Special Article
Diarrheal Disease during Operation Desert Shield
N Engl J Med 1991; 325:1423-1428November 14, 1991
- Abstract
- Abstract
Background.
Under combat conditions infectious disease can become a major threat to military forces. During Operation Desert Shield, there were numerous outbreaks of diarrhea among the U.S. forces. To evaluate the causes of and risk factors for diarrheal disease, we collected clinical and epidemiologic data from U.S. troops stationed in northeastern Saudi Arabia.
Methods.
432 military personnel who presented with diarrhea, cramps, vomiting, or hematochezia. In addition, a questionnaire was administered to 2022 soldiers in U.S. military units located in various regions of Saudi Arabia.
Results.
A bacterial enteric pathogen was identified in 49.5 percent of the troops with gastroenteritis. Enterotoxigenic Escherichia coli and Shigella sonnei were the most common bacterial pathogens. Of 125 E. coli infections, 39 percent were resistant to trimethoprim–sulfamethoxazole, 63 percent to tetracycline, and 48 percent to ampicillin. Of 113 shigella infections, 85 percent were resistant to trimethoprim–sulfamethoxazole, 68 percent to tetracycline, and 21 percent to ampicillin. All bacterial isolates were sensitive to norfloxacin and ciprofloxacin.
After an average of two months in Saudi Arabia, 57 percent of the surveyed troops had at least one episode of diarrhea, and 20 percent reported that they were temporarily unable to carry out their duties because of diarrheal symptoms. Vomiting was infrequently reported as a primary symptom, but of 11 military personnel in whom vomiting was a major symptom, 9 (82 percent) had serologic evidence of infection with the Norwalk virus.
Conclusions.
Gastroenteritis caused by enterotoxigenic E. coli and shigella resistant to a number of drugs was a major problem that frequently interfered with the duties of U.S. troops during Operation Desert Shield. (N Engl J Med 1991;325:1423–8.)
Media in This Article
Table 1
Bacterial Enteropathogens Identified in 432 U.S. Military Personnel with Gastroenteritis.Table 2
Antimicrobial Resistance of Enterotoxigenic E. coli and Shigella Infections.Article Activity
- Article
DIARRHEAL disease has long been a serious problem for military forces, especially during combat.1 2 3 Acute diarrhea continues to be an important cause of morbidity and absence from work among U.S. military personnel who are deployed overseas.4 5 6 7 During Operation Desert Shield, diarrheal disease became a major threat to U.S. military forces.
The U.S. military personnel deployed in Operation Desert Shield lived under widely varying conditions in broadly dispersed geographic locations. Many ground troops slept on cots in tents, or in sleeping bags on the sand or atop equipment. Some military personnel stayed temporarily in warehouses, and others were permanently housed in buildings. Toilet facilities ranged from open trenches to covered wooden latrines and indoor flush toilets. In the field, flies were a constant problem. Under these hurriedly organized living arrangements, substantial efforts were needed to maintain adequate levels of personal hygiene and sanitation. Adding to the hardships were the extremes of weather in northeastern Saudi Arabia, with very hot, humid conditions in late summer and fall and cold, dry weather in December.
Because of the rapid deployment of more than 200,000 military personnel during the initial phase of Operation Desert Shield, an enormous effort was needed to provide sufficient food for the incoming troops. Food was shipped from the United States in cans and frozen containers and as prepackaged meals. Fresh produce was usually obtained from other southwest Asian countries, and dairy products from Saudi Arabia itself. Fresh fruits and vegetables were highly desired by troops who had eaten prepackaged meals for more than a few days. The means of preparing the food varied widely: from the simple heating of prepackaged meals to cooking in field-kitchen tents and large mess halls, where foreign workers were sometimes involved.
The sources of drinking water were less varied. Potable water was generally supplied from reverse-osmosis units run by the U.S. military, from local commercial distributors of bottled water, and from municipal systems providing chlorinated water. The coliform levels in all sources of potable water were routinely measured by U.S. military personnel.
During the initial phase of very rapid preparation for hostilities in late August 1990, large outbreaks of watery diarrhea began among U.S. troops. In September 1990, outbreaks of more severe, bloody diarrhea began. On the basis of numbers of visits to treatment facilities, rates of diarrheal disease of 50 to 100 cases per 1000 soldiers per week were recorded in some units during the initial stage of Operation Desert Shield.8 , 9
In September 1990, the U.S. Naval Medical Research and Development Command established a theater-wide reference laboratory on the northeastern coast of Saudi Arabia. The primary responsibility of this Navy Forward Laboratory was to investigate threats of infectious disease during Operation Desert Shield.
Methods
Clinical Investigation
Between September 22 and December 26, 1990, stool samples and clinical questionnaires were obtained from U.S. troops who had gastroenteritis after arriving in Saudi Arabia. Patients presenting with any of the following symptoms were defined as having gastroenteritis: diarrhea (defined as three or more loose or watery stools within a 24-hour period), abdominal cramps, vomiting, and heraatochezia. Patients with gastroenteritis presenting to field hospitals and medical-aid stations were sequentially investigated on submission of a stool specimen. No attempt was made to screen patients according to particular symptoms, the duration of gastroenteritis, or the use of antibiotic therapy.
Military medical personnel were encouraged to submit stool specimens from patients with gastroenteritis. Although transportation was a major limitation, specimens were obtained from all branches of the military and from various regions of northeastern Saudi Arabia.
Laboratory Analyses
Stool samples were usually processed within four hours of collection in stool cups; otherwise, samples were placed in Cary—Blair transport medium (n = 59). Stool samples were cultured for Escherichia coli, salmonella, shigella, aeromonas, plesiomonas, yersinia, vibrio species, and campylobacter, as previously described.10 , 11 Bacterial enteropathogens were identified with standard methods.12 , 13
To provide clinically useful information about enterotoxigenic E. coli while outbreaks of diarrhea were occurring, five lactose-fermenting and up to five non—lactose-fermenting E. coli—like organisms from each patient's stool were tested for heat-labile and heat-stable toxin with alkaline phosphatase—conjugated oligonucleotide DNA probes (Molecular Biosystems, San Diego, Calif.).11 A duplicate set of E. coli isolates was sent to the U.S. Armed Forces Research Institute of Medical Sciences in Bangkok, Thailand, and tested within two months of collection for the production of heat-labile toxin and heat-stable toxin in the Y-1 adrenal-cell and suckling-mouse assays, respectively.14 , 15 All enterotoxigenic E. coli results reported here are based on Y-1 adrenal-cell and suckling-mouse assays.
E. coli—like isolates were also tested in Bangkok with DNA probes to identify enteroinvasive E. coli, enteropathogenic E. coli adhesion factor, and isolates containing genes coding for shiga-like toxins 1 and 2.16 Isolates that hybridized with the enteroinvasive E. coli probe were separated according to species and examined in the Sereny test.17
During the initial outbreaks of diarrheal disease in September, 12 heads of lettuce were obtained from food-distribution facilities and examined for coliforms by standard methods.18 E. coli—like isolates from lettuce samples were tested for the production and hybridization of heat-labile toxin and heat-stable toxin with the DNA probes listed above.
The antimicrobial susceptibility of bacterial enteropathogens was determined by the disk diffusion test.19 Susceptibility to the antimicrobial agents most often available for the treatment of diarrhea — including trimethoprim–sulfamethoxazole, tetracycline, ampicillin, norfloxacin, and ciprofloxacin — was evaluated. Plasmid profiles of Shigella sonnei isolates were determined by the method of Birnboim and Doly.20 Plasmid profiles were also compared after digestion with the restriction endonucleases BamHI and EcoRI.
Stool samples were examined for parasites by direct microscopy after fixation in polyvinyl alcohol and staining with Lugol's iodine solution. Stool specimens were examined for group A rotavirus in Saudi Arabia with a commercial monoclonal antibody—based immunoassay (Rotaclone, Cambridge Bioscience, Worcester, Mass.).
Stool samples collected in November and December from 19 patients with vomiting and diarrhea and from an additional 68 patients with diarrhea but no vomiting were examined in the United States (at the National Institutes of Health) for rotavirus, adenovirus (Adenoclone, Cambridge Bioscience), and Norwalk virus by enzyme immunoassay.21 22 23 24 25 In addition, stools (10 percent suspensions) from a subgroup of 31 of these 87 patients were examined for viral enteropathogens by immune electron microscopy, with human serum immunoglobulin (1:10 dilution) as the source of antibody, as described previously.25 , 26
Paired serum samples from the acute and convalescent phases of disease in 2 of the 19 patients with vomiting and diarrhea and from an additional 9 patients with vomiting only (no stool specimen available) were evaluated for a fourfold or greater increase in serum antibody to Norwalk virus on a blocking enzyme immunoassay, to rotavirus on an IgA antibody—detecting enzyme immunoassay, to rotavirus ("O" agent) or adenovirus on complement-fixation test; and by an antigen-detection enzyme immunoassay for circulating staphylococcal and Clostridium perfringens enterotoxin.21 , 22 , 24 , 27 Because the nine patients with vomiting only did not submit stool samples, they were not included in the overall clinical analysis of the study participants who submitted stool specimens.
Epidemiologic Survey
To determine the overall prevalence of diarrhea during Operation Desert Shield, a questionnaire was administered to male military personnel assigned to five U.S. units deployed in Saudi Arabia. Military units from various geographic areas in northeastern Saudi Arabia living under different conditions were selected to obtain a diverse sample. More than 95 percent of the men in the units participated in the survey.
Survey participants were asked about the occurrence of diarrhea and associated symptoms since their arrival in Saudi Arabia. Diarrhea was defined as three or more loose or watery stools within a 24-hour period. To evaluate potential risk factors for transmission, military personnel were asked where they obtained food and water and whether they had eaten lettuce.
Statistical Analysis
Mean (±SD) values were compared with use of Student's t-test; proportions were compared with use of the chi-square test with Yates' correction or Fisher's exact test. Unconditional multiple logistic-regression analysis was performed with use of the SPSS/PC statistical package (SPSS, Chicago). Logistic models were developed by the maximum-likelihood method. The outcome variable for all logistic models was the occurrence of any episode of diarrhea, coded as a dichotomous variable. Confidence intervals were calculated by the method of Woolf for univariate analysis and with the use of logistic-regression parameter estimates and their standard errors for multivariate analysis.28 A two-tailed P value of 0.05 was considered to indicate statistical significance.
Results
Clinical Investigation
Stool samples were collected from 432 U.S. soldiers with gastroenteritis. Their mean age was 25.9 years (range, 19 to 59); 93 percent were men, and 87 percent were from the enlisted ranks. The patients had symptoms of gastroenteritis for a mean of 4.1 days before collection of the sample, and they reported a mean of 6.9 stools during the preceding 24 hours. Twenty percent of the soldiers had received antimicrobial therapy before the sample was submitted.
A bacterial enteric pathogen was identified in 214 patients (49.5 percent), 36 of whom had mixed infections with more than one pathogen (Table 1Table 1
Bacterial Enteropathogens Identified in 432 U.S. Military Personnel with Gastroenteritis.). Enterotoxigenic E. coli and S. sonnei were the most common enteric pathogens: enterotoxigenic E. coli was found in 21 percent of the patients and shigella in 19 percent as a single infection, and dual infections with E. coli and shigella were found in 7 percent of the patients. No Salmonella typhi, Vibrio cholerae, Giardia lamblia, Entamoeba histolytica, or other intestinal parasites were identified in any stool sample. One stool specimen tested in Saudi Arabia was positive for rotavirus. Coliforms were detected in all 12 heads of lettuce examined, and enterotoxigenic E. coli producing heat-labile toxin and heat-labile—heat-stable toxin were identified in two samples.The prevalence of shigella may have been underestimated in 59 patients with samples submitted in Cary—Blair medium, since shigella was only isolated from 3 (5 percent) of these patients, as compared with 30 percent of the patients submitting actual stool samples. There was no difference in the isolation of enterotoxigenic E. coli between the two types of samples. Bacterial enteropathogens were identified in similar percentages of patients with diarrhea and patients with gastrointestinal symptoms without diarrhea.
A bacterial pathogen was found in 48 percent of the patients who reported taking antibiotics and in 51 percent of the patients who had not received antimicrobial therapy. The percentage of stool samples from which a bacterial enteropathogen was identified was lower among the 33 patients reporting previous quino-lone therapy than among the 31 patients who reported receiving trimethoprim–sulfamethoxazole (27 percent vs. 68 percent, respectively; P = 0.003).
In a high percentage of infections with enterotoxigenic E. coli and shigella, resistance to trimethoprim–sulfamethoxazole, tetracycline, and ampicillin was found (Table 2Table 2
Antimicrobial Resistance of Enterotoxigenic E. coli and Shigella Infections.). Among 125 enterotoxigenic E. coli infections, 17 percent involved isolates resistant to two of these antimicrobial agents, and 30 percent isolates resistant to all three. Among 113 shigella infections, 54 percent involved isolates resistant to two and 13 percent isolates resistant to three of the agents. All bacterial enteropathogens were sensitive to norfloxacin and ciprofloxacin. There was no increase in the frequency of multiple-drug resistance among isolates recovered from patients who had received antimicrobial therapy.S. sonnei isolates exhibited two common patterns of antimicrobial susceptibility: isolates in one group of 46 patients were resistant to both trimethoprim–sulfamethoxazole and tetracycline and sensitive to ampicillin, and isolates in another group of 22 patients were resistant to trimethoprim–sulfamethoxazole and sensitive to tetracycline and ampicillin. The patterns clustered predominantly in two locations that were more than 80 km (50 miles) apart and had separate dining facilities. The plasmid profiles of 31 randomly chosen S. sonnei isolates also differed between these two locations, varying primarily in the range of 3 to 7 kilobases (kb). Fourteen of the 17 isolates from one location carried 3-kb and 7-kb plasmids, whereas all 14 isolates from the other location carried only a single 5-kb plasmid. The susceptibility patterns of enterotoxigenic E. coli isolates did not vary according to geographic location.
When patients whose stools were positive for shigella or enterotoxigenic E. coli as the sole pathogen were compared, fever (80 percent vs. 25 percent) and reports of being unable to work (64 percent vs. 21 percent) were more often found in troops infected with shigella (P<0.001 for both comparisons).
Vomiting was seldom reported as a primary symptom in this population, except for 19 cases of vomiting and diarrhea that occurred in November and December. These cases were not clustered according to camp location but were dispersed in various military units. Stool samples from 3 of the patients were positive for Norwalk virus on enzyme immunoassay; the stools from all 19 were negative for group A rotavirus on confirmatory enzyme immunoassay and for adenovirus on commercially available enzyme immunoassay. Stool samples from a comparison group of 68 patients who presented during the same period with diarrhea but without vomiting were negative for Norwalk virus, rotavirus, and adenovirus.
Stools from 13 of the 19 patients with vomiting and diarrhea and 18 of the 68 patients with diarrhea but no vomiting were examined by immune electron microscopy; 4 contained particles that were morphologically similar to the Norwalk virus. Three of the four particle-positive stools were from the 13 patients in the group with vomiting and diarrhea, and these three had been positive for Norwalk virus on enzyme immunoassay. The fourth particle-positive stool was from 1 of the 18 patients in the group without vomiting; it had been negative for Norwalk virus on enzyme immunoassay. There was no evidence of infection with rotavirus, adenovirus, calicivirus, astrovirus, or coronavirus-like agents on immune electron microscopy in any of the 31 stools. Serum samples collected during the acute and convalescent phases of disease in 9 (82 percent) of 11 patients (2 with vomiting and diarrhea and 9 with vomiting alone) demonstrated a fourfold or greater increase in antibody to Norwalk virus (Table 3Table 3
Serologic Response to Norwalk Virus as Measured by a Blocking Antibody Immunoassay in 11 Patients with Vomiting and Diarrhea.). Stools were available from only 2 of these 11 patients, both of whom had a serologic response to Norwalk virus; 1 of the 2 patients shed the Norwalk virus. Antibody responses to group A rotavirus and adenovirus were not observed in these 11 patients, and all were negative for circulating staphylococcal and C. perfringens enterotoxins.Epidemiologic Survey
A total of 2022 men were surveyed by questionnaire between October and December 1990. Their mean (±SD) age was 26±6 years (range, 18 to 52), and 86 percent belonged to the enlisted ranks. They had been in Saudi Arabia for a mean of 55±19 days (range, 4 to 120).
At least one episode of diarrhea was reported by 57 percent of these troops. Two or more separate episodes of diarrhea were reported by 32 percent. The prevalence of diarrhea ranged from 36 to 81 percent in the five military units. Of the entire population surveyed, 17 percent reported fever with diarrhea, 22 percent had sought medical care because of diarrhea, and 20 percent stated that they had been unable to work because of diarrheal symptoms; there was a significant association among these three findings (P<0.001 for each two-way comparison).
There was no significant difference between the age and rank of the soldiers with diarrhea and those without. Those who reported an episode of diarrhea had been deployed for a longer period than those who had not had diarrhea (60 vs. 48 days, P<0.001). Among the troops who had been in Saudi Arabia for more than 51 days (the median length of deployment), 71 percent reported an episode of diarrhea.
In univariate analysis of the potential risk factors for the transmission of diarrheal disease, an association was suggested between an episode of diarrhea and eating salad, dining in a mess hall, and drinking from a canteen. No association was found for obtaining food from local vendors, eating in a local restaurant, or drinking bottled water (Table 4Table 4
Odds of Having an Episode of Diarrhea, According to Potential Risk Factors for Transmission in a Survey of 2022 U.S. Soldiers.*).Logistic-regression analysis was used to control for the duration of deployment. When we evaluated the potential risk factors individually while controlling for the length of deployment, we found that eating in a local restaurant was inversely associated with having diarrhea, and drinking from a canteen was positively associated (Table 4). When we performed logistic analysis using a forward selection process to evaluate all potential risk factors for the transmission of diarrhea in a single model while adjusting for the duration of deployment, the same risk factors were again found to be significant.
Discussion
Diarrhea due to enterotoxigenic E. coli and shigella resistant to multiple drugs was a serious problem for U.S. troops in Operation Desert Shield. More than half the surveyed troops reported at least one episode of diarrhea. For approximately 20 percent of them, diarrhea interfered with work and resulted in a medical visit.
As in other studies of diarrhea in travelers, enterotoxigenic E. coli was found to be a major cause.29 , 30 In addition, shigellosis was common and resulted in more severe morbidity and time away from duty than enterotoxigenic E. coli infection. It was not possible to determine which infection was the more common overall cause of gastroenteritis in U.S. troops. However, the fact that 83 percent of those with diarrhea in our epidemiologic survey did not report fever suggests that enterotoxigenic E. coli predominated. Had the troops been deployed at another time of year, other enteropathogens might have been more important.
Norwalk virus appeared to be the principal etiologic agent in the troops with vomiting. Several large outbreaks of acute vomiting were reported in separate military units during November and December 1990, indicating that Norwalk virus may have been a widespread cause of gastroenteritis during the cooler months of Operation Desert Shield. Viral causes of gastroenteritis have previously been found in soldiers deployed to areas with temperate climates.6 , 31 The greater efficiency of serology over antigen detection in demonstrating Norwalk virus infection is consistent with the results of other studies.32
The high levels of antimicrobial resistance unrelated to current antibiotic therapy that we found reflect the increase in resistance to drugs commonly used to treat acute diarrhea.33 , 34 Susceptibility patterns among the strains of shigella and E. coli isolated from Operation Desert Shield troops were comparable to those previously reported from the Middle East.3 , 35 36 37 38
During the early stages of deployment, trimethoprim–sulfamethoxazole was the drug most often used to treat diarrhea; clinical response was inconsistent, however, perhaps because of the high levels of antimicrobial resistance.39 , 40 Because nearly all patients appeared to respond rapidly to norfloxacin or ciprofloxacin, these agents became the drugs of choice. Although fluid replacement was the primary treatment for diarrhea, quinolone drugs were widely used to shorten the duration of gastrointestinal symptoms in critical combat troops.41
Uncooked vegetables, particularly lettuce, were suspected sources of enteric disease pathogens during the early phases of Operation Desert Shield. Foreign workers were considered unlikely sources of infection since they were not employed in most food-preparation facilities. This hypothesis was supported by the identification of enterotoxigenic E. coli in cultures of lettuce and by the fact that contaminated lettuce has been implicated in previous outbreaks of enterotoxigenic E. coli, shigellosis, and Norwalk virus infection.42 43 44 45 There were a number of sources of infection for these outbreaks of diarrhea, as indicated by the different sero-groups, patterns of antibiotic susceptibility, and plasmid profiles of shigella in various geographic locations.
When large outbreaks of diarrhea began, raw vegetables were usually removed from the diet, or more effective techniques of disinfection were instituted. However, enterotoxigenic E. coli and shigella continued to cause diarrhea and appeared to be transmitted endemically. Flies and less attention to personal hygiene because of living in the field may have been important in the spread of enterotoxigenic E. coli and shigella as endemic infections.46 , 47
Multivariate analysis of the survey data suggested a protective effect of eating in local restaurants and a positive risk in drinking out of a canteen. These findings of risk are inconsistent with known modes of transmission of diarrheal disease and probably represent surrogate markers of general levels of hygiene. Only troops stationed in more permanent housing in larger cities with modern sanitation had access to local restaurants. These soldiers therefore lived in relatively better facilities that provided a higher level of hygiene and less risk of transmission of diarrheal disease. In contrast, soldiers drinking out of canteens were more likely to be living in the field, with a lower level of hygiene and a higher risk of infection.
Preventing infectious diseases was a priority for all branches of the U.S. military during Operation Desert Shield. Nevertheless, despite extensive efforts to secure a safe supply of food and water and a high level of sanitation, there were epidemics of infectious diarrhea, as there have been throughout history when large numbers of soldiers are deployed. Because epidemic diarrhea may potentially compromise the capabilities of the U.S. military during critical periods, effective vaccines are needed to prevent the disease.
Supported by the U.S. Naval Medical Research and Development Command (62770A–3M162770.A870.AR122 and 62770A–3M162770.A870.AR) and the U.S. Army Medical Research and Development Command (623002.810.AB).
The opinions and assertions contained herein are those of the authors and are not to be construed as official or as reflecting the views of the departments of the Navy, Army, or Defense.
We are indebted to the U.S. Navy Central Command Medical Officer, Capt. T. Cook, and his entire staff in Bahrain; Capt. M. Kilpatrick and the entire staff of the U.S. Naval Medical Research Unit No. 3, Cairo; Capt. F. Daniell and HMC C. Lauxman, U.S. Navy Environmental and Preventive Medicine Unit No. 7, Naples; and Capt. R. Walker, U.S. Naval Medical Research Institute, Bethesda, for critical administrative and logistic support during the entire operation; HM2 C. Houston and HM1 J. Huettner for their laboratory assistance in Saudi Arabia; to the personnel of the U.S. 1st Medical Battalion, 1st Force Service Support Group, 1st Marine Expeditionary Force, for their help in establishing the Navy Forward Laboratory; and to M. Wagner, C. Banks, E. Williams, J. Jackson, and J. Valdesuso for excellent technical assistance.
Source Information
From the Epidemiology Division, U.S. Naval Medical Research Institute, Bethesda, Md. (K.C.H., B.R.M.); the Epidemiology Division, U.S. Naval Medical Research Unit No. 3, Cairo, Egypt (A.L.B., S.A.T.); the U.S. Navy Environmental and Preventive Medicine Unit No. 7, Naples, Italy (P.R.); the U.S. Naval Medical Research Institute Detachment, Lima, Peru (J.E.); the Department of Pediatrics, William Beaumont Army Medical Center, El Paso, Tex. (G.M.W.); the Preventive Medicine Service, U.S. Army Medical Department Activity, Fort Campbell, Ky. (A.B.); the Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand (P.E.); the Laboratory of Infectious Diseases, National Institutes of Health, Bethesda, Md. (K.Y.G., A.Z.K.); and the U.S. Naval Medical Research and Development Command, Bethesda, Md. (J.N.W.). Address reprint requests to Dr. Hyams at the Naval Medical Research Institute, 12300 Washington Ave., Rockville, MD 20852.
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