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Future Health Assessment and Risk-Management Integration for Infectious Diseases and Biological Weapons for Deployed U.S. Forces by Joan B. Roses ABSTRACT The health of the United States armed forces has been viewed as a critical component of the strength, readiness, and electiveness of the military's ability to meet various degrees of threats to peace, human rights abuses, and other global disasters in the United States and the world. Compared with any other country or entity in the world, the U.S. military has one of the best surveillance and monitoring systems for assessing the risk of infectious disease globally. The monitoring is broad-based, specific for a large list of pathogenic agents, but includes generic symptomology that might be due to a multitude of current, emerging, or reemerging microorganisms; the monitoring is also timely. Gas- trointestinal illness and respiratory and skin infections remain a problem for deployed troops. It is now well known that microbial infections can result in chronic outcomes associated with heart, neurological, and immunological disorders. Therefore, hospitalization data will no longer suffice as the sole measure of severity and lost electiveness to the troop force at large. Better assessment of antibiotic-resistant bacteria, coxsackieviruses, and Legionella and an evaluation of the underdiagnosis and underreporting of protozoa such as Cryptosporidium are needed. New microorganisms are being reported every year that might be associated with many of these illnesses, and prospective surveillance might be needed using new techniques to better understand the infection rates and asymptomatic infections. Risk-assessment methods can now be used to quantify the risk of microbial infections and to address exposure and potential outcome from naturally occurring microorganisms and biological weapons. Hazard identification includes the identification of the microbial agent as well as the spectrum of human illnesses ranging from asymptomatic infections to death. The host response to the microorganisms with regard to immunity and multiple exposures should be addressed here, as well as the adequacy of animal models for studying human impacts. Endemic and epidemic disease investigations, case studies, hospi- 1Department of Marine Sciences, University of South Florida, 140 7th Ave., S., St. Petersburg, FL, 33701; email: jrose @ seas.marine.usf.edu. 59

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60 STRATEGIES TO PROTECT THE HEALTH OF DEPLOYED U.S. FORCES: WORKSHOP PROCEEDINGS talization studies, and other epidemiological data are needed to complete this step in the risk assess- ment. The variables need to be carefully defined and the data quantified as ratios. The dose-response assessment is the mathematical characterization of the relationship between the dose administered and the probability of infection or disease in the exposed population. Dose-response assessments have been referred to as probability-of-infection models, which are developed from mostly human volunteer stud- ies. The exposure assessment determines the size and nature of the population exposed, the route, concentrations, and distribution of the microorganisms, and the duration of the exposure. The descrip- tion of exposure includes not only occurrence based on concentrations but also the prevalence (how often the microorganisms are found) and distribution of microorganisms in space and over time. Exposure assessment is determined through occurrence monitoring and predictive microbiology. Quan- titative risk characterization should estimate the magnitude of the public health problem, and demon- strate the variability and uncertainty of the hazard, using four distributions: (1) the spectrum of health outcomes; (2) the confidence limits surrounding the dose-response model; (3) the distribution of the occurrence or; the microorganism; and (4) the exposure distribution. Assessments of occurrence and exposure can be further delineated by distributions surrounding the method of recovery and survival (treatment) distributions. The risk-assessment framework already fits into the Department of Defense's (DOD's) programs associated with risk management. The critical need will be the development of databases that can be used in the decision and management process. Although health outcomes and morbidity and mortality statistics are available from numerous databases and surveillance programs, the data lacking are often the long-term assessments and chronic outcomes. The exposure assessment, particularly during de- ployment, is more suspect to uncertainty, especially in terms of quantitative evaluations. Geographic, climatic, seasonal, dose-response, and exposure scenarios can be used to develop tools for setting priorities for assessment of predeployment risks. Risk models can be evaluated for plausibility during outbreak investigations or disease surveillance operations. Exposure and health outcomes must be better assessed. The use of quantitative assessments allows one to begin to build exposure scenarios in which thresholds associated with ineffectiveness in the troops in a given time frame can be determined for specific agents. For biological weapons, dose-response models should be developed and time and concentration exposure and consequence scenarios should be built and evaluated. Finally, the formal expansion of DOD's mission on emerging infectious diseases in June 1996 by Presidential Decision Directive NSTC-7 now includes global surveillance, training, research, and response. One of the major assets in implementing this new directive is the overseas research labora- tory system that is currently in place: the DOD Infectious Disease Research Laboratories. At a minimum, each laboratory sta~should be trained in risk-assessment methods, should have molecular capabilities (polymerase chain reaction [PCR]), and be trained in the use of the global information system (GIS) for maintaining and analyzing the databases. INTRODUCTION The health of United States armed forces has been viewed as a critical component of the strength, readiness, and effectiveness of the military's ability to meet various degrees of threats to peace, human rights abuses, and other global disasters in the United States and the world. Much effort has gone into the development of frameworks for addressing the hazards that the military might face, particularly when deployed to hostile and foreign environments. A deployment of U.S. troops is defined as a "movement resulting from a Joint Chiefs of Staff /unified command deployment order for 30 continuous

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INFECTIOUS DISEASES AND BIOLOGICAL WEAPONS 6 days or greater to a land-based location outside the United States that does not have a permanent U.S. military medical treatment facility" (Memorandum for Under Secretary of Defense for Personnel and Readiness, Office of the Chairman, The Joint Chiefs of Staff, December 4, 1998~. There has been a tremendous change throughout the twentieth century in the types of health risks that the armed forces might face, and in the ability to identify and monitor these risks and to manage or control them. Health surveillance has improved and there is an enhanced ability to monitor the environ- ment for hazardous exposures. Despite these gains, as the twenty-first century nears, the world is faced with the emergence and reemergence of infectious diseases. Disease surveillance at the global level has identified, in addition to endemic levels of diarrhea and respiratory disease, new bacteria, parasites, and viruses. These have been identified through dramatic outbreaks such as Legionnaire' s disease from the bacterium Legionella and hemorrhagic fevers associated with the Hanta virus and other types of viruses; specific studies associating peptic ulcer disease and Helicobacter; epidemic levels of bloodborne and sexually transmitted HIV; and outbreaks of Cryptosporidiosis from drinking water and Escherichia cold 0157:H7 from food (Lederberg 1997~. In addition, antibiotic resistance has emerged, causing a threat to the control of old-world killers such as tuberculosis. There is currently a greater appreciation of the diversity, adaptability, and evolutionary complexities associated with infectious diseases, and much of this appreciation has been gained through research and studies with new molecular techniques. The technological advances in the study of microbiology, infectious disease, and molecular biology have also paved the way for a potential increased risk associ- ated with the development and use of biological weapons. Force Health Protection (FHP) is a framework that describes procedures for assessing the types of hazards, the exposure and populations at risk, and the monitoring of the health of all personnel deployed. FHP and other force protection plans have adapted various versions of the National Research Council's (NRC's) risk-assessment paradigm and integrated this assessment into management strategies to ad- dress the health of troops before, during, and after deployment and to protect defense personnel from hazardous chemicals and toxic materials. The use of this type of framework for biological and infec- tious agents is relatively new. Risk-assessment methods following the NRC paradigm were initially used on a limited scale for judging waterborne pathogenic microorganisms (Haas 1983; Gerba and Haas 1988; Regli et al. 1991; Rose and Gerba, 1991; Rose et al. 1991; Haas et al. 1993~. Haas (1983) was the first to look quantita- tively at microbial risks associated with drinking water based on dose-response modeling. Rose et al. (1991) used an exponential model with quantitative risk assessment in the development of the Surface Water Treatment Rule to address in particular the performance-based standards for the control of Giardia as part of the requirements under the Safe Drinking Water Act (EPA 1989~. Currently, risk assessment is being used for assessing food protection programs. In a study for the U.S. Army, Cooper et al. (1986) attempted to quantify the risks of water-related infection and illness to Army units in the field. They reviewed the literature on infectious dose and clinical illness for potential waterborne pathogens. Using this information, the probability of infection was assessed using logistic, beta, exponential, and lognormal models. A generalized model was then developed incorporating expected pathogenic concentrations, consumption volume, and risk of infec- tion for different military units. The study attempted to incorporate organism concentrations, effective treatment, and risk of infection. This attempt, however, was hampered by a limited existing database on microbial concentrations and infectious dose. Quantitative microbial risk assessment (QMRA) has now gained wide acceptance in the evaluation of waterborne and foodborne disease. Methods and databases for development of QMRA for microbial agents associated with airborne, vectorborne, and dermal exposure have received less attention. How- 1 1 ~7

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62 STRATEGIES TO PROTECT THE HEALTH OF DEPLOYED U.S. FORCES: WORKSHOP PROCEEDINGS ever, the data on health, exposure, and dose-response, although limited, might be sufficient for under- taking preliminary risk assessments. The development of QMRAs along with improved methods for environmental monitoring will likely lead to more effective management and prevention strategies for U.S. deployed troops. The purpose of this report is to: summarize the emerging infectious diseases and microbiological contaminant risks that U.S. deployed troops might face currently and in the future; briefly examine the various health disease databases that are available; and address quantitative research and data needs for integration of the microbial and biological risks into DOD risk-assessment and risk-management frameworks. REVIEW OF PAST INCIDENCES AND FUTURE RISKS Disease and Non-Battle-Injury Reports Health promotion and disease prevention in the field are seen as critical to deployed troops, because illness can significantly compromise the objectives of the mission. Surveillance of infectious disease risks are determined by measured rates, usually as the number of people who have disease X per 1,000 or 10,000 people per some unit of time. In U.S. health databases, the rates are usually reported on an annual basis per 10,000 or 100,000 people. It is important to understand that most infections and diseases are underreported because of the failure of individuals to seek medical attention, laboratories to conduct proper tests, and the reporting system. The identification of disease (or illness) is made by one of several methods (Table 1~. The differ- ence between disease and illness is minor in some cases. Disease is defined as the process or mechanism that ultimately results in an illness or a condition that impairs vital functions. An individual could have a disease without initially having any symptoms. Symptoms are effects of the illness that can be described by the individual who is ill, also known as self-reporting (e.g., headache, diarrhea, stomach cramps, vomiting, fatigue). Clinical assessment of the illness is generally defined by a measurable description of the illness (e.g., fever, bloody stool). Infection is colonization of the microorganism in the body and might result in disease and symptoms, which is the initial step in the microbial disease process. However, this can also result in asymptomatic, or subclinical, infections. Symptoms and clinical descriptions (fever, rash, inflammation) can be very specific, as with measles, which is associ- ated with one specific agent, or they can be generic, as with diarrhea, which is associated with many different types of microorganisms. The second means of identification is clinical diagnosis, which is the detection of the specific micro- organism in a host specimen (e.g., laboratory identification in a liquid stool of an enteric pathogen). This requires the collection of a specimen (sputum, feces, blood, biopsy) and a specific diagnostic test (specific growth, biochemical tests, stains, genetic or protein markers, microscopic identification). This also means that there is some understanding of the agents that might be responsible for the disease symptoms and the process of disease resulting in the infection of specific cells or organs in the body. Infection without the individual reporting symptoms (an asymptomatic infection) can be detected by clinical diagnosis. The final method of identification is associated with the response of the host system to infection that elicits an antibody response that can be detected in blood or, in some cases, saliva. This antibody response might be associated with past or current exposure, and in some cases, depending on the type of antibody and amount, one can determine the approximate timing of the exposure and infection. Expo-

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INFECTIOUS DISEASES AND BIOLOGICAL WEAPONS TABLE 1 Methods for Diagnosing Infections and Disease 63 Method Approach Advantages and Disadvantages Symptoms and clinical Based on individual's feelings Can easily diagnose, or identify individuals; descriptors (headache) and measurable impacts however is not generally agent specific but more (fever, rash). generic (e.g., diarrhea). Clinical diagnosis Based on testing specimens (sputum, Can specifically identify agent; however feces or blood) for presence of the individual must deliver a specimen and there agent.a must exist a test method for the agent. Antibody response An indirect test (blood or in some Is specific to the agent and in some cases might (serological testing) cases saliva) for the presence of be able to determine the timing of the exposure antibodies that the body produces as a and infection. Test method must exist. result of infection.b aAsymptomatic infections can be detected. bAntibody response may or may not be protective from subsequent exposure and infection and does not usually occur without infection. Source: Haas et al. 1999. sure without infection rarely causes an antibody response, except in the case of repeated exposure to very high concentrations of the agent, such as occurs with some vaccinations. The Disease and Non-Battle-Injury (DNBI) reporting system is a tool used at the unit level to assess the "vital signs of the unit." This system is set up to evaluate the health of individuals predeployment, during deployment, and post-deployment. The primary function of the DNBI reports is to bring imme- diate attention to unacceptable high rates of illness, and thus to provide better prevention, treatment, and intervention in a timely manner. During Redeployment, health is evaluated on self-reporting of symptoms; only a few specific tests are undertaken. Blood samples were rarely collected until the Bosnia deployment. Readiness is addressed through education and management approaches and immunizations: Health assessment undertaken based on self-reporting of symptomology. Testing for specific type of microbial agent only with referral. Specific tests: HIV (within 12 months) and tuberculosis skin test (within 24 months). Education on known biological, chemical, and physical hazards (providing known countermea- sures, e.g., insect repellent). Immunizations: Required are tetanus-diphtheria, influenza, hepatitis A virus (HAV), measles- rubella/measles-mumps-rubella (MR/MMR), and polio. Others might include yellow fever, hepatitis B virus (HBV), typhoid, and plague. During deployment, the DNBI reports are made weekly. The tracking of disease is summarized weekly and reported at measured rates in percentages based on the number of patients seen divided by the average troop strength deployed. These reports are based on self-reporting illnesses of a serious enough level to require a visit to the medical staff. Primary complaints and final diagnoses are included in the report, as well as days of light duty, lost work days, and admissions. Text Box 1, from the Memorandum for Under Secretary of Defense for Personnel and Readiness, Office of the Chairman, The Joint Chiefs of Staff, December 4, 1998, has the list of infectious agents that are reportable.

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64 STRATEGIES TO PROTECT THE HEALTH OF DEPLOYED U.S. FORCES: WORKSHOP PROCEEDINGS Suggested reference rates are rough general guidance numbers (acceptable limits); rates above these rates might indicate a problem. Expert judgment is used to make final decisions regarding the imme- diacy of the risks and the actions to be taken in further assessment and control. Temporal trends of illness are also tracked. Table 2 shows suggested limits for categories of general illnesses. Upon post-deployment, health evaluations are again made by self-reporting of symptoms. Positive responses are followed up. However, no testing is undertaken routinely. It is generally accepted that surveillance systems greatly underestimate the level of disease in any given community and, although providing a picture of past risk, thus might not accurately reflect future risk. This becomes problematic for emerging pathogens for which there is no established procedure for testing patients, and surveillance systems rarely address the various exposure or transmission pathways.

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INFECTIOUS DISEASES AND BIOLOGICAL WEAPONS TABLE 2 Weekly DNBI Report for Category of Illness and Suggested Acceptable Levels Category Suggested Reference Ratea Combat/operational-stress reactions Dermatological GI, infectious Gynecologic Heat/cold injuries Injury: recreational/sports Injury: motor vehicle accidents Injury: work/training Injury: other Ophthalmologic Psychiatric, mental disorders Respiratory STDs Fever, unexplained All other medical and surgical Total DNBI 0. 1% (1/1,000) 0.5% (5/1,000) 0.5% 0.5% 0.5% 1.0% (10/1,000) 1.0% 1.0% 1.0% 0.1% 0.1% 0.4% (4/1,000) 0.5% 0.0% 4.0% (40/1,000) aTime frame is weekly assessment. Source: Memorandum (MCM-251-98) from Chairman of the Joint Chiefs of Staff dated 04 December 1998. TABLE 3 Advantages and Limitations of the DNBI Report 65 Advantages Limitations 1 Reports on generic symptoms (GI, respiratory). 2. Large number of agents that are reportable (Textbox 1). 3. Weekly reporting. 4. Severity data recorded (days lost, hospitalization). 1. Excludes Helicobacter and most enteric viruses. 2. Relies primarily on self-reporting; clinical diagnosis might not be routine (e.g., are all diarrhea specimens examined for Cryptosporidium?) and antibody assessments (seroprevalence data) are not routinely included (only in specialized reports). 3. Report is indication of past exposures and might not indicate the route of exposure. 4. Data on the unknown etiologies category are not included in the sum total. In addition, outcome might be assessed by mortality in the extreme case or without identification of consequence (e.g., severity of the illness, number of days sick, medical care). The advantages of the DNBI reporting system over most systems are in the broad scope of the specific and generic assessments made and the timeliness of the reporting. The DNBI systems might then identify unknown pathogens or microorganisms that cause more than one type of symptom in those exposed. There are a few limitations; for example, ulcers from the gastrointestinal infections are excluded, although it is now recognized that Helicobacter is a cause of this type of illness (Taylor and Blaser 1991~. In addition, because most illnesses are exhibited after an incubation time ranging from 1 day (bacteria), 7 days (parasite), to 21 days (HAV), the DNBI record is a record of past exposures (Table 3~.

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66 Burden of Disease 1997 1.2% 2.0% 6.1 _ ~~ - \ A STDs Fecal-Oral / Respiratory ElVectorborne STRATEGIES TO PROTECT THE HEALTH OF DEPLOYED U.S. FORCES: WORKSHOP PROCEEDINGS Burden of Disease 1996 1.1% 2.5% 8.6% ~~ Cl STDs \ Fecal-Oral I E~Vectorborne | 3 Respiratory FIGURE 1 Conditions reported by the Defense Medical Surveillance System, Jan.-Dec., 1996 and 1997 (MSMR 1997a, 1998a). The Defense Medical Surveillance System reports all DNBI data on a monthly basis. The follow- ing is a brief review of the cumulative 1997 and 1998 reports, followed by some summaries and conclusions. Figure 1 shows the disease reports for 1996 and 1997 within the military for four main categories of illnesses by route of transmission (sexually-transmitted disease [STD], fecal-oral, vectorborne, and respiratory). These data come from 7,061 case reports in 1996 and 10,007 case reports in 1997. STDs accounted for 88% and 87% of the cases in 1996 and 1997, respectively (chlamydia, gonorrhea, urethri- tis, herpes, and then syphilis). Fecal-oral agents were second, contributing to 8.6% and 6.1% of the cases for the two years, respectively. Included in the top four in descending order were Salmonella, Campylobacter, Shigella, and Giardia in 1996, and Salmonella, Shigella, Campylobacter, and Giardia in 1997. Guillain-Barre syndrome, a neurological complication associated with Campylobacter infec- tions was reported in both years (3 and 4 cases, respectively). This outcome has also been related to reactions to immunizations (Medical Surveillance Monthly Report (MSMR) 1995~. Viral meningitis could likely be due to enteric viruses and should be considered fecal-oral (41 and 92 cases, respectively). Respiratory illness contributed to 2.5% and 2.0% in 1996 and 1997, respectively, with varicella contrib- uting to most other cases, followed by influenza and tuberculosis. Vectorborne diseases were associated with 1.1% and 1.2% of the cases for 1996 and 1997, respectively. Malaria, leishmaniasis, and Lyme disease were the top microbial pathogens in this category. Hospitalization records and days lost from effective work were used to evaluate the severity of the outcomes. When muscular and joint problems were excluded (which are the number one cause of reported hospitalizations) the top five causes of hospitalizations were diseases of the digestive system, followed by respiratory diseases, genitourinary diseases, infectious and parasitic diseases, and diseases of the skin and subcutaneous tissue (Figure 2~. These data are for all troops stationed in the United States, Europe, Pacific, and other regions (e.g., Korea). No discernable differences were noted geographically for the STDs. Although STDs are

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INFECTIOUS DISEASES AND BIOLOGICAL WEAPONS 25 20 - o 15- ._ - o 10- In 5 - O - Diseases of the Digestive Diseases of the System Respiratory System 67 2003 11.6 9.6 5.9 3.8 Diseases of the Infectious and Parasitic Diseases of the Skin and Genitourinary System Diseases Subcutaneous Tissue FIGURE 2 Seventy based on active-duty hospitalization rates, U. S. Army (MSMR 1998b). problematic, the attendance by a physician, diagnosis, and reporting are likely much greater than many of the other types of infections; thus, the infectious disease risks based on this reporting system appear skewed. These data might be particularly misleading regarding the risk for deployed troops outside the United States. The completeness of reporting is dependent on the etiological agent; for example, for the two militarily important tropical infectious diseases, malaria and leishmaniasis, reporting was 67% and 81% complete. Reporting of varicella and Lyme disease was 20 to 25% complete. For diseases such as hepatitis, dengue, and campylobacteriosis, 0% were reported of those that were reportable. Therefore, underreporting is likely a problem for many of the fecal-oral and respiratory agents. Respiratory disease is one that continues to plague the troops. Recruits, trainees, and those upon initial deployment appear to be at greater risk. Immunizations are available for adenovirus Type 4 and Type 7 and the influenza viruses (Table 4~. However, outbreaks of influenza continue to occur due to the variety of subtypes that exist throughout the world. In an outbreak of influenzalike illness in an aviation squadron in Hawaii, the efficacy of the vaccine for preventing the illness was only 16.7% (MSMR 1998c). Therefore, use of year-round vaccination and treatment has been able to reduce the respiratory disease but has not been able to eliminate it. The military's surveillance program for respiratory disease includes 14 sentinel bases (seven foreign bases, Germany, Guam, two in Japan, Korea, Turkey, and United Kingdom, and seven U.S. bases, Alaska, California, Colorado, Mississippi, New Jersey, and two in Texas). Throat swabs are obtained from those who meet a case definition; therefore, asymptomatic cases are not detected. Transmission of respiratory agents can be person to person through hands (thus handwashing can facilitate prevention) or through contaminated fomites (surface disinfection might prove useful for

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68 STRATEGIES TO PROTECT THE HEALTH OF DEPLOYED U.S. FORCES: WORKSHOP PROCEEDINGS TABLE 4 Results of the 1995-1996 Respiratory Surveillance Program Microorganism Number Isolated Treatment/Vaccine Comments Streptococcus A 86/1,071 Benazthine Beta hemolytic 8% Penicillin Chemoprophylaxis Total viruses 512/1,634 31.8% Influenza A 358/1,634 Vaccines Nov. -Jan. peak 22% Influenza B 56/1,634 Vaccines Mar. -May peak 3.4% Enteroviruses ~52 None 3.2% Adenoviruses ~27 Vaccine for Types 4 and 7 1.6% Parainfluenza ~ 12 None Types 1, 2, and 3 0.7% Herpes simplex virus ~8 None 0.5% Source: MSMR 1996a. prevention), and enteroviruses (coxsackieviruses) might account for some of the dramatic spread of infections through troops. Respiratory transmission (aerosolization) is the final route, although in some cases the pathway is not very well defined. Interestingly for Group A streptococci, Ferrieri et al. (1972) have proposed a sequence of spread from skin infections to the nose and throat (Figure 3~. This bacterium is one of the major causes of impetigo and has been associated with infections after scratches and bites from insects, which can be controlled to some extent through the use of antibacterial lotions applied to the abrasions. The seasonality of diseases such as influenza has been hypothesized to be a result of animal reservoirs and survival potential of the pathogenic agent. For those on active duty, coming from field sites, Adult Respiratory Distress Syndrome (ARDS) apparently is common. Studies have reported on individual cases of ARDS (MSMR 1997b); however, the etiologies, trends, and rates have not been reported, although studies are under way. Therefore, unknown respiratory illnesses are likely the majority of the reported cases of ARDS. Fever of unknown origin (FUO) is a term described for those experiencing elevated temperature that could not be ascribed to any specific agent. Studies on the more severe cases (those hospitalized for 1 day or more) reported a rate of 2.68/100,000 (0.03/1,000) per month. Of these cases, 45% were diagnosed upon primary assessment as FUOs and in 12.7% that was the only diagnosis (total of 1,437 hospitalizations from 1990-1997 (MSMR 1998~. Vaccine reactions were found to be contributing to 5.3% of these FUOs, and other types of unknown infections, throat (7.4%), respiratory (2.1%), and gastrointestinal (4.9%), accounted for much of the remainder. Infantry men more than any other military occupational group were found to be at a greater risk among those hospitalized three days or longer where vaccine reactions were eliminated. The diagnosis and reporting of FUOs has been inconsistent for those FUOs of shorter duration (1 to 2 days); trends and unusual occurrences are more difficult to ascertain due to the high variability. The more severe illness, which lasts for more than 3 days, shows much less variability.

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INFECTIOUS DISEASES AND BIOLOGICAL WEAPONS Group A Streptococci (Source Uncertain} Normal Skin ~ 11/o~ / Skin Lesions Nose Throat | 69 200 FIGURE 3 Concept of the sequence of spread of Group A streptococci among different body sites (Fernen et al. 1972). Reports on deployment surveillance have shown that gastrointestinal and respiratory risks are the most significant cause of immediate acute outcomes associated with clinic visits and hospitalizations. Trends also demonstrate a decrease in the number of cases with time. Therefore, the greatest burden of illness is reported early on in deployment. Gastrointestinal illness was the leading cause of morbidity among U.S. troops in the Persian Gulf deployment during 1990-1991 (Hyams et al. 1995~. Parasitic infections were not found to be a signifi- cant cause of disease. Although Escherichia cold and Shigella sonnet were the primary pathogens identified, of great concern was the high level of antibiotic resistance identified (20 to 80% of the isolates were resistant). Outbreaks of the Norwalk virus and other unknown etiologies likely to be viruses were common. Serological investigations (antibody testing) found 6% of the combat units might have been infected with the Norwalk virus. The source of the diseases was associated primarily with vegetables and fruits imported from neighboring countries. It is clear from the identification of the Shigella and Norwalk agents that human fecal wastes and perhaps untreated sewage were the cause of much of the contamination. Diarrheal disease was also quite high in an exercise in Thailand, and risks there were also associated with consumption of indigenous foods (MSMR 1998e). Gastrointestinal outbreaks have been associ- ated with both food and water. A United Nations deployment to Haiti in June 1995 experienced a suspected waterborne outbreak due to the consumption of unapproved bottled water. The rate ranged between 15 to as high as 94 cases per 1,000 per month, with a high weekly rate seen in the third month (40/1,000/wk). Common cold and upper respiratory complaints were common during deployment. Studies found ~7 1 ~ that troops living and working in tightly constructed air conditioned buildings were at greatest risk. Possible causes of this, such as Legionella, were not investigated. Comparing hospitalizations with clinic visits demonstrates that the level of disease in a force is likely to be 50 to 100 times greater than what is reported by hospitalization rates. This has been shown

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102 STRATEGIES TO PROTECT THE HEALTH OF DEPLOYED U.S. FORCES: WORKSHOP PROCEEDINGS DOD INFECTIOUS DISEASE RESEARCH LABORATORIES Summary of the Laboratories' History and Missions There are nine DOD infectious disease research laboratories, three in the Washington, DC, area in the United States and one in each of the following countries, Peru, Brazil, Kenya, Egypt, Indonesia, and Thailand. Table 16 is a brief summary of the laboratories. Early in the history of the United States, it was clearly recognized that conflicts, wars, and deploy- ment of troops carried with them special medical needs in regards to infectious disease. No doubt the high morbidity and mortality associated with early conflicts such as the Civil War led to the realization of the importance of disease in these situations. In the late 1800s and early 1900s, great strides were being made in science and medicine. Methods were being developed for diagnosing diseases and characterizing microorganisms. There was a greater understanding of the disease process and transmis- sion, and vaccines were being developed. In 1893, the Army Medical School was established to train physicians in the art and science of military medicine. Now known as the Walter Reed Army Institute of Research (WRAIR), this is the oldest and largest facility. The current mission of the WRAIR is "biomedical research focused on soldier health and readi- ness." Early in its history, the development of a vaccine for typhoid fever and the study of yellow fever by Major Walter Reed in Cuba during the Spanish-American War were major accomplishments that led to a recognition of the benefits from such an organization. Since that time WRAIR has been involved in addressing the key plagues of the troops (such as malaria, hepatitis, dysentery, dengue) from WWI through the Bosnian conflict. Vaccine development, treatments, diagnostics, surveillance, assistance with deployments, and education have remained key components of the facility. Infectious diseases, combat casualty care, army operational medicine and medical chemical and biological defense are the four areas where research is conducted. Although WRAIR is the largest laboratory within the U.S. Army Medical Research and Materiel Command, three other units were established outside of the United States. The largest of the three, the Armed Forces Research Institute of Medical Sciences (AFRIMS), functions as a Special Foreign Activ- ity of the WRAIR. Established in 1959 in Bangkok, Thailand, the original mission was to research the cholera epidemic as was a part of the Southeast Asia Treaty Organization Cholera Research Laboratory. Command is with the Royal Thai Army and joint research on tropical diseases has included studies on Japanese encephalitis, hepatitis A and E, dengue, diarrhea, malaria, and drug-resistant scrubtyphus. The scientists have also been responsible for field-testing new drugs and vaccines. Epidemiological inves- tigation, surveillance, rapid diagnostics, and advice on tropical diseases are part of the primary objec- tives of the laboratory. TABLE 16 Rate of Infection and Clinical Cryptosporidiosis Dose of oocysts Exposed Infected Ill 30 s 1 0 100 8 3 3 300 3 2 0 Soo 6 s 2 >1000 7 7 2 Source: DuPont et al. 1995

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INFECTIOUS DISEASES AND BIOLOGICAL WEAPONS 103 Two smaller laboratories, known as U.S. Army Medical Research Units (USAMRU) were estab- lished, Unit K in Nairobi, Kenya, in 1969 and Unit B in Brazil (Rio De Janeiro and several other satellite locations) in 1973. U.S. personnel are limited at these facilities and they house host-country scientists and medical personnel. USAMRU B collaborates with PAHO, Institute of Biology of the Brazilian Army, University of Espirtu Santu, Vitoria and Instituto de Medicina Tropical do Amazonas to study emerging infectious disease agents in the Brazilian Amazon. The USAMRU K is affiliated with the Kenya Medical Research Institute and works out of two main facilities, a central laboratory in Nairobi and a field laboratory in Kisumu/Kisian in western Kenya. There are many joint collaborations with other organization including the U.S. Centers for Disease Control (CDC) and the Japanese International Cooperative Agency. The research has focused on drug resistance and vectorborne disease (tryptosomiasis, leishmaniasis, arboviruses). Molecular techniques such as PCR are used for microbial detection and characterizations and the facility houses a rearing laboratory for sand flies and mosquitoes. Originally established in 1956 and officially named in 1969, the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) was established in Ft. Detrick, Maryland. This is the second largest Army facility with approximately 450 scientists and other personnel. Their mission is to "conduct research to develop strategies, products, information, procedures and training programs for medical defense against biological warfare threats and infectious diseases." The research here is focused on deployment, and special scientific teams are developed and dispatched to assist in various types of investigations. The facility has one of the few biological level (BL)-4 containment laboratories to work on highly infectious and deadly diseases. The research is focused on biological weapons in addition to other areas including vaccine and drug development. The Navy Medical Research Institute (NMRI) was established in 1942 and is located in Washington, D.C. During the war NMRI's mission was focused on immediate operational problems and in particular was commissioned to study the atomic bomb survivors and develop methods for treatment of radiation exposure. The facility housed the first tissue bank in the world and pioneered studies on freeze-drying techniques used in preservation of human tissues for grafting and use of hypothermia for open-heart surgery. Among the recent accomplishments, scientists have also developed handheld assays for identification of BWs, and a PCR-based diagnosis system for Campylobacter. The NMRI and the WRIAR work as co-tenants (as a combined Army-Navy medical research program) and will soon be housed in a new facility in Forest Glen, Maryland. In 1940 and 1942, Naval Medical Research Units (NAMRU) 2 and 3 were established in Guam (relocated to Taipei, Thailand) and Cairo, Egypt, respectively. Unit 2 is focusing on significant diseases in Asia, and is a WHO-collaborating center for emerging infectious diseases. Because it houses an animal facility, research on hemorragic fevers is of interest. Unit 3 has historically studied rickettsial disease, cholera, smallpox and meningitis, but has begun examining drug-resistant malaria, entero- toxogenic E. coli, Campylobacter, Shigella, and emerging viruses. This unit is also a WHO-collaborat- ing facility for the study of the new strains of cholera and also has an animal facility. Finally, in 1983, the Naval Medical Research Institute Detachment (NMRID) was established in Lima, Peru (10 years after USAMRU B in Brazil). Antibiotic resistance and drug-resistance in malaria were of interest and the research moved to address the dengue virus using PCR. This laboratory also contains an animal facility. DOD Global Emerging Infectious Surveillance and Response System The formal expansion of DOD's mission on emerging infectious diseases in June 1996 by Presiden- tial Decision Directive NSTC-7 now includes global surveillance, training, research, and response. A 5- year strategic plan has been developed in parallel with CDC. Four goals have been articulated and are described in Table 17.

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106 STRATEGIES TO PROTECT THE HEALTH OF DEPLOYED U.S. FORCES: WORKSHOP PROCEEDINGS One of the major assets in implementing this new directive is the overseas research laboratory system that is currently in place. All of the laboratories are undertaking various aspects related to all four goals. Clearly, although geographic locale is of some interest for some of the diseases, there is widespread global distribution of many of the microbial hazards. New resources will likely be needed to enhance not only the laboratory infrastructure and equipment but also to address personnel gaps. The evaluation and assessment of each laboratory is needed. Although specific activities matched to each laboratory's capabilities have been identified under each of the goals, there is no formal process for identifying and setting priorities for the various hazards, the specific activities, and the resources distribution. The use of risk-assessment methodologies offers an opportunity to use a scientific-based process for identifying and setting priorities for the most efficient and productive allocation of resources to the overseas laboratories. Opportunities for Research Using a Risk-Assessment Method It is proposed that a risk-assessment framework be used to develop criteria documents or briefs on the various microbial hazards, dose-response models, exposure assessments, and risk characterization, followed by a risk-management strategy. These documents can be used to fill data gaps and then be matched to the capabilities of the various laboratories. Clearly, laboratories with animal facilities could begin to fill gaps on dose-response and mixtures data. Laboratories with insect facilities can further evaluate the vectorborne models that have been developed. The overseas laboratories involved in treatment and vaccine development will fall into a category associated with risk-management research. However, one of the greatest needs will be to adapt the available tools to quantitate the hazards and, in particular, the exposure assessment in a prospective manner. Environmental health programs focusing on exposure assessment using modeling and monitoring data will need to be developed. Data on the quality of food, water, air, and environment (surfaces) and health surveillance of the people will be needed. This will spur the development of better methods for environmental monitoring and lead to evaluation of the current tools. At a minimum, each laboratory staff should be trained in risk-assessment methods, should have PCR capabilities, and be trained in the use of the Geographical Information Systems (GIS ) for maintaining and analyzing the database. LESSONS LEARNED AND RECOMMENDATIONS Lessons Learned from Deployments and Disease Surveillance 1. Intestinal illness and upper respiratory infection remain one of the greatest threats to deployed troops. These are largely of an unknown etiology and the hazards have not been properly identified. The illnesses are also time-dependent, with the greatest risk associated with early deployment. 2. There is seasonality and geographic variation in the diseases, although the factors associated with these trends are often not known. 3. Indigenous foods, fruits and vegetables, and bottled waters are associated with gastrointestinal risks. 4. The indoor environment is associated with upper respiratory illness. 5. Despite vaccination programs, with evolution will come new strains of pathogens that will continue to emerge (e.g., influenza) causing illness in troops. Assessment of these episodes will provide insight into the spread of disease globally. 6. Although vectorborne disease remains a concern, predeployment assessment of risk and preven-

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INFECTIOUS DISEASES AND BIOLOGICAL WEAPONS 107 tion has been shown to be successful; however, diligence is needed because exposures as low as a few hours can result in serious illness. 7. Although much is known about types of biological weapons that could be used, concerns regard- ing availability of vaccines has emerged, as well as the ability to detect and respond to an attack. 8. Some emerging infectious diseases are being studied and assessed in troops; however, the data are limited. Of concern are the emergence of antibiotic-resistant bacteria, resistant forms of parasites, and the lack of vaccines for many of these diseases. These factors have led to a limitation in treatment options, and better prevention strategies are needed. Some Recommendations Emerging Hazards Coxsackieviruses can exhibit chronic outcomes and these infections should be followed with serology. The use of urinary antigen could be used to screen for prevalence for Legionella as a cause of indoor respiratory disease. All Hanta virus and rodent distributions should be mapped. Streptococci skin infections and associated upper respiratory disease should be of interest. Risk Assessment comes. Health surveillance databases need to include asymptomatic infections and quantitative out- Dose-response databases should be developed. Geographic, climatic, seasonal, dose-response, and exposure scenarios can be used to develop tools for setting priorities for assessment of predeployment risks. Risk models can be evaluated for plausibility during outbreak investigations or disease surveil- lance operations. Exposure and health outcomes must be better assessed. The use of quantitative assessments allows one to begin to build exposure scenarios in which thresholds associated with ineffectiveness in the troops in a given time frame can be determined for specific agents. Biological Weapons Dose-response models should be developed. Time and concentration exposure and consequence scenarios should be built and evaluated. Mixtures and Multiple Stressors Microbial hazards should be added to animal research studies to test for mixtures effects (e.g., vaccination followed by coxsackieviruses, metals and viruses effects, and nutrition and infection). Special focus should be given to those microorganisms with possible immunological and neurological outcomes.

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