined (43,51). Such investigations should provide more definitive data concerning the genetic diversity among hantaviruses in nature. Evolution of Hantaviruses Phylogenetic trees derived by comparing complete or partial S (Figure), M, or L segment nucleotide sequences (41,52,53) show two major lineages of hantaviruses, one leading to HTN, SEO, Thailand, and DOB viruses, and one leading to PUU, Prospect Hill, SN, and other New World hantaviruses. TPM virus, the first hantavirus isolated in cell culture (54), may be the most antigenically and genetically disparate member of the genus; however, comparison of the complete nucleotide sequence of the TPM S segment (A. Toney, B. Meyer, C. Schmaljohn, unpub. data) suggests that TPM virus is more closely related to HTN, SEO, and DOB viruses than to any of the other viruses in the genus (Figure). Nucleotide sequence homologies of the M and S segments of any two hantaviruses have approximately the same degree of divergence between each of the three segments, which suggests similar evolutionary rates for these two gene segments. A slightly higher homology among L segments sequenced to date perhaps indicates a greater need for conservation of either RNA or protein functions (47). Point mutations appear to account for most of the genetic drift among hantaviruses. Recombination has not been reported for hantaviruses, although segment reassortment within a particular species appears common (52,55). The exchange of gene segments is suggested to be nonrandom, with a higher propensity for M segment swapping, than for S or L (55). Whether it contributes to the pathogenesis of hantaviruses is not known, but reassortment certainly provides an avenue for more rapid accumulation of changes than could occur by point mutation. There is no evidence that reassortment can occur between different species of hantaviruses; however, this has not been studied systematically. Murid rodents have probably harbored inapparent hantavirus infections for thousands, perhaps millions of years. It is likely that the genus Hantavirus evolved in the Old World and that viruses were carried by rodents across the Bering land bridge when they migrated during the Oligocene, and into South America in the Pliocene (71). Humans are incidental hosts, the victims of spillover infections from the natural host rodents. One of the two major forms of hantaviral diseases is endemic in each hemisphere. Both HFRS and HPS can be divided into distinct clinical subtypes, and the viral strain is a key determinant of the severity and nature of the clinical abnormalities. Not covered in this review are clinical studies of HFRS and HPS patients, which suggest that pathogenesis may be immunologic and may be mediated by cytokine responses (72). New outbreaks with novel hantavirus strains are still being uncovered, especially in South America. However, the largest clinical caseload and largest number of deaths occur in Asia and Europe. Dr. Schmaljohn is chief, Department of Molecular Virology, USAMRID. Current research interests include the development of molecular vaccines for hantaviruses, filoviruses, and flaviviruses. Dr. Hjelle has been active in studies of the molecular biology, evolution, epidemiology, and clinical aspects of hantavirus disease. His laboratory is a reference diagnostic center for hantavirus infections of humans and animals and has recently received funding to develop innovative vaccine strategies against HPS and other emerging viral diseases. Address for correspondence: Connie Schmaljohn, Virology Division, USAMRID, Fort Detrick, Frederick, MD 21702-5011; fax: 301-619-2439; e-mail: cschmaljohn@detrick.army.mil References 1. Lee H, van der Groen G. Hemorrhagic fever with renal syndrome. 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Chicago: Mosby Year Book Inc., 1996:373-425. --------------------------------------------------------------------------- [Emerging Infectious Diseases * Volume 3 * Number 2 * April-June 1997] Synopses Japanese Spotted Fever: Report of 31 Cases and Review of the Literature Fumihiko Mahara Mahara Hospital, Tokushima, Japan --------------------------------------------------------------------------- This article is also available in Japanese. The Japanese version can be accessed at http://www.cdc.gov/ncidod/EID/eid.htm Spotted fever group (SFG) rickettsioses, which are transmitted by ticks, were long thought not to exist in Japan. Three clinical cases of Japanese spotted fever (JSF) were first reported in 1984. The causative agent was isolated and named Rickettsia japonica. Through October 1996, 31 cases were diagnosed as JSF in Tokushima Prefecture. Infected patients typically had acute high fever, headache, and characteristic exanthema; eschar was observed in 90%. After the discovery of JSF, more than a hundred cases were reported in southwestern and central Japan. Recent surveys show ticks to be the most probable vectors. As an emerging infectious disease, JSF is not commonly recognized by clinicians; therefore, even though it has not caused fatal cases, it merits careful monitoring. The spotted fever group (SFG) rickettsioses, which are transmitted by ticks, have a worldwide distribution. Japanese spotted fever (JSF) is one of the newcomers of this group (1); the first clinical cases were reported in 1984 (2). The causative agent was isolated and named Rickettsia japonica (3). Because outbreaks were sporadic and limited, clinical reports concerning JSF, especially from specialists in dermatology and physiology and from general practitioners, were scarce. JSF was first found in Tokushima Prefecture, on the island of Shikoku in southwestern Japan; Tsutsugamushi disease, an important rickettsiosis in Japan, was found there soon afterwards (4). Through October 1996, 31 clinical cases of JSF and 11 cases of Tsutsugamushi disease were diagnosed at Mahara Hospital, Tokushima Prefecture. During the same period, 45 cases of human tick bites were recorded in this JSF-endemic area in the same hospital. This article describes JSF's history, clinical characteristics, and differences from Tsutsugamushi disease and summarizes current information about the epidemiology, vectors, and causative agent of JSF. History In the 1980s, clinicians believed that Tsutsugamushi disease (scrub typhus) was the only rickettsial disease in Japan except for sporadic outbreaks of epidemic typhus in the 1950s. In Tokushima Prefecture, neither disease has been reported in the last two decades. In May 1984, a 63-year-old woman (the wife of a farmer) was hospitalized at Mahara Hospital with high fever and erythematous nonpruritic skin eruptions over the entire body. Antibiotics (ß-lactam and aminoglycoside) used for common febrile infections were not effective, but the patient gradually became afebrile in 2 weeks without effective treatment. In May and July 1984, two additional patients with similar symptoms were treated at the same hospital. Doxycycline was markedly effective in these cases. Before the onset of illness, the patients had collected shoots from bamboo plantations on the same mountain. In two of the patients, an eschar was observed. Tsutsugamushi disease was suspected. However, results of Weil-Felix tests showed positive OX2 serum agglutinins, and OXK were negative in all three cases. These results did not indicate Tsutsugamushi disease, but rather OX2-positive infections, i.e., SFG rickettsioses (1). The cases were subsequently confirmed by complement fixation test with antigens of SFG rickettsiae (5,6). The name Japanese spotted fever was proposed for these infections (7) and has been commonly used since then (8-10). Oriental spotted fever (11) is a synonym for JSF. The causative agent was isolated in 1986 (12) and named R. japonica (3). Clinical Features The clinical features of the 31 patients whose illness was diagnosed as JSF at Mahara Hospital from 1984 to October 1996 were analyzed. The disease developed abruptly, with the common symptoms of headache (25 [80%] of 31 patients), fever (31 [100%] of patients), and shaking chills (27 [87%]). Other major objective symptoms of JSF included skin eruptions (31 [100%]) and tick bite eschars (28 [90%]). Most patients (28 [90%]) complained of malaise; joint and muscle pain or numbness of the extremities was rarely mentioned. In the acute stage, remittent fever accompanied by shaking chills was frequently observed. In severe cases, high fever (40°C or more) continued for several days (Figure 1). The maximum body temperature was 38.5°C to 40.8°C (mean 39.5°C), which was higher than that seen in patients with Tsutsugamushi disease (38.5°C ~ 39.1°C). With abrupt high fever or, a few days after onset, fever of unknown origin, the characteristic erythemas developed on the extremities and spread rapidly (in a few hours) to all parts of the body including palms and soles, without accompanying pain or itching. These eruptions were the size of a grain of rice or soybean, and the margin of each of the spots was unclear (Figure 2). The erythemas became remarkable during the febrile period and tended to spread more over the extremities than the trunk. Palmar erythema, a characteristic finding not seen in Tsutsugamushi disease, disappeared in the early stage of the disease. The erythemas became petechial after 3 to 4 days, peaked in a week or 10 days, and disappeared in 2 weeks. However, in severe petechial cases, the brown pigmentation remained for 2 months or more. Eschar was observed on the hands, feet, neck, trunk, and shoulders of patients (Figure 3). This eschar generally remained for 1 to 2 weeks, but in some cases it disappeared in a few days. Eschars in JSF patients are smaller than those seen in patients with Tsutsugamushi disease and may be missed without careful observation. Regional or generalized lymphadenopathy, which is observed in almost all cases of Tsutsugamushi disease, was not remarkable in JSF patients. Swelling of the liver and spleen was observed in a few patients. One patient had cardiomegaly (5), and in another area, a patient had central nervous system involvement (13). [Figure 1] [Figures not available in ASCII version] Figure 1. Fever and clinical course, 62-year-old woman. [Figure 2] [Figures not available in ASCII version] Figure 2. Skin eruptions, hospital day 3. [Figure 3] [Figures not available in ASCII version] Figure 3. Small and shallow eschar on admission, which disappeared in a few days. Laboratory Examinations The results of laboratory examinations of JSF patients are almost the same as those of patients with common SFG rickettsioses. During clinical examinations at the initial stage of the disease, urinalyses registered a slight positive reading for protein and occult blood, which may lead to a misdiagnosis of urinary infection. In the acute stage, leukocytosis may also be found with leukopenia (3,600~12,800), and a left shift in leukocyte count was observed. Thrombocytopenia (6.8~35.3) may also be found. In week 1 to 2, leukocyte counts increased slightly, and lymphocyte counts tended to increase. Among biochemical examinations, C-reactive proteins were strongly positive, and liver functions were slightly impaired but returned to normal in 2 to 3 weeks. Serologic Results Serodiagnosis for JSF is usually performed by the indirect immunoperoxidase (IP) or immunofluorescence (IF) techniques, with antigens prepared from R. japonica or other SFG rickettsiae. With the IP test, IgG and IgM antibodies were detected in the sera beginning on day 9 after the onset of fever; titers of IgG antibodies were higher than those of IgM antibodies (14). The IF test had similar results (15). In the 31 clinically diagnosed cases of JSF in Tokushima Prefecture at Mahara Hospital, all patients had significant changes in serum IP antibody titers to R. japonica, and 27 (87%) had significant changes in OX2 agglutinin titers by the Weil-Felix technique (10,14; F. Mahara, unpub. data). Treatment Antibiotics such as penicillins, ß-lactams, or