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INFECTIOUS DISEASES DIAGNOSED IN US TROOPS WHO SERVED IN THE PERSIAN GULF WAR, OPERATION ENDURING FREEDOM, OR OPERATION IRAQI FREEDOM

Infectious diseases have accompanied war throughout recorded history; the clinical aspects of Operation Desert Shield (ODSh), Operation Desert Storm (ODSt), Operation Iraqi Freedom (OIF), and Operation Enduring Freedom (OEF) have been no different. Although medical and epidemiologic personnel in the US military can anticipate troops’ exposure to many pathogens and mitigate their effects, naturally-occurring pathogens infected some troops during these operations. This chapter summarizes information about the infectious diseases and pathogens identified in US troops who served or are serving in ODSh, ODSt, OIF, or OEF. That information comes from several sources, including published scientific literature, medical surveillance monthly reports published by the Army Medical Surveillance Activity, the Centers for Disease Control and Prevention (CDC), and infectious disease experts at the Department of Defense (DOD) and the Department of Veterans Affairs. In Chapter 5, the committee evaluates the published scientific literature about the possible long-term adverse health outcomes of nine of the diseases discussed in this chapter.

Thriving on the troops’ crowded and sometimes unsanitary living conditions, microbial pathogens have caused primarily diarrheal illnesses and acute upper respiratory infections during ODSt, ODSh, OEF, and OIF (Hyams et al. 2001a; Paparello et al. 1993; Richards et al. 1993a; Thornton et al. 2005; Wasserman et al. 1997). Smaller numbers of military personnel have had various insect-borne diseases, nosocomial infections, brucellosis, chickenpox, meningococcal disease, and Q fever.

Even this chapter’s comprehensive review of public documents may not capture the full burden of infectious disease on US troops who have served in southwest and south-central Asia. Military medical investigators’ primary mission is to apply their findings to maintain troops’ health and they might not always publish summary reports in medical journals. In addition, field commanders may be reluctant to report illnesses perceived as trivial (such as vomiting and diarrhea) even when an outbreak of disease interferes with military operations (Matson 2005). Finally, a new policy purveyed by the DOD restricts the publication of some kinds of medical information that enemy combatants could use to gain an advantage over US troops (Department of the Army 2005b).



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Gulf War and Health: Volume 5. Infectious Diseases 4 INFECTIOUS DISEASES DIAGNOSED IN US TROOPS WHO SERVED IN THE PERSIAN GULF WAR, OPERATION ENDURING FREEDOM, OR OPERATION IRAQI FREEDOM Infectious diseases have accompanied war throughout recorded history; the clinical aspects of Operation Desert Shield (ODSh), Operation Desert Storm (ODSt), Operation Iraqi Freedom (OIF), and Operation Enduring Freedom (OEF) have been no different. Although medical and epidemiologic personnel in the US military can anticipate troops’ exposure to many pathogens and mitigate their effects, naturally-occurring pathogens infected some troops during these operations. This chapter summarizes information about the infectious diseases and pathogens identified in US troops who served or are serving in ODSh, ODSt, OIF, or OEF. That information comes from several sources, including published scientific literature, medical surveillance monthly reports published by the Army Medical Surveillance Activity, the Centers for Disease Control and Prevention (CDC), and infectious disease experts at the Department of Defense (DOD) and the Department of Veterans Affairs. In Chapter 5, the committee evaluates the published scientific literature about the possible long-term adverse health outcomes of nine of the diseases discussed in this chapter. Thriving on the troops’ crowded and sometimes unsanitary living conditions, microbial pathogens have caused primarily diarrheal illnesses and acute upper respiratory infections during ODSt, ODSh, OEF, and OIF (Hyams et al. 2001a; Paparello et al. 1993; Richards et al. 1993a; Thornton et al. 2005; Wasserman et al. 1997). Smaller numbers of military personnel have had various insect-borne diseases, nosocomial infections, brucellosis, chickenpox, meningococcal disease, and Q fever. Even this chapter’s comprehensive review of public documents may not capture the full burden of infectious disease on US troops who have served in southwest and south-central Asia. Military medical investigators’ primary mission is to apply their findings to maintain troops’ health and they might not always publish summary reports in medical journals. In addition, field commanders may be reluctant to report illnesses perceived as trivial (such as vomiting and diarrhea) even when an outbreak of disease interferes with military operations (Matson 2005). Finally, a new policy purveyed by the DOD restricts the publication of some kinds of medical information that enemy combatants could use to gain an advantage over US troops (Department of the Army 2005b).

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Gulf War and Health: Volume 5. Infectious Diseases DIARRHEAL DISEASE Enteric Infections in the Gulf War The leading cause of morbidity among American forces deployed to the Persian Gulf region was diarrheal disease (Hyams et al. 1995a). From August 1990 to May 1991, about 50% of surveyed ground troops and personnel onboard the USNS Mercy experienced at least one episode of acute diarrhea (Haberberger et al. 1994; Hyams et al. 1991). Large outbreaks of watery diarrhea began in August 1990; outbreaks of more severe, bloody diarrhea began in the following month. In addition, gastroenteritis with vomiting as a primary symptom occurred both sporadically and epidemically throughout the war. Ground Troops Laboratory Analysis Hyams and colleagues collected clinical and epidemiologic data from male US troops stationed in northeastern Saudi Arabia to determine the causes and prevalence of diarrheal disease among the troops, risk factors for diarrheal disease in the field, and the effectiveness of pharmacologic treatments (Hyams et al. 1991). From 432 soldiers who sought medical care and presented with gastroenteritis, stool samples were collected and examined for numerous enteropathogens, as described below and summarized in Table 4.1. The soldiers collectively represented all branches of the military, several regions of northeastern Saudi Arabia, and a variety of living conditions. Gastroenteritis was defined as diarrhea (three or more loose or watery stools within 24 hours), abdominal cramps, vomiting, or bloody stools. The stool specimens were cultured for various pathogens: E. coli, Salmonella, Shigella, Aeromonas, Plesiomonas, Yersinia, Vibrio spp., and Campylobacter. Bacterial enteropathogens were identified with the methods described in Manual of Clinical Biology, 4th edition (Kelly et al. 1985). The specimens were also examined for parasites with direct microscopy and for group A rotavirus with a commercial monoclonal-antibody-based immunoassay. Stool specimens and serum from subsets of patients underwent other tests for adenovirus, astrovirus, calicivirus, coronavirus-like agents, group A rotavirus, and norovirus (also known as Norwalk virus). One or more bacterial enteropathogens were identified in 49.5% of the stool cultures, representing 214 patients. Enterotoxigenic E. coli (ETEC), Shigella sonnei, or both were found in cultures from 205 of those patients. The scientists also found nontyphoid Salmonella spp., enteroinvasive E. coli, and Campylobacter. Tests for viruses yielded positive results for norovirus and rotavirus. There was no evidence of parasitic infection. TABLE 4.1 Summary of Test Results for Enteropathogens in Stool or Serum from 432 US Military Personnel with Gastroenteritis During Operation Desert Shield   Identified Enteropathogen or Enterotoxin Yes (No. patients) No (No. patients) Bacteria     Aeromonas -- x Campylobacter spp. x (2) x (430) Enteroinvasive E. coli x (3) x (429) Enterotoxigenic E. coli x (128) x (304) Plesiomonas -- x

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Gulf War and Health: Volume 5. Infectious Diseases   Identified Enteropathogen or Enterotoxin Yes (No. patients) No (No. patients) Salmonella spp. (not S. typhi) x (7) x (425) Salmonella typhi   x Shigella spp. x (113) x (319) Vibrio cholerae -- x Yersinia spp. -- x Enterotoxins     Circulating Clostridium perfringens enterotoxins -- x Circulating staphylococcal enterotoxins -- x Parasites     Entamoeba histolytica -- x Giardia lamblia -- x Viruses     Adenovirus -- x Astrovirus -- x Calicivirus -- x Coronavirus-like agents -- x Norovirusa x (1-9)b x (17) Rotavirus (group A) x (1) x (431) aStool contained particles that were morphologically similar to norovirus. bMultiple tests for viral enteropathogens were conducted on subsets of stool and serum samples, and the number of samples that tested positive for norovirus varied by test from 1 to 9 (Table 4.2). SOURCE: Adapted with permission from Hyams et al. 1991. Only 19 of the 432 soldiers in the study reported vomiting as a primary symptom. These cases were clustered temporally (in November and December) but not geographically. The testing of stool samples and paired serum samples suggested that norovirus was the principal etiologic agent in troops with vomiting (Table 4.2). Various investigators later conducted studies specifically on norovirus in the Gulf War context, as discussed below. TABLE 4.2 Summary of Test Results for Viral Enteropathogens and Enterotoxins in Stool or Serum from Subsetsa of US Military Personnel with Gastroenteritis During Operation Desert Shield   Identified Enteropathogen Yes (No. patients) No (No. patients) In stool samples from 19 patients with vomiting as a primary symptom, November-December 1990 Enzyme immunoassay results:     Adenovirus -- x Norovirus x (3) x (16) Rotavirus (group A) -- x Immune electron microscopy results (in 13 of 19 specimens):     Adenovirus -- x Astrovirus -- x Calicivirus -- x Coronavirus-like agents -- x

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Gulf War and Health: Volume 5. Infectious Diseases   Identified Enteropathogen or Enterotoxin Yes (No. patients) No (No. patients) Norovirusb x (3) x (10) Rotavirus -- x In stool samples from 68 patients with diarrhea but no vomiting, November-December 1990 Enzyme immunoassay results:     Adenovirus -- x Norovirus -- x Rotavirus -- x Immune electron microscopy results (in 18 of 68 specimens):     Adenovirus -- x Astrovirus -- x Calicivirus -- x Coronavirus-like agents -- x Norovirusb x (1) x (17) Rotavirus -- x Paired serum samples from 11 patients with vomiting alone or vomiting and diarrhea Evaluated for a 4-fold or greater increase in serum antibody titer to:     Adenovirus -- x Circulating Clostridium perfringens enterotoxins -- x Circulating staphylococcal enterotoxins -- x Norovirus x (9) x (2) Rotavirus (group A) -- x a'These groups of patients were part of a cohort of 432 troops. bStool contained particles that were morphologically similar to norovirus. SOURCE: Adapted from Hyams et al. 1991. Characterization of ETEC. The high prevalence of ETEC and Shigella isolates led investigators to characterize these organisms further (Table 4.3). Shigella isolates were identified by species; additional studies about the occurrence of Shigella among Gulf War troops are discussed below. TABLE 4.3 Bacterial Enteropathogens Identified in Stool Specimens from 214a U.S. Military Personnel with Gastroenteritis Enteropathogen No. (%)b of Patients Enterotoxigenic E. coli   Heat-labile 15 (3.5) Heat-stabile 44 (10.2) Heat-labile and heat-stabile 64 (14.8) Mixedc heat-labile and heat-stabile 2 (0.5) Enteroinvasive E. coli 3 (0.7) Shigella   S. dysenteriae 4 (0.9) S. flexneri 12 (2.8) S. boydii 8 (1.9) S. sonnei 89 (20.6)

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Gulf War and Health: Volume 5. Infectious Diseases Enteropathogen No. (%)b of Patients Salmonella (not S. typhi) 7 (1.6) Campylobacter 2 (0.5) a Bacterial enteropathogens were identified in 214 (49.5%) of the 432 stool samples collected. b The total percentage of isolates is higher than the percentage of patients with an identified enteropathogen because 36 patients had mixed infections. c Two patients had mixed heat-labile and heat-stabile enterotoxigenic E. coli infections, with individual colonies producing either heat-labile or heat-stable toxin alone. SOURCE: Reprinted with permission from Hyams et al. 1991. Hyams and colleagues tested E. coli-like organisms for heat-labile and heat-stabile toxin by using alkaline phosphate-conjugated oligonucleotide DNA probes and Y-1 adrenal cell and suckling-mouse assays (Hyams et al. 1991). Later, Wolf and colleagues further analyzed the Hyams et al. ETEC isolates for their toxin distribution, and other factors (Wolf et al. 1993). A given strain of ETEC may produce heat-labile enterotoxin (LT), heat-stabile enterotoxin (ST), or both. LT is nearly identical with the toxin that causes cholera. Some 85% of 132 ETEC isolates from 124 symptomatic Gulf War troops produced LT (Table 4.4). TABLE 4.4 Toxin distribution Among 132 ETEC Isolates from 124 US Troops with Gastroenteritis during Operation Desert Storm Toxin No. (percentage) of isolates LT and ST 59 (45) LT 53 (40) ST 20 (15) SOURCE: Adapted with permission from Wolf et al. 1993. Antimicrobial susceptibility. Using the disk-diffusion method, Hyams and colleagues determined which of five antibiotics would most effectively treat the strains of ETEC and Shigella identified in the stool cultures. Up to 63% of the ETEC and up to 85% of the Shigella specimens were resistant to several of the antibiotics most accessible to clinicians in the field (Table 4.5), including trimethoprim-sulfamethoxazole, the antibiotic most frequently used to treat diarrhea during the early stages of ODSh deployment. In contrast, the scientists found, ETEC and Shigella were 100% susceptible to ciprofloxacin and norfloxacin. Hyams and colleagues reported that empiric results of antibiotic treatment for diarrheal disease in the field led military clinicians to gravitate toward ciprofloxacin and norfloxacin over time. Clinicians also reportedly administered quinolone drugs to affected critical combat troops to shorten the duration of gastroenteric symptoms. TABLE 4.5 Antimicrobial Resistance of Enterotoxigenic E. coli and Shigella Specimens   Proportion of Resistant Specimens, % Antibiotic Enterotoxigenic E. coli (N = 125) Shigella (N = 113) Trimethoprim-sulfamethoxazole 39 85 Tetracycline 63 68 Ampicillin 48 21 Ciprofloxacin 0 0 Norfloxacin 0 0 SOURCE: Adapted with permission from Hyams et al. 1991.

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Gulf War and Health: Volume 5. Infectious Diseases Epidemiologic Analysis To learn the prevalence of and risk factors for diarrheal disease among US troops stationed in northeastern Saudi Arabia during ODSh, Hyams and colleagues administered an epidemiologic survey to 2,022 personnel from all branches of the military in October-December 1990 (Hyams et al. 1991). After an average of 2 months in Saudi Arabia, 57% of those surveyed had suffered at least one episode of diarrhea. The symptoms of diarrheal disease had led 22% of all respondents to seek medical care, and had prevented 20% of all respondents from performing their duties. Thirty-two percent of those surveyed had experienced two or more separate episodes of diarrhea. In some units, the attack rate was 5-10% per week. A univariate analysis of potential risk factors for the transmission of diarrheal disease during ODSh suggested an association between an episode of diarrhea and eating salad, dining in a mess hall, and drinking from a canteen. (A laboratory study of 12 heads of lettuce obtained from food-distribution facilities in September 1990 found coliform bacteria in all 12; ETEC was identified in two (Hyams et al. 1991).) No association was found between an episode of diarrhea and obtaining food from local vendors, eating in a local restaurant, or drinking bottled water. A multivariate analysis of these risk factors and an evaluation of published research on the transmission of Shigella indicated that flies and relatively poor personal hygiene probably accounted for the spread of ETEC and Shigella. The disabling effect of repeated outbreaks of diarrheal disease in US forces during ODSh despite the best available preventive measures led Hyams and colleagues to call for the development of a vaccine to protect troops (Hyams et al. 1991). DOD is supporting development of such vaccines (Stephens and Nataro 2004). Shigella The presence of immunoglobulin A (IgA) and immunoglobulin G (IgG) anti-Shigella lipopolysaccharide (LPS) in predeployment serum did not offer protective immunity to infection by Shigella spp. among US ground troops who participated in the Persian Gulf War, Hyams and colleagues reported (Hyams et al. 1995b). The investigators reached that conclusion by studying a cohort of 883 combat troops and support personnel in three Marine Corps units who were flown directly to Saudi Arabia in late December 1990 and directly back to the United States in May 1991. Initially stationed in Saudi Arabia, and then relocated to Kuwait, the subjects lived in remote, rugged, desert camps. US military personnel prepared most of their food, which came from the United States except for local fresh produce. The subjects drank both locally produced bottled water and water purified by reverse-osmosis (Hyams et al. 1993). The investigators obtained serum samples from all members of the three units who were accessible during the week before their deployment and the 2 two days after their return (827 subjects). Paired serum samples were tested for antibodies to both S. sonnei and S. flexneri. Epidemiologic questionnaires were also administered to this cohort before and after deployment. Among the 827 subjects, 18% seroconverted during ODSh and ODSt; that underscored earlier findings that troops deployed to ODSh and ODSt faced a considerable risk of Shigella infection. The study revealed the absence of an association between seroconversion and the occurrence of diarrheal symptoms. Overall, 60% of the cohort reported one or more episodes of diarrhea, and 18% reported diarrhea with fever. In contrast, many troops who seroconverted were asymptomatic. Because S. sonnei LPS cross-reacts with the LPS of Plesiomonas shigelloides, some of the high concentrations of serum antibodies observed in samples from the 827 marines might not have been the result of exposure to Shigella spp. To determine whether exposure to Shigella led

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Gulf War and Health: Volume 5. Infectious Diseases to persistently high antibody concentrations in some subjects and seroconversions in others, Mikhail and colleagues examined how a subset of the paired serum samples reacted to four Shigella invasion plasmids, which cross-react with just one enteroinvasive strain of E. coli (Mikhail et al. 1996). They also used ELISA to detect antibodies to S. sonnei LPS. In their report, the authors noted that antibodies to LPS and invasion plasmid antigens in serum increase and decrease within 4 months during naturally acquired Shigella infections. Only 12 sets of serum samples were large enough to use for this experiment (six from seroconverters and six with persistently high concentrations of antibodies to S. sonnei LPS). By using Western blot, the investigators observed antibody reactions to numerous invasion plasmid antigens both before and after deployment in serum from troops with persistently high concentrations of antibodies to S. sonnei LPS, which suggest that they had been exposed to S. sonnei before deployment and were repeatedly exposed to it during deployment. In the postdeployment serum from troops who seroconverted, the scientists observed IgA and IgG recognition of additional invasion plasmid antigens and increased concentrations of antibodies to S. sonnei LPS—even in two soldiers who were asymptomatic for diarrheal illness throughout the war. The authors interpreted those results as an indication that troops who seroconverted had been exposed repeatedly to S. sonnei in the field. Norovirus Norovirus (NV) and Norwalk-like viruses caused both sporadic cases and outbreaks of acute gastroenteritis among ground troops and shipboard personnel throughout the Gulf War. Brief and debilitating, NV gastroenteritis usually causes acute vomiting, diarrhea, nausea, and abdominal cramps that last 1-2 days. Some people never develop symptoms even after direct challenge, but others are repeatedly susceptible to symptomatic infection. All infected people shed highly contagious NV in stools from as early as 15 hours after exposure to as late as 14 days after. Studies of NV infections among military personnel indicate that crowding is the most important risk factor for transmission (McCarthy et al. 2000). After the Gulf War, Hyams and colleagues demonstrated the incidence of NV infection among troops deployed to Saudi Arabia and Kuwait from late December 1990 through May 1991 (Hyams et al. 1993). Using the paired serum samples from the 883-troop cohort described above, the investigators used ELISA to measure antibody activity to recombinant NV particles. The investigators defined evidence of infection as a 4-fold or greater increase in titer of anti-NV antibodies from predeployment serum to postdeployment serum. Matching the ELISA results with the subjects’ clinical symptoms, as reported in the aforementioned postdeployment epidemiologic questionnaire, the investigators obtained the results displayed in Table 4.6. After adjusting for oversampling of subjects with vomiting, the investigators estimated that NV infected 6% of the study population. The scientists could not determine the specific sources of infection, although they enumerated the probable opportunities for person-to-person spread of NV: rapid deployment of massive numbers of soldiers, overcrowding, and rugged desert living conditions that included communal temporary latrines and bathing facilities. To aid the development of a vaccine against NV and Norwalk-like virus for the US military, Lew and colleagues compared the published genetic sequence of NV with sequences of NV strains extracted from three stool specimens from US troops who developed gastroenteritis while deployed to Saudi Arabia for ODSh (Lew et al. 1994).

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Gulf War and Health: Volume 5. Infectious Diseases TABLE 4.6 Number of Subjects with Various Clinical Manifestations of Enteric Disease and Serologic Evidence of Norovirus Infection   No. (%) with Complaint No. (%) with ≥ 4-fold Increase in Norovirus Antibody (n = 32) Clinical Manifestation Entire Cohort (n = 883) Subjects Tested for Norovirus Infection (n = 404) Vomiting alone 17 (1.9) 17 (4.2) 4 (23.5) Vomiting and diarrhea 117 (13.3) 117 (29.0) 14 (12.0) Diarrhea alone 406 (46.0) 170 (42.1) 11 (6.5) No vomiting or diarrhea 343 (38.8) 100 (24.8) 3 (3.0) SOURCE: Reprinted with Permission from Hyams et al. 1993. Enteric Parasitic Infections Enteric parasites may have infected a small percentage of troops deployed to the Persian Gulf region in 1990 and 1991 (Malone et al. 1991). Malone and colleagues studied the risk of enteric parasitic disease in a cohort of 422 marines returning from Saudi Arabia and Kuwait after 5 months of service on the front lines of ODSt. Like the marines described above, this cohort had little contact with local populations. The investigators collected stool samples from the troops within 2 days of their arrival in the United States. The specimens were analyzed for evidence of helminthic and protozoan infections according to the thimerisol (Merthiolate)-iodine-formalin concentration technique. The only evidence of enteric parasitic infection found in the cohort was Giardia lamblia cysts in specimens from nine marines, or 2% of the subjects. Four of the nine troops had experienced an episode of diarrhea while deployed to the Middle East, and seven of the nine had previously been deployed aboard a ship that made port calls in the Mediterranean. None of the nine marines had diarrhea when their stool samples were obtained. Oster and Sanford make passing reference to “a few” cases of amebiasis among troops deployed to the Persian Gulf War (Oster and Sanford 1992); however, the report lacks supporting epidemiologic, clinical, and microbiologic data. The committee is unaware of other reports of amebiasis among Gulf War troops. Shipboard Military Personnel About 46% of the 870 military personnel deployed to the Persian Gulf aboard the hospital ship USNS Mercy T-AH 19 had at least one episode of diarrhea in the period August 1990-January 1991 (Paparello et al. 1993). That finding is derived from the results of an epidemiologic survey designed to assess the prevalence and effects of diarrheal illness among shipboard personnel deployed to the Middle East during ODSh. The USNS Mercy was a referral hospital for patients from other ships in the Persian Gulf and ground-based medical facilities during ODSh. From December 13, 1990, to January 7, 1991, investigators distributed a voluntary questionnaire to all Navy personnel aboard the ship; about 83% (N = 722) completed it (Table 4.6). The questions covered demographics; history of eating off the ship; job description; location of spaces where subjects worked, ate, and slept; and gastrointestinal symptoms. In contrast with the populations of most other studies described in this chapter, 32% of the subjects were female. In addition to the results listed in Table 4.7, the investigators found that officers were more likely to report an episode of diarrhea and more often unable to perform routine duties due to diarrhea than enlisted personnel. One explanation, the authors speculated, is that officers tended to eat in a wide variety of local restaurants during visits to foreign ports, whereas enlisted

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Gulf War and Health: Volume 5. Infectious Diseases personnel did not. The investigators also found independent associations between lower age (range, 17 to 31 years) and an episode of diarrhea with vomiting and between female sex and an episode of diarrhea with vomiting. The authors speculated about many explanations for the latter finding: that women were more likely to report symptoms to sick call, that a greater percentage of women than men were officers, and that women worked more closely with patients and thus were more often exposed to diarrheal pathogens. TABLE 4.7 Morbidity Due to Diarrheal Disease Among 722 US Navy Shipboard Personnel Deployed to the Persian Gulf During ODSh Symptoms and Outcomes Fraction of Troops (N = 722), % Diarrhea 46.3 Diarrhea and fever 11.6 Diarrhea and vomiting 6.2 Sick-call visit 7.6 Inability to work 6.0 SOURCE: Adapted with permission from Paparello et al. 1993. Most of the 8.3% of subjects who received medication responded to treatment with norfloxacin or ciprofloxacin. The investigators suspected but could not confirm an infectious etiology for most cases of diarrheal disease among the USNS Mercy’s crew on the basis of the acute onset and short duration of most cases and a frequent association with eating in foreign ports. The relatively small space for living, eating, and attending to patients aboard the USNS Mercy promoted close contact that may have facilitated the transmission and spread of enteric pathogens among the crew and between patients and crew. Gastroenteritis in Operation Enduring Freedom and Operation Iraqi Freedom Epidemiologic Investigations of Gastroenteritis An epidemiologic survey of 15,459 deployed troops conducted in January-March 2004 revealed that 74.5% of military personnel had experienced at least one episode of diarrhea while serving in OEF, OIF, or both (Sanders et al. 2005a). Sanders and colleagues of the Navy’s Enteric Disease Research Program reached that finding and others through a survey designed to assess the incidence and effect of the most common illnesses and noncombat injuries among deployed US troops participating in OEF and OIF. The investigators’ findings related to diarrheal disease are discussed here, and findings pertinent to respiratory disease and leishmaniasis are presented later. The survey posed 199 questions that covered demographics, clinical information, general health, and health-risk behaviors and attitudes. The questions were dispersed among 20 unique single-page forms, each containing 19-21 questions (some questions appeared on multiple forms). That enabled the researchers to obtain a representative distribution of responses. The investigators verified the accuracy, integrity, and internal validity of the data obtained from each form. The troops who completed the questionnaire represented about 11% of the US military force in OEF and OIF during the study period. The study subjects either were participating in the military’s rest and recuperation (R&R) program in Doha, Qatar, or had stopped at an American

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Gulf War and Health: Volume 5. Infectious Diseases air base en route to the United States for a 2-week break after an initial tour of duty in Afghanistan or Iraq. Analysis of the survey data revealed that self-reported symptoms of diarrheal disease were moderately severe and multiple episodes common. Gastroenteritis occurred more frequently among troops deployed to Iraq (76.8%) than to Afghanistan (54.4%). The duration and severity of symptoms were greater for troops in Iraq than in Afghanistan. Table 4.8 contains additional salient data obtained through the survey about the occurrence of diarrheal illness among US forces during OEF and OIF. TABLE 4.8 Impact of Diarrhea Among US Military Personnel Deployed to Iraq and Afghanistan, 2003-2004 Characteristics of illness No. cases in Iraq (N, % or rangea) No. cases in Afghanistan (N, % or rangea) p Experienced diarrhea 7,553 (76.8) 543 (54.4) < 0.0001 Number of episodes 5 (2-8) 2 (2-5) 0.0003 Duration (days) 4 (1.5-4) 1.5 (1.5-4) 0.008 Maximal number loose stools per day 5 (2.5-5) 2.5 (2.5-5) < 0.0001 Reported more than six stools per day 1,166 (20.8) 55 (14.0)   Illness characteristics from Iraq and Afghanistanb combined Percentage 95% CI Sought care for diarrhea 40.2 38.0-42.5 Number of clinic visitsc 2.0 1-2 Fever with diarrhea 25.8 22.3-29.2 Vomiting with diarrhea 18.0 15.0-21.1 Vomiting without diarrhea 16.5 14.0-19.1 Persistent diarrhea (>14 days) 9.8 7.5-12.1 Chronic diarrhea (>30 days) 3.3 1.9-4.7 Disposition Confined to quarters (bedrest) 14.2 11.5-16.9 Days in quartersc 2.0 1-2 Hospitalized 1.8 0.7-2.8 NOTE : CI = confidence interval. a Ranges are from the 25th percentile to the 75th percentile (the interquartile range). b No statistical differences in these characteristics were observed between sites. c Values are median and interquartile range. SOURCE: Adapted with permission from Sanders et al. 2005a. Sanders and colleagues note that recall and selection bias may have influenced their results. They assert that the point estimates derived probably can be generalized to the entire population of US troops deployed to Iraq and Afghanistan for OEF and OIF. The results presented above validate the findings of an earlier, smaller study in which Sanders and colleagues found that diarrheal illness among troops deployed to OEF and OIF occurred at a high rate and frequently manifested with severe symptoms (Sanders et al. 2005b; Sanders et al. 2004). They also found that diarrheal illness appeared to interfere with military operations more during OEF and OIF than during ODSh. They reached those conclusions by analyzing data collected from an anonymous questionnaire administered to 4,348 volunteers in the period October 27, 2003-January 27, 2004.

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Gulf War and Health: Volume 5. Infectious Diseases The epidemiologic questionnaire was designed to assess the incidence of diarrheal illness and its associated symptoms, treatment, and impact on military missions. Diarrhea was defined as three or more loose or liquid stools in 24 hours or two or more loose or liquid stools associated with other gastrointestinal symptoms or fever. The respondents, who participated voluntarily, had been deployed for a median of 8 months to Iraq and 6.7 months to Afghanistan. Most were on R&R in Doha, Qatar; others were traveling through Incirlik Air Base, Turkey, after their deployment to Iraq had ended. Although Sanders and colleagues noted several sampling biases in their study, they concluded that it was unlikely that their results overestimated rates of diarrheal illness in the overall population of troops in Iraq and Afghanistan. Sixty-four percent of respondents stationed in Afghanistan and 77% stationed in Iraq reported one or more episodes of diarrhea during their deployment. More than half the subjects reported multiple episodes. The amount of time spent off a military compound was associated with an increased risk of developing diarrhea. The investigators concluded that time spent off a base probably represented a surrogate measure of exposure to local food and drink. The investigators found that diarrheal illness affected military operations in OEF and OIF more than it had during ODSh. Of the survey participants, 45% experienced an episode of diarrhea severe enough to decrease job performance for a median of 3 days; 62% of subjects sought medical care for diarrheal illness at least once, and 17% were consequently confined to bed rest for a median of 2 days. For nearly one-third of troops with diarrhea, treatment included intravenous rehydration. Personnel deployed to Iraq were more likely to experience diarrheal illness, to have multiple episodes, and to have severe diarrhea (more than 10 stools per day). Sanders and colleagues did not attempt to identify the etiologic agents of diarrheal illness in their study population. Nevertheless, they speculated that ETEC and other enteropathogenic forms of E. coli probably caused most episodes of diarrhea that respondents described as watery (Table 4.9). They also speculated that norovirus caused many cases of diarrheal disease in troops who experienced vomiting as a primary symptom. TABLE 4.9 Demographics and Diarrheal Illness Characteristics of US Military Personnel Deployed to Iraq and Afghanistan Characterizationa of Diarrhea Occurrence Among Troops Stationed in Iraq (N = 3915) [N (%)] Occurrence Among Troops Stationed in Afghanistan (N = 255) [N (%)] Watery 2815 (72) 149 (58) Vomiting (mainly) 317 (8) 6 (2) Blood in diarrhea 128 (3) 5 (2) Diarrhea with fever 471 (12) 23 (9) a These characterizations reflect absolute responses that are not mutually exclusive and may include symptoms across multiple episodes. SOURCE: Adapted with permission from Sanders et al. 2005b. Laboratory Analysis of Gastroenteritis More than any other type of infectious disease, gastroenteritis due to norovirus1 and Shigella spp. plagued the population of 83,000 US marines deployed to Iraq in spring 2003 according to a study led by staff of a Navy preventive medicine laboratory that provided clinical 1 Includes Norwalk-like viruses (Matson 2005).

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Gulf War and Health: Volume 5. Infectious Diseases All eight patients in this study first sought medical care while stationed in northern Iraq. The first three patients were in northern Iraq when their symptoms of pneumonia began. The investigators postulated that humans may be at greater risk of contracting Q fever in northern Iraq owing to the larger concentrations of livestock that may exist there because the land is favorable for ruminants to graze. One of the first three patients reported drinking raw sheep’s milk, two reported tick bites within 30 days of becoming ill, and all three reported contact with dogs, cats, sheep, goats, and camels (potential reservoirs of C. burnetii). VIRAL HEPATITIS Clinicians diagnosed a few cases of hepatitis A and B among deployed US troops during the Gulf War, according to Hyams and colleagues (Hyams et al. 1995a); the exact number of cases is unclear. The committee is unaware of published reports about those cases. The hospitalization rates for acute hepatitis among all active-duty military personnel in 1990 and 1991 were 187 per 100,000 and 168 per 100,000 respectively (Table 4.19) (Hyams et al. 2001b). The data do not indicate how many cases were associated with participation in ODSh or ODSt. Staff at the Armed Forces Institute of Pathology diagnosed one case of hepatitis B and 15 cases of hepatitis C among Gulf War veterans from 1992 to 1997 (Specht et al. 2000). The investigators reportedly lacked the data to determine whether the patients had contracted hepatitis before, during, or after the war. Hepatitis A and B vaccination policies differ among the services (IOM 1996). In the past, the Army, Navy, Marine Corps, and Coast Guard administered the hepatitis A vaccine as directed by the applicable surgeon general or the commandant of the Coast Guard; the Air Force vaccinated its personnel against hepatitis A when deploying them to a high-risk area. As of 1996, all services administered the hepatitis B vaccine to personnel in high-risk occupational groups or as directed by the applicable surgeon general or the commandant of the Coast Guard. More recently, DOD policy requires that all personnel be vaccinated for hepatitis A (Department of Defense 2006a; Military Vaccine Agency 2005a) and Army policy requires that all deployed personnel be vaccinated for hepatitis B (Department of the Army 2005a). TABLE 4.19 Age- and Sex-Adjusted Hospitalization Rates per 100,000 Personnel for Acute Hepatitis Among Active Duty U.S. Military Forces, 1990 and 1991 Year Acute Hepatitis A Acute Hepatitis B Acute Hepatitis C Acute Unspecified Viral Hepatitis Total No. Rate No. Rate No. Rate No. Rate No. Rate 1990 113 3.52 0 -- 0 -- 75 3.08 187 6.56 1991 74 2.87 25 0.96 1 0.05 72 3.07 168 6.75 SOURCE: Adapted with permission from Hyams et al. 2001a. TUBERCULOSIS No cases of active tuberculosis (TB) were recognized in military personnel who served in ODSt and ODSh (Hyams et al. 1995a). In many soldiers in some units, however, tuberculin skin tests (TSTs) were negative before the Gulf War and positive afterward (Oster and Sanford 1992). Among military personnel deployed to OEF and OIF, approximately 2.5 percent of those given pre- and post-deployment TSTs converted from negative to positive (Kilpatrick 2005). TST

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Gulf War and Health: Volume 5. Infectious Diseases conversion is pathognomonic of acute infection with Mycobacterium tuberculosis; thus, transmission of M. tuberculosis occurred within some military units deployed to southwest and south-central Asia. Immunocompetent individuals who become infected with M. tuberculosis face a 10 percent lifetime risk for developing active TB in the absence of prophylactic treatment. The committee discusses TB at length in Chapter 5. DEPARTMENT OF DEFENSE MEDICAL DATABASES On January 10, 2006, IOM submitted a request to DOD to conduct a search of the Defense Medical Surveillance System (DMSS) database (described in Rubertone and Brundage (2002)) for numbers of cases of infectious diseases coded by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The request included searching for infectious diseases diagnosed in military personnel deployed to the Gulf War, OIF, and OEF. DOD approved IOM’s request on January 20. Because the DMSS database does not contain many data pertaining to in-theater morbidity during the Gulf War, DOD recommended that an additional search be conducted with a different DOD database on Gulf War in-theater hospitalization data. On June 2, 2006, IOM received the results of the search of the Gulf War in-theater hospitalization database. Those results are presented in Table 4.20. DOD developed the database to investigate in-theater hospitalizations during the Gulf War (Smith et al. 2004). It contains records from almost 20,000 admissions occurring in the Kuwaiti theater of operations and evacuated admissions to hospitals in Europe. The committee reviewed the search results and determined that the results would not have changed the committee’s approach to its charge or conclusions. At the time of completion of this report, IOM had not received the results of the DMSS database search on infectious diseases diagnosed during OIF and OEF. TABLE 4.20 Numbers of Cases of Infectious Diseases in the Gulf War In-Theater Hospitalization Database ICD-9CM Category Disease No. Cases 003.0 Salmonella gastroenteritis 9 003.9 Salmonella infection, unspecified 2 004.9 Shigellosis, unspecified 3 005.0 Staphylococcal food poisoning 2 005.9 Food poisoning, unspecified 18 006.0 Acute amebic dysentery without mention of abscess 3 006.8 Amebic infection of other sites 3 006.9 Amebiasis, unspecified 14 008.5 Bacterial enteritis, unspecified 6 008.69 Other viral enteritis 2 008.8 Intestinal infection due to other organism, not elsewhere classified 86 009.0 Infectious colitis, enteritis, and gastroenteritis 23 009.1 Colitis, enteritis, gastroenteritis, presumed infectious origin 2 009.2 Infectious diarrhea 34 009.3 Diarrhea of presumed infectious origin 4 011.60 Tuberculous pneumonia (any form), unspecified examination 1 011.90 Unspecified pulmonary tuberculosis, unspecified examination 1 034.0 Streptococcal sore throat 19

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Gulf War and Health: Volume 5. Infectious Diseases ICD-9CM Category Disease No. Cases 035 Erysipelas 1 038.10 Staphylococcal septicemia, unspecified 1 038.9 Unspecified septicemia 2 040.0 Gas gangrene 1 041.10 Staphylococcus, unspecified, in condition classified elsewhere 1 041.4 Escherichia coli infection 1 042 Human immunodeficiency virus disease 2 047.9 Unspecified viral meningitis 3 048 Other enterovirus diseases of the central nervous system 1 052.1 Varicella (hemorrhagic) pneumonitis 1 052.7 Chickenpox with other specified complications 1 052.8 Chickenpox with unspecified complication 3 052.9 Varicella without mention of complication 64 053.8 Herpes zoster with unspecified complication 1 053.9 Herpes zoster without mention of complication 11 054.10 Genital herpes, unspecified 2 054.19 Other genital herpes 1 054.2 Herpetic gingivostomatitis 2 054.43 Herpes simplex disciform keratitis 3 054.79 Herpes simplex with other specified complications 1 054.9 Herpes simplex without mention of complication 1 055.9 Measles without mention of complication 1 057.8 Other specified viral exanthemata 1 057.9 Viral exanthem, unspecified 1 066.0 Phlebotomus fever 5 070.10 Viral hepatitis A without mention of a hepatic coma, lab test confirmed 4 070.30 Viral hepatitis B without coma, acute/ unspecified without hepatic delta, lab test confirmed 6 070.9 Unspecified viral hepatitis without hepatic coma 3 072.9 Mumps without mention of complication 1 074.1 Epidemic pleurodynia 1 075 Infectious mononucleosis 27 077.8 Other viral conjunctivitis 3 078.10 Other diseases due to viruses and chlamydiae, viral warts, unspecified 29 078.11 Other diseases due to viruses and chlamydiae, condyloma acuminatum 9 078.19 Other diseases due to viruses and chlamydiae, other specified viral warts 6 079.89 Other specified viral infections 5 079.98 Unspecified chlamydial 1 079.99 Unspecified viral infections 299 084.1 Vivax malaria (benign tertian) 7 084.6 Malaria, unspecified 4 085.0 Leishmaniasis visceral (kala-azar) 1 085.1 Cutaneous leishmaniasis, urban 1 085.9 Leishmaniasis, unspecified 2 091.3 Secondary syphilis of skin or mucous membranes 1 091.50 Syphilitic uveitis, unspecified 1 098.0 Acute gonococcal infection, lower genito-urinary tract 1 098.16 Acute gonococcal endometritis 1 099.3 Reiter's disease 6

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Gulf War and Health: Volume 5. Infectious Diseases ICD-9CM Category Disease No. Cases 099.40 Other nongonococcal urethritis unspecified 2 099.9 Venereal disease, unspecified 1 101 Vincents angina 1 110.3 Dermatophytosis of groin and perianal area 1 110.4 Dermatophytosis of foot 10 110.6 Deep seated dermatophytosis 1 111.0 Pityriasis versicolor 2 116.0 Blastomycosis 1 117.9 Other and unspecified mycoses 2 120.9 Schistosomiasis, unspecified 1 127.3 Trichuriasis 1 130.2 Chorioretinitis due to toxoplasmosis 3 130.7 Toxoplasmosis of other specified sites 1 133.0 Scabies 2 135 Sarcoidosis 16 136.1 Behcet's syndrome 1 136.9 Unspecified infectious and parasitic diseases 1 320.1 Pneumococcal meningitis 1 480.9 Pneumonia due to virus, unspecified 6 481 Pneumococcal pneumonia (streptococcus pneumoniae pneumonia) 1 482.30 Pneumonia due to streptococcus, unspecified 1 482.89 Pneumonia due to other specified bacteria 1 482.9 Pneumonia due to unspecified bacteria 3 483.0 Mycoplasma pneumoniae 5 485 Bronchopneumonia, organism unspecified 9 486 Pneumonia, organism unspecified 168 487.0 Influenza with pneumonia 1 487.1 Influenza with other respiratory manifestations 27 487.8 Influenza with other manifestations 2 711.06 Pyogenic arthritis involving lower leg 5 711.90 Unspecified infective arthritis, site unspecified 1 711.96 Unspecified infective arthritis involving lower leg 1 711.97 Unspecified infective arthritis involving ankle and foot 1 NOTE: ICD-9CM = International Classification of Diseases, Ninth Revision, Clinical Modification. SOURCE: Smith 2006. DEPARTMENT OF DEFENSE POLICY REGARDING PREDEPLOYMENT AND POSTDEPLOYMENT SERUM COLLECTION DOD policy specifies that “predeployment serum specimens for medical examinations will routinely be collected within one year of deployment” and that “postdeployment serum specimens for medical examinations will be collected no later than 30 days after arrival at the demobilization site, home station, or in-patient medical treatment facility” (Department of Defense 2006b). Predeployment and postdeployment serum samples are required for all deployments outside the continental United States that are longer than 30 days and to areas without fixed US medical treatment facilities (Kilpatrick 2006). The serum samples are stored indefinitely at the DOD Serum Repository.

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Gulf War and Health: Volume 5. Infectious Diseases Routine testing of the serum samples is not conducted except testing for HIV (Kilpatrick 2006). However, the serum samples have been used for research studies (for example, on Lyme disease, Helicobacter pylori infection, and leishmaniasis), and for operational studies (for example, on severe acute pneumonia cases during OIF, malaria among Marines in Liberia, and WNV). The committee agrees with DOD’s overall policy regarding collection and use of serum specimens. However, for banked serum specimens to be most useful for determining whether infectious exposures occurred during deployment, the predeployment specimens need to be collected before travel. Current policy allows for collection of predeployment serum specimens up to a year after deployment. If specimens are not collected until after deployment, it would be difficult to ascertain whether any signs of infection found in the “predeployment” specimens are due to exposure during the current deployment or before it. REFERENCES Anderson AD, Smoak B, Shuping E, Ockenhouse C, Petruccelli B. 2005. Q fever and the US military. Emerging Infectious Diseases 11(8):1320-1322. Andrews RB. 2004. Brucellosis in a soldier who recently returned from Iraq. Medical Surveillance Monthly Report 10(4):30. Boecken GH, Bronnert J. 2005. Pathogenesis and management of a late manifestation of vivax malaria after deployment to Afghanistan: Conclusions for NATO Armed Forces Medical Services. Military Medicine 170(6):488-491. CDC (Centers for Disease Control and Prevention). 1992. Viscerotropic leishmaniasis in persons returning from Operation Desert Storm—1990-1991. Morbidity and Mortality Weekly Report 41(8):131-134. CDC. 2003a. Severe Acute Pneumonitis Among Deployed US Military Personnel—Southwest Asia, March—August 2003. Morbidity and Mortality Weekly Report 52(36):857-859. CDC. 2003b. Cutaneous leishmaniasis in US military personnel—Southwest/Central Asia, 2002-2003. Morbidity and Mortality Weekly Report 52(42):1009-1012. CDC. 2004a. Two cases of visceral leishmaniasis in US military personnel—Afghanistan, 2002-2004. Morbidity and Mortality Weekly Report 53(12):265-268. CDC. 2004b. Update: Cutaneous leishmaniasis in US military personnel—Southwest/Central Asia, 2002-2004. Morbidity and Mortality Weekly Report 53(12):264-265. CDC. 2004c. Acinetobacter baumannii infections among patients at military medical facilities treating injured US service members, 2002-2004. Morbidity and Mortality Weekly Report 53(45):1063-1066. Davis KA, Moran KA, McAllister CK, Gray PJ. 2005. Multidrug-resistant Acinetobacter extremity infections in soldiers. Emerging Infectious Diseases 11(8):1218-1224. Defense Manpower Data Center. Military Casualty Information. [Online]. Available: http://www.dior.whs.mil/mmid/casualty/castop.htm [accessed March 2006].

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Gulf War and Health: Volume 5. Infectious Diseases Department of the Army. 2005a. Medical Screening of Personnel Mobilized for Deployment or Deployed in Support of Contingency Operations (Predeployment Screening Requirements). Falls Church, VA: Office of the Surgeon General. Department of the Army. 2005b. Release of Actionable Medical Information Policy Memorandum. Fort Sam Houston, TX: Headquarters, United States Army Medical Command. DOD (Department of Defense). 2005. Principal Wars in Which the United States Participated US Military Personnel Serving and Casualties A. [Online]. Available: http://www.dior.whs.mil/mmid/casualty/WCPRINCIPAL.pdf [accessed March 2006]. DOD. 2006a. Individual Medical Readiness. Department of Defense Instruction. Washington, DC. DOD. 2006b. Policy for Pre- and Post-Deployment Serum Collection. Washington, DC: Assistant Secretary of Defense. Donowitz GR, Mandell GL. 2000. Acute pneumonia. In: Mandell GL, Bennett JE, Dolin R, Editors. Principles and Practice of Infectious Diseases. 5th ed. New York: Churchill Livingstone. Pp. 717-743. Ferrante MA, Dolan MJ. 1993. Q fever meningoencephalitis in a soldier returning from the Persian Gulf War. Clinical Infectious Diseases 16(4):489-496. Gasser RA Jr, Magill AJ, Oster CN, Tramont EC. 1991. The threat of infectious disease in Americans returning from Operation Desert Storm. New England Journal of Medicine 324(12):859-864. Gwaltney JM, Jr. 2000a. Acute Bronchitis. In: Mandell GL, Bennett JE, Dolin R, Editors. Principles and Practice of Infectious Diseases. 5th ed. New York: Churchill Livingstone. Pp. 703-706. Gwaltney JM, Jr. 2000b. Sinusitis. In: Mandell GL, Bennett JE, Dolin R, Editors. Principles and Practice of Infectious Diseases. 5th ed. New York: Churchill Livingstone. Pp. 676-686. Haberberger RL, Scott DA, Thornton SA, Hyams KC. 1994. Diarrheal disease aboard a US Navy ship after a brief port visit to a high risk area. Military Medicine 159(6):445-448. Halsey ES, Bryce LM, Wortmann GW, Weina PJ, Ryan JR, DeWitt CC. 2004. Visceral leishmaniasis in a soldier returning from Operation Enduring Freedom. Military Medicine 169(9):699-701. Heymann DL. 2004. Control of Communicable Diseases Manual. Washington, DC: American Public Health Association. Hyams KC. 1999. Gulf War Syndrome: Potential role of infectious diseases. Current Opinion in Infectious Diseases 12(5):439-443. Hyams KC, Bourgeois AL, Merrell BR, Rozmajzl P, Escamilla J, Thornton SA, Wasserman GM, Burke A, Echeverria P, Green KY, et al. 1991. Diarrheal disease during Operation Desert Shield. New England Journal of Medicine 325(20):1423-1428.

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Gulf War and Health: Volume 5. Infectious Diseases Hyams KC, Malone JD, Kapikian AZ, Estes MK, Xi J, Bourgeois AL, Paparello S, Hawkins RE, Green KY. 1993. Norwalk virus infection among Desert Storm troops. Journal of Infectious Diseases 167(4):986-987. Hyams KC, Hanson K, Wignall FS, Escamilla J, Oldfield EC, 3rd. 1995a. The impact of infectious diseases on the health of US troops deployed to the Persian Gulf during operations Desert Shield and Desert Storm. Clinical Infectious Diseases 20(6):1497-1504. Hyams KC, Malone JD, Bourgeois AL, Hawkins R, Hale TL, Murphy JR. 1995b. Serum antibody to lipopolysaccharide antigens of Shigella species among US military peronnel deployed to Saudi Arabia and Kuwait during Operation Desert Storm. Clinical and Diagnostic Laboratory Immunology 2(6):700-703. Hyams KC, Riddle J, Trump DH, Graham JT. 2001a. Endemic infectious diseases and biological warfare during the Gulf War: A decade of analysis and final concerns. American Journal of Tropical Medicine and Hygiene 65(5):664-670. Hyams KC, Smith TC, Riddle J, Trump DH, Gray G. 2001b. Viral hepatitis in the US military: A study of hospitalization records from 1974 to 1999. Military Medicine 166(10):862-865. IOM (Institute of Medicine). 1996. Interaction of Drugs, Biologics, and Chemicals in US Military Forces: Current and Future Issues. Washington, DC: National Academy Press. Johnson KE. 2004. Malaria, US Army, 2003. Medical Surveillance Monthly Report 10(1):6-8. Kelly MT, Brenner DJ, Farmer JJIII. 1985. Enterobacteriaceae. In: Lennette EH, Balows A, Hausler WJ, Jr., Shadomy HJ, Editors. Manual of Clinical Microbiology. 4th ed. Washington, DC: American Society for Microbiology. Pp. 263-277. Kilpatrick ME. 2005. Presentation to IOM Committee on Gulf War and Health: Infectious Diseases. Washington, DC. Kilpatrick ME. 2006. Deployment Health Support Office of the Assistant Secretary of Defense, Health Affairs. Personal Communication. Kotwal RS, Wenzel RB, Sterling RA, Porter WD, Jordan NN, Petruccelli BP. 2005. An outbreak of malaria in US Army Rangers returning from Afghanistan. Journal of the American Medical Association 293(2):212-216. Kreutzer RD, Grogl M, Neva FA, Fryauff DJ, Magill AJ, Aleman-Munoz MM. 1993. Identification and genetic comparison of leishmanial parasites causing viscerotropic and cutaneous disease in soldiers returning from Operation Desert Storm. American Journal of Tropical Medicine and Hygiene 49(3):357-363. Lay JC. 2005. Malaria, US Army, 2004. Medical Surveillance Monthly Report 11(1):7-10. Lew JF, Kapikian AZ, Jiang X, Estes MK, Green KY. 1994. Molecular characterization and expression of the capsid protein of a Norwalk-like virus recovered from a Desert Shield troop with gastroenteritis. Virology 200(1):319-325. Magill AJ. 2005. Leishmaniasis in Veterans of Desert Storm and Iraqi Freedom. Presentation to IOM Committee on Gulf War and Health: Infectious Diseases. Washington, DC.

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Gulf War and Health: Volume 5. Infectious Diseases Magill AJ, Grogl M, Gasser RA Jr, Sun W, Oster CN. 1993. Visceral infection caused by Leishmania tropica in veterans of Operation Desert Storm. New England Journal of Medicine 328(19):1383-1387. Magill AJ, Grogl M, Johnson SC, Gasser RA Jr. 1994. Visceral infection due to Leishmania tropica in a veteran of Operation Desert Storm who presented 2 years after leaving Saudi Arabia. Clinical Infectious Diseases 19(4):805-806. Malone JD, Paparello S, Thornton S, Mapes T, Haberberger R, Hyams KC. 1991. Parasitic infections in troops returning from Operation Desert Storm. New England Journal of Medicine 325(20):1448-1449. Mandell GL, Bennett JE, Dolin R. 2005. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, PA: Elsevier Churchill Livingstone. Martin S, Gambel J, Jackson J, Aronson N, Gupta R, Rowton E, Perich M, McEvoy P, Berman J, Magill A, Hoke C. 1998. Leishmaniasis in the United States military. Military Medicine 163(12):801-807. Matson DO. 2005. Norovirus gastroenteritis in US Marines in Iraq. Clinical Infectious Diseases 40(4):526-527. McCarthy M, Estes MK, Hyams KC. 2000. Norwalk-like virus infection in military forces: Epidemic potential, sporadic disease, and the future direction of prevention and control efforts. Journal of Infectious Diseases 181(2 Suppl):S387-S391. Mikhail MM, Mansour MM, Oyofo BA, Malone JD. 1996. Immune response to Shigella sonnei in US Marines. Infection and Immunity 64(9):3942-3945. Military Vaccine Agency. 2005a. Hepatitis A Infection and Hepatitis A Vaccine. Military Vaccine (MILVAX) Agency, Office of The Army Surgeon General, US Army. Military Vaccine Agency. 2005b. Chickenpox Vaccination Program: Questions and Answers. Military Vaccine (MILVAX) Agency, Office of The Army Surgeon General, US Army. MSMR (Medical Surveillance Monthly Report). 1995. Malaria in active duty soldiers. Medical Surveillance Monthly Report 1(4):9. Ohl CA, Hyams KC, Malone JD, Oldfield E 3rd. 1993. Leishmaniasis among Desert Storm veterans: A diagnostic and therapeutic dilemma. Military Medicine 158(11):726-729. Oldfield EC 3rd, Wallace MR, Hyams KC, Yousif AA, Lewis DE, Bourgeois AL. 1991. Endemic infectious diseases of the Middle East. Reviews of Infectious Diseases 13(3 Suppl)S199-S217. Oster CN, Sanford JP. 1992. Febrile illness in a Desert Storm veteran. Hospital Practice (Office Edition) 27(11):145-148, 151, 155-160. Paparello SF, Garst P, Bourgeois AL, Hyams KC. 1993. Diarrheal and respiratory disease aboard the hospital ship, USNS-Mercy T-AH 19, during Operation Desert Shield. Military Medicine 158(6):392-395. Richards AL, Hyams KC, Merrell BR, Dasch GA, Woody JN, Ksiazek TG, LeDuc JW, Watts DM. 1991. Medical aspects of Operation Desert Storm. New England Journal of Medicine 325(13):970-971.

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Gulf War and Health: Volume 5. Infectious Diseases Richards AL, Hyams KC, Watts DM, Rozmajzl PJ, Woody JN, Merrell BR. 1993a. Respiratory disease among military personnel in Saudi Arabia during Operation Desert Shield. American Journal of Public Health 83(9):1326-1329. Richards AL, Malone JD, Sheris S, Weddle JR, Rossi CA, Ksiazek TG, LeDuc JW, Dasch GA, Hyams KC. 1993b. Arbovirus and rickettsial infections among combat troops during Operation Desert Shield/Desert Storm. Journal of Infectious Diseases 168(4):1080-1081. Rubertone MV, Brundage JF. 2002. The Defense Medical Surveillance System and the Department of Defense serum repository: Glimpses of the future of public health surveillance. American Journal of Public Health 92(12):1900-1904. Sanders JW, Putnam SD, Riddle MS, Tribble DR, Jobanputra NK, Jones JJ, Scott DA, Frenck RW. 2004. The epidemiology of self-reported diarrhea in operations Iraqi freedom and enduring freedom. Diagnostic Microbiology and Infectious Disease 50(2):89-93. Sanders JW, Putnam SD, Frankart C, Frenck RW, Monteville MR, Riddle MS, Rockabrand DM, Sharp TW, Tribble DR. 2005a. Impact of illness and non-combat injury during operations iraqi freedom and enduring freedom (Afghanistan). American Journal of Tropical Medicine and Hygiene 73(4):713-719. Sanders JW, Putnam SD, Riddle MS, Tribble DR. 2005b. Military importance of diarrhea: Lessons from the Middle East. Current Opinion in Gastroenterology 21(1):9-14. Schlagenhauf P. 2003. Malaria in Iraq—the pitfalls of Plasmodium vivax prophylaxis. Lancet Infectious Diseases 3(8):460. Scott P, Artis D, Uzonna J, Zaph C. 2004. The development of effector and memory T cells in cutaneous leishmaniasis: The implications for vaccine development. Immunological Reviews 201:318-338. Smith TC. 2006. Results of IOM Requested Database Search for Infectious Disease Cases During the Gulf War. San Diego, CA: Department of Defense Center for Deployment Health Research, Naval Health Research Center. Smith TC, Corbeil TE, Ryan MA, Heller JM, Gray GC. 2004. In-theater hospitalizations of US and allied personnel during the 1991 Gulf War. American Journal of Epidemiology 159(11):1064-1076. Specht CS, Lewin-Smith MR, Kalasinsky VF, Peterson MR, Mullick FG. 2000. The surgical pathology and cytopathology of US Persian Gulf War military veterans: Identification of diseases endemic to the theater of operations. Archives of Pathology and Laboratory Medicine 124(9):1299-1301. Spudick JM, Garcia LS, Graham DM, Haake DA. 2005. Diagnostic and therapeutic pitfalls associated with primaquine-tolerant Plasmodium vivax. Journal of Clinical Microbiology 43(2):978-981. Stephens I, Nataro JP. 2004. Prevention of enteric diseases. Advances in Experimental Medicine and Biology 549:71-82. Thornton SA, Sherman SS, Farkas T, Zhong W, Torres P, Jiang X. 2005. Gastroenteritis in US Marines during Operation Iraqi Freedom. Clinical Infectious Diseases 40(4):519-525.

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Gulf War and Health: Volume 5. Infectious Diseases Wallace MR, Hale BR, Utz GC, Olson PE, Earhart KC, Thornton SA, Hyams KC. 2002. Endemic infectious diseases of Afghanistan. Clinical Infectious Diseases 34(5 Suppl):S171-S207. Wasserman GM, Martin BL, Hyams KC, Merrill BR, Oaks HG, McAdoo HA. 1997. A survey of outpatient visits in a United States Army forward unit during Operation Desert Shield. Military Medicine 162(6):374-379. Weina PJ, Neafie RC, Wortmann G, Polhemus M, Aronson NE. 2004. Old world leishmaniasis: An emerging infection among deployed US military and civilian workers. Clinical Infectious Diseases 39(11):1674-1680. Willard RJ, Jeffcoat AM, Benson PM, Walsh DS. 2005. Cutaneous leishmaniasis in soldiers from Fort Campbell, Kentucky returning from Operation Iraqi Freedom highlights diagnostic and therapeutic options. Journal of the American Academy of Dermatology 52(6):977-987. Wolf MK, Taylor DN, Boedeker EC, Hyams KC, Maneval DR, Levine MM, Tamura K, Wilson RA , Echeverria P. 1993. Characterization of enterotoxigenic Escherichia coli isolated from US troops deployed to the Middle East. Journal of Clinical Microbiology 31(4):851-856. Writer JV, DeFraites RF, Brundage JF. 1996. Comparative mortality among US military personnel in the Persian Gulf region and worldwide during Operations Desert Shield and Desert Storm. Journal of the American Medical Association 275(2):118-121. Young RC Jr, Rachal RE, Huguley JW 3rd. 1992. Environmental health concerns of the Persian Gulf War. Journal of the National Medical Association 84(5):417-424. Zapor MJ, Moran KA. 2005. Infectious diseases during wartime. Current Opinion in Infectious Diseases 18(5):395-399.

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