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Incidence, Etiology, and Impact of Diarrhea among long-term travelers (US Military and Similar Populations): A Systematic Review
Abstract
To determine regional estimates of pathogen-specific prevalence and incidence, as well as, describe morbidity associated with diarrhea among deployed US military and similar populations, a systematic review was conducted for publications between January 1990 to June 2005. Point estimates and confidence intervals of pathogen prevalence and travelers' diarrhea incidence were combined in a random effects model and assessed for heterogeneity. In total, 262 studies were identified for potential inclusion, of which 52 fulfilled inclusion criteria. Overall, 38% were from the Middle East, 29% from Southeast Asia, 27% from Latin America/Caribbean, and 6% from sub-Saharan Africa. Median duration of travel was 1.5 months (interquartile range, 1-3 months). Enterotoxigenic Escherichia coli (ETEC), Campylobacter, and Shigella were identified as causing 38-45% of diarrhea, with regional and population differences. Incidence based on self-report was higher than studies using passive surveillance or clinic-based methods (29 versus 7 versus 6 episodes per 100 person-months, respectively) without regional differences.
Supplementary resource (1)
Data
December 2012
... Although TD in most cases resolves spontaneously within a few days without treatment and is unlikely to be fatal, it has a significant impact on quality of life and economics of healthcare service use, travel change expenses, loss of man-hours, and changes of vacation or business plans [4,5]. As many as 40% of TD cases modify their activities, 23% seek medical treatment, and 1% require hospitalization [5][6][7][8]. ...
... However, significant regional variations in pathogen distributions have been reported. In Southeast Asia, Campylobacter (32.4%) and Enteropathogenic E. coli (EPEC) (18.0%) have been isolated most frequently, and multiple pathogen infections are apparently more common than in other regions [8,9]. More detailed knowledge of regional pathogen distribution may enable more accurate predictions of vaccine-preventable disease and may also have implications for empiric treatment and pre-travel health advice. ...
... Isolation percentages for Shigella, Salmonella, Aeromonas, ETEC, EIEC, Giardia, Cryptosporidium, and rotavirus were within three percentage points of the Southeast Asian regional estimates from Shah et al. [9]. Our data also supports Riddle's finding that TD cases in Southeast Asia have a high risk of co-infection [8]. Unlike in Nepal, protozoa appear to cause little traveler's diarrhea in travelers to Thailand [31], and cases with protozoa detected in this study were mainly associated with travel to a high-risk destination prior to visiting Thailand. ...
Background:
Traveler's diarrhea (TD) is a common health problem among visitors from developed to developing countries. Although global and regional estimates of pathogen distribution are available, the etiology of diarrhea among non-military travelers to Thailand is largely unknown.
Methods:
A prospective TD case-control study was conducted among adult travelers from developed countries at a prominent hospital in Bangkok, Thailand during 2001-2003. Stool samples were collected from acute TD cases and non-diarrheal controls and analyzed for bacterial, viral, and protozoan pathogens by microbiology, ELISA or PCR methods. Calculation of adjusted odd ratios for risk factors was performed by logistic regression using STATA statistical software.
Results:
Stool samples were collected and analyzed from 389 TD cases and 400 non-diarrhea controls. At least one pathogen was detected in 227 (58%) cases and 124 (31%) controls. Plesiomonas (14%), Vibrio (14%), Campylobacter (14%), and norovirus (12%) were the most frequently isolated pathogens among cases and significantly associated with diarrhea at p = 0.006, p < 0.001, p < 0.001, p < 0.001, respectively. Shigella (3%) and ETEC (8%), detected in lower prevalence, also showed significant association with TD at p < 0.001 and p = 0.002, respectively. Travelers from East Asian countries had an increased risk of Vibrio infection (Crude odds ratio: 3.1, p-value = 0.001); travelers from the United States, Canada, and Europe had an increased risk of Campylobacter infection (Crude odds ratio: 2.6, p-value = 0.001); and travelers from Australia and New Zealand had an increased risk of Salmonella infection (Crude odds ratio: 3.2, p-value = 0.009).
Conclusions:
Etiology of TD in Thailand is mainly of bacterial origin. Plesiomonas, Vibrio, and norovirus are underappreciated diarrheagenic pathogens. In our study, the origin of the traveler plays an important role in diarrhea etiology. Understanding variations in TD severity and etiology among travelers from different regions warrants further study.
... While most cases are self-limited and do not require targeted therapy, enteric illnesses account for an estimated annual cost of $93.2 billion [1]. In contrast, among travelers to developing countries, the rate of acute enteric disease has been historically much higher, with an estimated attack rate of 29% per month [2]. In addition, bacteria predominate as the cause of acute illness, with diarrheagenic E. coli, Campylobacter spp., and Shigella spp. ...
... representing the most commonly isolated pathogens [3][4][5]. And while rates of travelers' diarrhea (TD) among short-term travelers (less than one month) may be decreasing [6], we previously reported unchanged rates of disease among long-term travelers [2]. ...
... Our 2006 systematic review highlighted the incidence, etiology, and impact of travelers' diarrhea among US military personnel and similar travelers [2]. Since that time major changes to the pattern and tempo of military deployment and multiple new studies of TD in this population necessitate an update to the prior systematic review to include studies published since 2005 and better describe regional estimates of diarrheal disease incidence, pathogen-specific prevalence, and management options and morbidity among long-term travelers, including deployed US military personnel and similar populations. ...
Background
Travelers’ diarrhea remains a prevalent illness impacting individuals visiting developing countries, however most studies have focused on this disease in the context of short term travel. This study aims to determine the regional estimates of travelers’ diarrhea incidence, pathogen-specific prevalence, and describe the morbidity associated with diarrheal disease among deployed military personnel and similar long term travelers.
Methods
We updated a prior systematic review to include publications between January 1990 and June 2015. Point estimates and confidence intervals of travelers’ diarrhea and pathogen prevalence were combined in a random effects model and assessed for heterogeneity. Eighty-two studies were included in the analysis, including 29 new studies since the prior systematic review.
Results
Military personnel were evaluated in 69% of studies and non-military long term travelers in 34%, with a median duration of travel of 4.9 months, and travel predominantly to the Middle East, Southeast Asia, and Latin America and the Caribbean. Sixty-two percent of tested cases were due to bacterial pathogens, with enterotoxigenic E. coli (ETEC), enteroaggregative E. coli (EAEC), and Campylobacter predominating, and significant regional variability. The incidence of TD from studies with longitudinal data was 36.3 cases per 100 person-months, with the highest rates in Southeast Asia, Latin America and the Caribbean, and the Middle East, with higher estimates from those studies using self-reporting of disease. Morbidity remained significant, with 21% being incapacitated or placed sick in quarters (SIQ) by their illness, 15% requiring intravenous fluids, and 3% requiring hospitalization.
Conclusions
In comparison to results from the prior systematic review, there were no significant differences in incidence, pathogen prevalence, or morbidity; however there was a trend toward improved care-seeking by sick individuals.
... Significant mortality and morbidity in pediatric populations in low-to middle-income countries (LMICs), and are also caused by adult travelers to those same regions, is also caused by C. jejuni-attributed illness (Elaine Scallan et al., 2011;Platts-Mills et al., 2015;Olson et al., 2019). One group of travelers that is often at risk for campylobacteriosis, as well as other enteric diseases, is deployed military (Riddle et al., 2006). In fact, acute diarrhea is the leading infectious disease threat to deployed U.S. forces (Riddle et al., 2017). ...
... In fact, acute diarrhea is the leading infectious disease threat to deployed U.S. forces (Riddle et al., 2017). A recent study of deploying Air Force personnel noted that over 50 percent of study participants who deployed to the Middle East had at least one diarrheal incident while on deployment, consistent with multiple systematic reviews highlighting a high incidence of diarrhea in deploying populations (Riddle et al., 2006;Porter et al., 2017b;Olson et al., 2019;Stamps et al., 2020). One of the leading etiologies of diarrhea in military populations is C. jejuni, accounting for approximately 10% of all acute diarrheal illness (Connor et al., 2012). ...
Campylobacter jejuni infection is a leading cause of foodborne disease, common to children, adult travelers, and military populations in low- to middle-income countries. In the absence of a licensed vaccine, efforts to evaluate prophylactic agents are underway. The prophylactic efficacy of a twice-daily, 550 mg dose of the antibiotic rifaximin demonstrated no efficacy against campylobacteriosis in a controlled human infection model (CHIM); however, samples from the CHIM study were utilized to assess how the human gut microbiome responds to C. jejuni infection, and if a ‘protective’ microbiota exists in study participants not developing campylobacteriosis. Statistically significant, but minor, differences in study participant beta diversity were identified during the challenge period (p = 0.002, R ² = 0.042), but no significant differences were otherwise observed. Pre-challenge alpha diversity was elevated in study participants who did not develop campylobacteriosis compared to those who did (p < 0.001), but alpha diversity declined in all study participants from the pre-challenge period to post-discharge. Our work provides insight into gut microbiome shifts observed during a C. jejuni CHIM and following antibiotic treatment. This study utilized a high dose of 1.7 x 10 ⁵ colony-forming units of C. jejuni ; future work could include CHIM studies performed with inocula more closely mimicking natural exposure as well as field studies involving naturally-occurring enteric infections.
... 27 Our findings of no pathogen detected in 41% of samples agree with previous studies using stool samples collected during acute illness. 4 Regional differences of pathogen recovery reflect previous work as well, 24,28 with the highest pathogen recovery found in Southeast Asia and the next highest pathogen recovery found in South Asia. For locations with high numbers of no pathogen detections, the lack of detection could indicate that some etiologies are not being tested for, such as emerging pathogens or toxins that could play a meaningful role in clinical manifestations of TD. 25 Multiple-pathogen infections were not uncommon (16%), especially among travelers enrolled in the Asian countries participating in our study. ...
... Nepal may be a riskier area, in general, for TD, as previous work has shown that travel to Nepal has a higher association with TD than other countries, both regionally and globally. 31,32 It has also been found that studies of TD in U.S. military populations had higher pathogen detection than those conducted in nonmilitary individuals, 28 although we did not find this in our study. Although reasons for this are not completely clear, the comparatively lower proportions of U.S. military with pathogen detections (53%) in our study might have been related to the high percentage (83%) of U.S. military who were enrolled in Honduras, the country with the highest percentage of no pathogen detections. ...
The U.S. military personnel must be ready to deploy to locations worldwide, including environments with heightened risk of infectious disease. Diarrheal illnesses continue to be among the most significant infectious disease threats to operational capability. To better prevent, detect, and respond to infectious disease threats and improve synchronization across the Department of Defense (DoD) overseas laboratory network, a multisite Global Travelers' Diarrhea protocol was implemented with standardized case definitions and harmonized laboratory methods to identify enteric pathogens. Harmonized laboratory procedures for detection of Norovirus (NoV), enterotoxigenic Escherichia coli (ETEC), enteroaggregative E. coli, Shiga toxin-producing E. coli, enteropathogenic E. coli, Salmonella enterica, Shigella/enteroinvasive E. coli, and Campylobacter jejuni have been implemented for six DoD laboratories with surveillance sites in Egypt, Honduras, Peru, Nepal, Thailand, and Kenya. Samples from individuals traveling from wealthy to poorer countries were collected between June 2012 and May 2018, and of samples with all variables of interest available (n = 410), most participants enrolled were students (46%), tourists (26%), U.S. military personnel (13%), or other unspecified travelers (11%). One or more pathogens were detected in 59% of samples tested. Of samples tested, the most commonly detected pathogens were NoV (24%), ETEC (16%), and C. jejuni (14%), suggesting that NoV plays a larger role in travelers' diarrhea than has previously been described. Harmonized data collection and methods will ensure identification and characterization of enteric pathogens are consistent across the DoD laboratory network, ultimately resulting in more comparable data for global assessments, preventive measures, and treatment recommendations.
... Infectious diarrhea causes significant acute morbidity and mortality in infants and young children in low-middle income countries (LMICs), and substantial morbidity in travelers to these areas [1][2][3][4][5]. Enterotoxigenic Escherichia coli (ETEC) are among the leading bacterial causes of disease in these populations. ...
... Enterotoxigenic Escherichia coli (ETEC) are among the leading bacterial causes of disease in these populations. In travelers, ETEC account for 30%-50% of diarrhea in many developing areas, with incidence rates as high as 0.5 episodes per person over 1-2 weeks of initial exposure [1,2,5]. In LMICs, ETEC ranks among the top 5 causes of moderate to severe diarrhea. ...
Background:
Enterotoxigenic Escherichia coli (ETEC) commonly cause diarrhea in children living in developing countries and in travelers to those regions. ETEC are characterized by colonization factors (CFs) that mediate intestinal adherence. We assessed if bovine colostral IgG (bIgG) antibodies against a CF, CS17, or antibodies against CsbD, the minor tip subunit of CS17, would protect subjects against diarrhea following challenge with a CS17-expressing ETEC strain.
Methods:
Adult subjects were randomized (1:1:1) to receive oral bIgG against CS17, CsbD, or placebo. Two days prior to challenge, subjects began dosing 3 times daily with the bIgG products (or placebo). On day 3, subjects ingested 5 × 109 cfu ETEC strain LSN03-016011/A in buffer. Subjects were assessed for diarrhea for 120 hours postchallenge.
Results:
A total of 36 subjects began oral prophylaxis and 35 were challenged with ETEC. While 50.0% of the placebo recipients had watery diarrhea, none of the subjects receiving anti-CS17 had diarrhea (P = .01). In contrast, diarrhea rates between placebo and anti-CsbD recipients (41.7%) were comparable (P = 1.0).
Conclusions:
This is the first study to demonstrate anti-CS17 antibodies provide significant protection against ETEC expressing CS17. More research is needed to better understand why anti-CsbD was not comparably efficacious. Clinical Trials Registration. NCT00524004.
... 1,4 Shigella and ETEC are among the leading causes of diarrhoea in children and adults in LMICs, and among travellers and military personnel from high-income countries. [5][6][7][8][9][10][11] The detection of bacterial pathogens, especially shigella, through conventional approaches was, in the past, restricted by inconsistent diagnostic accuracy and inaccurate surveillance methods. The use of realtime PCR diagnostics has substantially improved the detection of shigella and ETEC pathogens and, therefore, has increased the fraction of moderate and severe diarrhoea cases that are attributable to these pathogens. ...
... 19 A systematic review suggests that ETEC was detected in 30·4% of cases of diarrhoea in travellers, with the highest rates seen in those travelling to areas with a high prevalence of ETEC. 11 Although shigellosis occurs worldwide, the greatest burden is among children in low-income countries. Repeated infection is not uncommon because of the multiple serotypes associated with illness, and the decrease in the incidence of disease with increasing age shows that immunity eventually develops. ...
Background:
Shigella and enterotoxigenic Escherichia coli (ETEC) are bacterial pathogens that are frequently associated with diarrhoeal disease, and are a significant cause of mortality and morbidity worldwide. The Global Burden of Diseases, Injuries, and Risk Factors study 2016 (GBD 2016) is a systematic, scientific effort to quantify the morbidity and mortality due to over 300 causes of death and disability. We aimed to analyse the global burden of shigella and ETEC diarrhoea according to age, sex, geography, and year from 1990 to 2016.
Methods:
We modelled shigella and ETEC-related mortality using a Bayesian hierarchical modelling platform that evaluates a wide range of covariates and model types on the basis of vital registration and verbal autopsy data. We used a compartmental meta-regression tool to model the incidence of shigella and ETEC, which enforces an association between incidence, prevalence, and remission on the basis of scientific literature, population representative surveys, and health-care data. We calculated 95% uncertainty intervals (UIs) for the point estimates.
Findings:
Shigella was the second leading cause of diarrhoeal mortality in 2016 among all ages, accounting for 212 438 deaths (95% UI 136 979-326 913) and about 13·2% (9·2-17·4) of all diarrhoea deaths. Shigella was responsible for 63 713 deaths (41 191-93 611) among children younger than 5 years and was frequently associated with diarrhoea across all adult age groups, increasing in elderly people, with broad geographical distribution. ETEC was the eighth leading cause of diarrhoea mortality in 2016 among all age groups, accounting for 51 186 deaths (26 757-83 064) and about 3·2% (1·8-4·7) of diarrhoea deaths. ETEC was responsible for about 4·2% (2·2-6·8) of diarrhoea deaths in children younger than 5 years.
Interpretation:
The health burden of bacterial diarrhoeal pathogens is difficult to estimate. Despite existing prevention and treatment options, they remain a major cause of morbidity and mortality globally. Additional emphasis by public health officials is needed on a reduction in disease due to shigella and ETEC to reduce disease burden.
Funding:
Bill & Melinda Gates Foundation.
... Shigellosis is a leading cause of diarrhoeal disease worldwide, but particularly in LMICs [54]; it is also a continuing problem for travellers visiting these regions [55,56]. Recent estimates put the number of deathsdmostly among children in LMICsdat approxi- mately 164,000 [54]. ...
... ETEC, one of several pathotypes of diarrhoeagenic E. coli, causes a secretory diarrhoea that can range in presentation from mild discomfort to a cholera-like illness. It is a highly prevalent bacterial cause of childhood diarrhoea in LMICs [76], with recent under-5 mortality estimates ranging between 7000 and 76,000 per year [77], and a leading cause of travellers' diarrhoea (30e50% of cases) [55,56,78,79]. As with Shigella, its dual importance in global public health and travel medicine has galvanized efforts to develop a safe and effective ETEC vaccine. ...
Background:
Acute diarrheal disease caused by viral, bacterial and parasitic infections is a major global health problem with substantial mortality and morbidity in children under 5 in low- and middle-income countries (LMICs). A number of these infections also impact large segments of populations in high-income countries (HICs), as well as individuals who travel overseas for work, business or pleasure.
Aims:
The aim of this review is to describe the current landscape of licensed enteric vaccines, potential new vaccines on the horizon, and the challenges of development and utilization of vaccines against enteric pathogens.
Sources:
Relevant data from the literature as well as clinical trials described in European and US registries were examined in the conduct of this review.
Content:
The review involves discussion of current licensed vaccines against rotavirus, cholera and typhoid, as well as potential second and third generation vaccines against these pathogens currently in the development pipeline. In addition, novel vaccines against enterotoxigenic E. coli, shigellosis andnorovirus in advanced development are described. Challenges to the development and utilization of global vaccines are discussed.
Implications:
Despite advances in population health, food security, improved sanitation, water quality and the reduction of poverty, acute enteric infections continue to plague global populations. Advancing utilization of current enteric vaccines is of critical public health importance, as well as the development of new vaccines, particularly for enteric pathogens where none currently exists .
... After the successful workshop on human challenge trials (HCTs), organized by the International Alliance for Biological Standardization (IABS) in Strasbourg, France, in 2014 [1], a follow-up meeting was held in Rockville, MD, USA, September [28][29][30]2017. The objective of this second meeting was to examine and promote the use of HCTs or controlled human infections (CHI), in response to the continuing human suffering caused by infectious diseases around the globe, which should be preventable by the development of new and improved vaccines for which the approach of CHI could be valuable. ...
... -Shigella. Although the global burden of disease has declined over the last decades [29], it remains high, and shigellosis is particularly of concern to the US military [30]. As few as 10 organisms can cause disease, presenting a significant risk in environments where Shigella may be present. ...
The International Alliance for Biological Standardization organized the second workshop on human challenge trials (HCT) in Rockville, MD, in September 2017. The objective of this meeting was to examine the use of HCT, in response to the continuing human suffering caused by infectious diseases, preventable by the development of new and improved vaccines. For this, the approach of HCT could be valuable, as HCT can provide key safety, tolerability, immunogenicity, and efficacy data, and can be used to study host-pathogen biology. HCT can generate these data with speed, efficiency and minimal expense, albeit not with the same level of robustness as clinical trials. Incorporated wisely into a clinical development plan, HCT can support optimization or down-selection of new vaccine candidates, assuring that only the worthiest candidates progress to field testing. HCT may also provide pivotal efficacy data in support of licensure, particularly when field efficacy studies are not feasible.
Many aspects of HCT were discussed by the participants, including new and existing models, standardization and ethics. A consensus was achieved that HCT, if ethically justified and performed with careful attention to safety and informed consent, should be pursued to promote and accelerate vaccine development.
... SMs are at increased risk of developing AD due to their deployments to overseas locations [15], and exacerbated by the fact that a number of those locations have concerning levels of AMR in relevant pathogens [9][10][11][12]. Episodes of diarrheal disease can have detrimental impact on troop readiness and mission operations, underscoring the importance of timely resolution of symptoms in this population [16][17][18][19]. It is therefore essential for military medical providers to understand the current trends in resistance profiles of enteropathogens in SMs to inform proper, timely treatment options. ...
Background
Acute diarrhea (AD) can have significant impacts on military troop readiness. Medical providers must understand current trends of enteropathogen antimicrobial resistance (AMR) in service members (SMs) to inform proper, timely treatment options. However, little is known of enteric pathogen profiles across the Military Health System (MHS). The primary objectives of this study were to identify gaps in enteric pathogen surveillance within the MHS, describe the epidemiology of AMR in enteric pathogens, and identify trends across the MHS both within the Continental United States (CONUS) and outside of the Continental United States (OCONUS).
Methods
Health Level 7 (HL7)-formatted laboratory data were queried for all specimens where Salmonella , Shigella , and Campylobacter species, as well as Shiga toxin-producing Escherichia coli ( E. coli ) (STEC) were isolated and certified between 1 January 2009 - 31 December 2019. Antibiotic susceptibility testing (AST) results were queried and summarized where available. Descriptive statistics were calculated for each organism by specimen source, year, and susceptibility testing availability.
Results
Among a total of 13,852 enteric bacterial isolates, 11,877 (86%) were submitted from CONUS locations. Out of 1479 Shigella spp. and 6755 Salmonella spp. isolates, 1221 (83%) and 5019 (74%), respectively, reported any susceptibility results through the MHS. Overall, only 15% of STEC and 4% of Campylobacter spp. specimens had AST results available. Comparing AST reporting at CONUS versus OCONUS locations, AST was reported for 1175 (83%) and 46 (78%) of Shigella isolates at CONUS and OCONUS locations, respectively, and for 4591 (76%) and 428 (63%) of Salmonella isolates at CONUS and OCONUS locations, respectively.
Conclusions
This study revealed inconsistent enteropathogen AST conducted across the MHS, with differing trends between CONUS and OCONUS locations. Additional work is needed to assess pathogen-specific gaps in testing and reporting to develop optimal surveillance that supports the health of the force.
... In addition to its impact in endemic settings, Shigella-attributable diarrhea among travelers and military populations can cause significant morbidity and incapacitation, requiring antibiotics, intravenous fluids and hospitalization (Riddle et al. 2006;Shah et al. 2009;Steffen 2017;Riddle 2018;Olson et al. 2019). Shigella is also considered an antimicrobial resistance (AMR) threat by the World Health Organization (WHO) and the US Center for Disease Control (CDC) (WHO 2017a; CDC 2019), leading the WHO Global Antimicrobial Resistance Surveillance System to identify Shigella as a priority pathogen for the development of new interventions. ...
Shigella-controlled human infection models (CHIMs) are an invaluable tool utilized by the vaccine community to combat one of the leading global causes of infectious diarrhea, which affects infants, children and adults regardless of socioeconomic status. The impact of shigellosis disproportionately affects children in low- and middle-income countries (LMICs) resulting in cognitive and physical stunting, perpetuating a cycle that must be halted. Shigella-CHIMs not only facilitate the early evaluation of enteric countermeasures and up-selection of the most promising products but also provide insight into mechanisms of infection and immunity that are not possible utilizing animal models or in vitro systems. The greater understanding of shigellosis obtained in CHIMs builds and empowers the development of new generation solutions to global health issues which are unattainable in the conventional laboratory and clinical settings. Therefore, refining, mining and expansion of safe and reproducible infection models hold the potential to create effective means to end diarrheal disease and associated co-morbidities associated with Shigella infection.Keywords
Shigella
Shigellosis
flexneri
sonnei
Challenge modelDiarrheaDysenteryVaccineImmune responseCorrelates of protection
... S. typhimurium (ΔaroA) containing a vector expressing cruzipain (Cz) has been shown to induce the immune system and reduce subsequent parasite load and muscle tissue damage (Cazorla et al., 2008). In an in vivo study with IFNγ -/mice it was demonstrated that S. enterica ΔaroA containing IFNγ plasmid can reinstate the expression of IFNγ and induce resistance against infections (Paglia et al., 2000 (Barzu et al., 1996;Katz et al., 2004;Riddle et al., 2006). ...
Vaccination is the most suitable and persuasive health care program for the prohibition of various deadly diseases. However, the higher production cost and purification strategies are out of reach for the developing nations. In this scenario, development of edible vaccine turns out to be the most promising alternative for remodeling the pharmaceutical industry with reduced production and purification costs. Generally, oral route of vaccination is mostly preferred due to its safety, compliance, low manufacturing cost and most importantly the ability to induce immunity in both systemic and mucosal sites. Genetically modified microorganisms and plants could efficiently be used as vehicles for edible vaccines. Edible vaccines are supposed to reduce the risk associated with traditional vaccines. Currently, oral vaccines are available in the market for several viral and bacterial diseases like cholera, hepatitis B, malaria, rabies etc. Herein, the review focuses on the breakthrough events in the area of edible vaccines associated with dietary microbes and plants for better control over diseases.
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... The genus is classified into four serogroups with numerous serotypes: A (S. dysenteriae, 12 serotypes); B (S. flexneri, 6 serotypes); C (S. boydii, 18 serotypes); and D (S. sonnei, 1 serotype). It is a bacterial type that can cause severe diarrhea, generally in children (Agtini et al., 2005;Riddle et al., 2006;Zafar et al., 2005). S. dysenteriae type 1 is responsible for the most severe form of bacterial dysentery, which is considered as epidemics in various developing countries (Faruque et al., 2003;Pazhani et al., 2008;Taneja & Mewara, 2016;Tuttle et al., 1995;von Seidlein et al., 2006). ...
Shigella dysenteriae type 1 is considered as an epidemic in different developing countries, which is responsible for the most severe form of bacterial dysentery. It habitually can develop to the most severe form of dysentery with deadly complications. Development of drugs against this disease is still ongoing. Therefore, we used in silico studies to screen the Inula britannica phytocompounds that are used in traditional Chinese and Kampo Medicines and have activities against different diseases. Spinacetin, eupatin, chrysoeriol and diosmetin were successfully passed through the docking-based screening and absorption, distribution, metabolism, excretion and toxicity (ADMET) filtration. The estimated docking affinities of eupatin, diosmetin, chrysoeriol and spinacetin with Dihydrofolate reductase type 1 (DHFR-1), were −6.5, −6.5, −6.3 and −6.1 kcal/mol, respectively. Which were selected for further investigations based on their favorable ADME/Tox characteristics. Then, the 100 ns molecular dynamics (MD) simulations of apo DHFR, spinacetin-DHFR, eupatin-DHFR, chrysoeriol-DHFR and diosmetin-DHFR complexes were carried out. The RMSD fluctuations of the spinacetin, eupatin, chrysoeriol and diosmetin inside the binding site were explored. Subsequently, the effect of binding Spinacetin, eupatin, chrysoeriol and diosmetin upon the dynamic stability of protein was assessed. Additionally, Principal Component Analysis (PCA) and Hydrogen bond analysis was performed for the apo protein and the protein ligand complexes. The results revealed that chrysoeriol and eupatin has good inhibitory effects against DHFR-1 as treatment for Shigella dysenteriae type when compared to other compounds under study. Hence this study implies that eupatin and chrysoeriol are a significantly potential drug like molecule for the treatment of Shigellosis and must undergo validation through in vivo and in vitro experiments.
Communicated by Ramaswamy H. Sarma
... In the present study, EAEC was the most common pathogen (50% of the cases), and was followed by ETEC and EPEC. In contrast, a 2006 systematic review regarding the etiology of TD reported that ETEC was the most common pathogen (a prevalence of 22.2%) and EAEC was the second most common pathogen (a prevalence of 13.3%) [11]. However, recent studies have suggested that EAEC and EPEC are as common as ETEC, which is probably related to the use of advanced diagnostic techniques with better pathogen coverage [6,12]. ...
Introduction
Traveler's diarrhea (TD) is the most common illness among people traveling from resource-rich regions to resource-limited regions, although the precise microbial etiology is unclear in many cases.
Methods
Stool specimens were prospectively collected from 106 consecutive patients with TD and 16 healthy controls without TD, and were tested using both the FilmArray gastrointestinal panel (BioFire Diagnostics) and conventional stool cultures.
Results
The 106 patients had traveled to Southeast Asia (55 cases), South Asia (22 cases), Africa (11 cases), and East Asia (7 cases). Among the 106 specimens, 95 specimens (89.6%) were positive for pathogens during the FilmArray testing. The FilmArray testing also identified multiple pathogens in 75.8% of the specimens from positive cases. Conventional stool cultures only detected pathogens in 23.6% of the specimens.
Conclusion
The FilmArray gastrointestinal panel significantly improved the detection of enteropathogens and allowed for a rapid assessment of the TD's etiology. In addition, conventional stool cultures are likely to underestimate co-infections with multiple infectious pathogens.
... Genes conferring resistance to AZM were observed in > 10% of the entire population, with Enterobacteriaceae strains from Egypt and Kenya having the highest rates of carriage (27% and 30%, respectively). The high prevalence of these ARDs is particularly concerning, as AZM has replaced FQs as a first-line therapeutic for moderate travelers' diarrhea in Southeast Asia and for severe travelers' diarrhea globally [105]. The low prevalence of the FQ resistance gene, qnrS, observed from all collection sites mirrored results from other studies [106][107][108]. ...
Infectious diarrhea affects over four billion individuals annually and causes over a million deaths each year. Though not typically prescribed for treatment of uncomplicated diarrheal disease, antimicrobials serve as a critical part of the armamentarium used to treat severe or persistent cases. Due to widespread over- and misuse of antimicrobials, there has been an alarming increase in global resistance, for which a standardized methodology for geographic surveillance would be highly beneficial. To demonstrate that a standardized methodology could be used to provide molecular surveillance of antimicrobial resistance (AMR) genes, we initiated a pilot study to test 130 diarrheal pathogens (Campylobacter spp., Escherichia coli, Salmonella, and Shigella spp.) from the USA, Peru, Egypt, Cambodia, and Kenya for the presence/absence of over 200 AMR determinants. We detected a total of 55 different determinants conferring resistance to ten different categories of antimicrobials: genes detected in ≥ 25 samples included blaTEM, tet(A), tet(B), mac(A), mac(B), aadA1/A2, strA, strB, sul1, sul2, qacEΔ1, cmr, and dfrA1. The number of determinants per strain ranged from none (several Campylobacter spp. strains) to sixteen, with isolates from Egypt harboring a wider variety and greater number of genes per isolate than other sites. Two samples harbored carbapenemase genes, blaOXA-48 or blaNDM. Genes conferring resistance to azithromycin (ere(A), mph(A)/mph(K), erm(B)), a first-line therapeutic for severe diarrhea, were detected in over 10% of all Enterobacteriaceae tested: these included >25% of the Enterobacteriaceae from Egypt and Kenya. Forty-six percent of the Egyptian Enterobacteriaceae harbored genes encoding CTX-M-1 or CTX-M-9 families of extended-spectrum β-lactamases. Overall, the data provide cross-comparable resistome information to establish regional trends in support of international surveillance activities and potentially guide geospatially informed medical care.
... Typical treatment for traveler's diarrhea includes the use antibiotics to include ciprofloxacin, azithromycin and rifaximin [6]. However, enteric pathogens and their associated antibiotic resistance patterns evolve over time and vary by region [7,8]; therefore, access to up-to-date data on the global epidemiology of present diarrheal agents and their respective resistances are vital for diminishing the risk of diarrheal infection [6]. ...
Abstract Background Diarrhea remains a major public health problem for both civilian and military populations. This study describes the prevalence of acute diarrheal illness etiological agents, their antibiotic resistance distribution patterns, the resulting impact upon military force health protection, and potential prevention and treatment strategies. Results Forty-eight acute diarrhea stool samples from US military personnel deployed to Thailand from 2013–2017 were screened for enteric pathogens using ELISA, the TaqMan Array Card (TAC), and conventional microbiological methods. These isolates were also evaluated using antimicrobial susceptibility testing (AST) against ampicillin (AMP), azithromycin (AZM), ceftriaxone (CRO), ciprofloxacin (CIP), nalidixic acid (NA), erythromycin (ERY), and trimethoprim-sulfamethoxazole (SXT) using commercial methodology. Susceptibility results were interpreted following the CLSI and NARM guidelines. Questionnaire data obtained from 47/48 volunteers indicated that 89.4% (42/47) reported eating local food and the most common clinical symptoms were nausea and abdominal pain (51%; 24/47). Multiple bacterial species were identified from the 48 stool samples with diarrhea etiological agents being detected in 79% (38/48) of the samples distributed as follows: 43.8% (21/48) Campylobacter jejuni and Campylobacter species, 42% (20/48) diarrheagenic Escherichia coli, and 23% (11/48) Salmonella. Co-infections were detected in 46% (22/48) of the samples. All C. jejuni isolates were resistant to CIP and NA. One C. jejuni isolate exhibited resistance to both AZM and ERY. Lastly, an association between exposure to poultry and subsequent detection of the diarrhea-associated pathogens E. coli and P. shigelloides was significant (p
... Enterotoxigenic Escherichia coli (ETEC) is a leading cause of acute bacterial diarrhea in young children in and travelers to developing countries [1][2][3][4][5][6][7]. ETEC adherence to the small intestine is promoted by the expression of one or more colonization factors (CFs), of which over 25 have been described [8]. ...
Surface-expressed colonization factors and their subunits are promising candidates for inclusion into a multivalent vaccine targeting enterotoxigenic Escherichia coli (ETEC), a leading cause of acute bacterial diarrhea in developing regions. However, soluble antigens are often poorly immunogenic in the absence of an adjuvant. We show here that the serum immune response to CfaE, the adhesin of the ETEC colonization factor CFA/I, can be enhanced in BALB/c mice by immunization with a chimeric antigen containing CfaE and pentameric cholera toxin B subunit (CTB) of cholera toxin from Vibrio cholerae. We constructed this antigen by replacing the coding sequence for the A1 domain of the cholera toxin A subunit (CTA) with the sequence of donor strand complemented CfaE (dscCfaE) within the cholera toxin operon, resulting in a dscCfaE-CTA2 fusion. After expression, via non-covalent interactions between CTA2 and CTB, the fusion and CTB polypeptides assemble into a complex containing a single dscCfaE-CTA2 protein bound to pentameric CTB (dscCfaE-CTA2/CTB). This holotoxin-like chimera retained the GM1 ganglioside binding activity of CTB, as well as the ability of CfaE to mediate the agglutination of bovine red blood cells when adsorbed to polystyrene beads. When administered intranasally to mice, the presence of CTB in the chimera significantly increased the serum immune response to CfaE compared to dscCfaE alone, stimulating a response similar to that obtained with a matched admixture of dscCfaE and CTB. However, by the orogastric route, immunization with the chimera elicited a superior functional immune response compared to an equivalent admixture of dscCfaE and CTB, supporting further investigation of the chimera as an ETEC vaccine candidate.
... Enterotoxigenic Escherichia coli (ETEC) is one of the leading causes of travelers' diarrhea and endemic childhood diarrhea in developing countries [1,2]. ETEC adhere to intestinal epithelial cells via one or more colonization factors (CFs), and produce either or both heat-labile (LT) and heat-stabile (ST) enterotoxins, leading to fluid and electrolyte secretion. ...
dscCfaE is a recombinant form of the CFA/I tip adhesin CfaE, expressed by a large proportion of enterotoxigenic E. coli (ETEC). It is highly immunogenic by the intranasal route in mice and Aotus nancymaae, protective against challenge with CFA/I+ ETEC in an A. nancymaae challenge model, and antibodies to dscCfaE passively protect against CFA/I+ ETEC challenge in human volunteers. Here, we show that transcutaneous immunization (TCI) with dscCfaE in mice resulted in strong anti-CfaE IgG serum responses, with a clear dose-response effect. Co-administration with heat-labile enterotoxin (LT) resulted in enhanced immune responses over those elicited by dscCfaE alone and strong anti-LT antibody responses. The highest dose of dscCfaE administered transcutaneously with LT elicited strong HAI titers, a surrogate for the neutralization of intestinal adhesion. Fecal anti-adhesin IgG and IgA antibody responses were also induced. These findings support the feasibility of TCI for the application of an adhesin-toxin based ETEC vaccine.
... 75,79 It is also a leading cause of foodborne enteric diseases in industrialized countries, sometimes more common than NTS 80,81 and ranked second after ETEC, as traveler's diarrhea etiologic agent. 82,83 There is growing evidence on the involvement of Campylobacter jejuni in chronic morbidity of neurological, hematological, and rheumatological systems. 84 The antimicrobial resistance of C. jejuni is emerging having usually multiresistance to antibiotics acquired from animal reservoir level (e.g., poultry). ...
... This finding is in agreement with 6.6% (95% CI 3.4-9.7) Shegilla prevalence in systematic review among US military and similar populations [45]. ...
Background:
Shigella species are a major cause of dysentery and may attribute for death worldwide. Currently antibiotic resistance became the critical challenges for management of infectious disease. The aim was to conduct a systematic review and meta-analysis of Shigella species and its drug resistance pattern in Ethiopia.
Methods:
A comprehensive literature search was conducted through internet searches using database of MEDLINE, PubMed, Google scholar, EMBASE, HINARI, Cochrane Library and reference lists of previous prevalence studies from January 1999 to November 2018. Results were presented in forest plot, tables and figures with 95% CI. The Cochrane Q test and I2 test statistic were used to test heterogeneity across studies. The Pooled estimate of Shigella species and its drug resistance pattern was computed by a random effects model.
Results:
The pooled prevalence of Shigella species in Ethiopia was 6.6% (95% CI 4.7-8.8). In the subgroup analysis, the highest prevalence was observed among patients in Health facility (8.5%, 95% CI 6.2-11.5) whereas the lowest prevalence was observed in Community based studies (1.6%, 95% CI 0.8-3.4). In addition, Shigella species were highly resistant to ampicillin, amoxicillin, erythromycin and multi-drug resistant (MDR) with the pooled resistance proportions of 83.1% (95% CI 75.7-88.6), 84.1% (95% CI 75.6-90.1), 86.5% (95% CI 70.9-94.4) and 83.2% (95% CI 77.1-87.9), respectively. On the other hand, comparably low resistance pattern was reported for ciprofloxacin 8.9% (95% CI 6.0-12.8), ceftriaxone 9.3% (95% CI 3.9-20.5), and norfloxacin 8.2% (95% CI 3.8-16.6) and gentamycin 17.3% (95% CI 11.2-25.9). Subgroup analyses indicated that study years were associated with a decreasing Shigella prevalence over time (p = 0.002).
Conclusion:
The pooled estimate showed high burden of Shigella infection and its high proportion of drug resistance pattern to ampicillin, amoxicillin and erythromycin in Ethiopia. Therefore, initiating and scale up of performing drug susceptibility test for each shigellosis case, educate the community and health care providers on appropriate use of antibiotics need to be considered and strengthened.
... Travelers' diarrhea is common, affecting 10-40% of travelers on short duration trips [9]. Etiology is subject to geographic variability, but bacterial organisms predominate [10,11]. Vaccines and other countermeasures against travelers' diarrhea can be licensed on the basis of field studies involving leisure traveler and analogous populations such as military and relief personnel; however, in the event that the rarity of the infection precludes a field trial, there is recent precedent with an oral attenuated cholera vaccine for licensure based on pivotal data from CHIM studies [12]. ...
Well-established, validated and clinically meaningful primary and secondary endpoints are critical in advancing vaccines through proof of principal studies, licensure and pre-qualification. To that end, the field of vaccine development for Shigella, enterotoxigenic Escherichia coli (ETEC) as well as other enteric pathogens would benefit greatly from a focused review of clinical endpoints and the use of common endpoints across the field to enable study-to-study comparisons as well as comparative assessments between vaccine candidates. A workshop was conducted to review clinical endpoints from controlled human challenge studies, field studies in naïve adult travelers and pediatric studies in low-middle income countries and to develop a consensus on clinical endpoints for future vaccine trials.
Following sequential presentations on different study designs (CHIM, travelers’ efficacy and pediatric efficacy), workshop participants broke into three simultaneous workgroups focused on those study designs to discuss a number of topics key to clinical endpoints specific to each study design. Previously utilized endpoints were reviewed with an eye towards potentially novel endpoints for future studies and consideration of the disease parameters and spectrum of disease targeted for prevention. The strength of support among workshop participants for the use of various endpoints is summarized as are recommendations for additional endpoints to be considered in future studies. It is anticipated that this report will facilitate endpoint determination in future efficacy trials of vaccine candidates.
... ETEC is without question one of the most common causes of diarrheal illness in travelers and in military deployed to endemic areas [18][19][20][21]. In 11 separate studies performed between 2010 and 2016, ETEC was the most common pathogen identified in traveler's diarrhea (TD) accounting for an average of 42% and 28% of cases in travelers to Latin America and Asia, respectively [22]. ...
Purpose of Review
Review recent developments pertaining to the epidemiology, molecular pathogenesis, and sequelae of enterotoxigenic Escherichia coli (ETEC) infections in addition to discussion of challenges for vaccinology.
Recent Findings
ETEC are a major cause of diarrheal illness in resource poor areas of the world where they contribute to unacceptable morbidity and continued mortality particularly among young children; yet, precise epidemiologic estimates of their contribution to death and chronic disease have been difficult to obtain. Although most pathogenesis studies, and consequently vaccine development have focused intensively on canonical antigens, more recently identified molecules unique to the ETEC pathovar may inform our understanding of ETEC virulence, and the approach to broadly protective vaccines.
Summary
ETEC undeniably continue to have a substantial impact on global health; however, further studies are needed to clarify the true impact of these infections, particularly in regions where access to care may be limited. Likewise, our present understanding of the relationship of ETEC infection to non-diarrheal sequelae is presently limited, and additional effort will be required to achieve a mechanistic understanding of these diseases and to fulfill Koch’s postulates on a molecular level. Precise elucidation of the role played by novel virulence factors, the global burden of acute illness, and the contribution of these pathogens and/or their toxins to non-diarrheal morbidity remain important imperatives.
... Shigella serotypes, Shigella flexneri 2a, S. flexneri 3a, and S. sonnei, demonstrate epidemiological prevalence globally. The diarrheal disease caused by these Shigella species impacts military, travelers 1 , and is a leading cause of diarrheal death among children under the age of 5 in developing countries 2 . There are currently no licensed vaccines to protect against Shigella, however, there are multiple candidate vaccines at various stages of the development. ...
Serum bactericidal assays (SBAs) measure the functional activity of antibodies and have been used for many decades. SBAs directly measure antibody killing activity by assessing the ability of antibodies in serum to bind to bacteria and activate complement. This complement activation results in the lysis and killing of the target bacteria. These assays are valuable because they go beyond quantifying antibody production to elucidate the biological functions that these antibodies have, allowing researchers to study the role that antibodies may play in preventing infection. SBAs have been used to study immune responses for many human pathogens, but there is no widely accepted methodology for Shigella at present. Historically, SBAs have been very labor-intensive, requiring many time-consuming steps to accurately quantify surviving bacteria. This protocol describes a simple, robust, and high-throughput assay that measures functional antibodies specific for Shigella in serum in vitro. The method described here offers many advantages over traditional SBAs, including the use of frozen bacterial stocks, 96 well assay plates, a micro-culture system, and automated colony-counting. All of these modifications make this assay less labor-intensive and more high-throughput. This protocol is simpler and faster to perform than traditional SBAs while still using simple technologies and readily available reagents. The protocol has been successfully applied in multiple independent laboratories and the assay is robust and reproducible. The assay can be used to assess immune responses in pre-clinical as well as clinical studies. Quantifying shigellacidal antibody titers both before and after antigen exposure (either by immunization or infection) allows for a broader understanding of how functional antibody responses are generated and their contribution to protective immunity. The development of this standardized, well-characterized assay may greatly facilitate Shigella vaccine design.
... Campylobacter jejuni, a gram negative motile bacterium, is considered as commensals of animals and the most common cause of the bacterial gastroenteritis in humans in industrialized countries (Butzler, 2004;Riddle et al., 2006). Infection with C. jejuni results in symptoms that range from mild watery diarrhea to more severe diarrhea with blood and leukocytes. ...
Physiologic and phenotypic alterations in the context of antibiotic resistance have been extensively studied in some bacteria. However there are not enough data addressing these alterations due to macrolide resistance in Campylobacter jejuni. The present study examined the fitness cost imposed by different macrolide resistance mutations and the phenotypic alterations due to exposure to macrolides in C. jejuni. C. jejuni was induced with different macrolide agents to obtain different macrolide resistance mutations. The results revealed that the mutations significantly imposed defect variations on the doubling time and the relative fitness in the resistant strains when competed against the susceptible strain. Furthermore macrolides through induction or exposure to sub-MIC concentrations impaired the motility of C. jejuni in 0.4% MH agar plates. Electron microscope analysis revealed the absence of flagellar filaments from strains exposed to macrolides. SDS-PAGE demonstrated that macrolides have no effect on protein synthesis and immunoblotting analysis further confirmed that flagellin was fully synthesized within C. jejuni strains exposed to macrolides. Nevertheless C. jejuni strains exposed to macrolides demonstrated defect in their excreted flagellin into the supernatant compared to strains not exposed to macrolides. Accordingly we speculated that macrolides inhibited flagellar filament formation in the strains exposed to macrolides via affecting the secretion of flagellin without affecting the amount synthesized within the bacteria. Taken together these findings demonstrated that different macrolide resistance mutations imposed different fitness costs and exposure to macrolides resulted in phenotypic alterations such as inhibition of flagellar filament formation and loss of motility in C. jejuni.
... 16 In travelers to LMICs, Campylobacter is a leading cause of travelers' diarrhea (TD) second only to diarrheagenic Escherichia coli. [17][18][19] Geographically, the incidence of Campylobacter-attributable TD varies with by far the highest rates observed in travelers to Southeast Asia. In addition to being a common cause of travelers' diarrhea, Campylobacter is often associated with a more severe disease. ...
Background: Acute diarrheal disease caused by viral, bacterial and parasitic infections are a major global health problem with substantial mortality and morbidity in children under five years of age in lower and middle income countries. However, a number of these infections also impact large segments of populations in upper income countries, as well as individuals who travel overseas for work, business or pleasure. Campylobacter has been and continues to be a leading cause of disease burden globally across all income countries.
Aims: The aim of this review is to describe recent understanding in burden of disease, consider the current landscape of Campylobacter vaccine development, and address the challenges that need to be overcome.
Sources: Relevant data from the literature as well as clinical trials described in European and US registries were used to conduct this review.
Content: Despite advances in population health, food security, improved sanitation, water quality and the reduction of poverty, Campylobacter infections continue to plague global populations. The emerging recognition of chronic health consequences attributed to this pathogen is changing the potential valuation of preventive interventions. Advancing development of new vaccines is a present opportunity and holds promise.
... Even illnesses with limited morbidity may have an exaggerated impact on mission outcome in military travelers. [14][15][16][17][18] Despite this, evaluation of military travelers has been limited in large surveillance studies. Less than 1% of enrollees in the GeoSentinel Surveillance Network were military travelers. ...
Travelers to developing regions are at risk for development of influenza-like illness (ILI). Little is known of traveler and trip characteristics associated with the development of ILI. TravMil is a prospective observational study, enrolling subjects presenting to six military travel clinics or predeployment-screening sites. We analyzed pre- and post-travel surveys from travelers visiting regions outside of the continental United States, Western or Northern Europe, Canada, Australia, or New Zealand between January 2010 and March 2016. Influenza-like illness was defined as a self-reported fever associated with either sore throat or cough. Trip and traveler characteristics were analyzed to determine risk factors for the development of ILI. Two thousand nine hundred and thirty-two trips were recorded (55% male, median age 45 years, 69% white, 51% on vacation, median travel duration 17 days). The 2,337 trips included the number of self-reported influenza vaccinations in the preceding 5 years (median 5). Eleven percent of the trips were complicated by an ILI lasting a median of 5 days; 70% and 17% of these reported upper and lower respiratory tract infection, respectively, and 12% reported both. On multivariate analysis, increased risk of ILI was associated with female gender (odds ratio [OR]: 1.60 [confidence interval (CI): 1.25-2.05], P < 0.01), age (years) (OR: 1.01 [CI: 1.01-1.02], P < 0.01); and duration of travel (days) (OR: 1.01 [CI: 1.00-1.01], P < 0.01). Influenza-like illness is common in travelers, regardless of traveler characteristics, purpose of travel, destination, or season of year. Female gender, older age, and longer duration of travel were associated with an increased risk of ILI. Additional tools and strategies are needed to prevent ILI in international travelers.
... Travelers' diarrhea (TD) is a common problem during overseas travel and military deployment [1,2]. Ascertaining the pathogen-specific epidemiology of TD is essential for the understanding of disease burden, as well as development of effective preventive and treatment measures. ...
The use of Polymerase Chain Reaction (PCR) assays for pathogen detection in travelers’ diarrhea (TD) field studies is limited by the on-site processing and storage requirements for fecal specimens. The objectives of this investigation were to i) characterize the pathogen distribution in deployed military personnel with TD using the TaqMan® Array Card PCR (TAC) on frozen stool and diarrheal smears on Whatman FTA Elute cards (FTA cards), and to ii) compare TAC detection of enteropathogen targets using smeared FTA cards and frozen stool, using TAC on frozen stool as the ‘reference standard’. Stool samples, obtained from active duty personnel with acute TD enrolled in a field trial, were smeared onto FTA cards and stored at room temperature. A corresponding aliquot of stool was frozen in a cryovial. FTA cards and frozen stool samples were tested at a central lab, using a customized TAC for detection of TD pathogens. 187 paired frozen stool samples and smeared FTA cards were stored for a median of 712 days (IQR 396–750) before testing. Overall detection rates were 78.6% for frozen stool and 73.2% for FTA cards. Diarrheagenic Escherichia coli were the most common bacteria identified. Using the TAC results on frozen stool as the reference, the overall sensitivity and specificity of TAC on FTA cards was 72.9% and 98.0% respectively. TAC on FTA cards demonstrated a decrease in sensitivity with increasing frozen stool quantification cycle (Cq) (90.0% in FTA cards with a corresponding frozen stool Cq < 30, and 72.9% in samples with a corresponding frozen stool Cq < 35). Our findings support the use and further development of FTA cards in combination with a quantitative PCR assay for enteropathogen detection in TD field studies.
... 5 Despite comprehensive vaccine and preventative medicine programs, military members are at high risk for a variety of infections (respiratory, gastrointestinal, etc.) in both peace time and combat activities, inevitably making antimicrobial resistance a serious health and readiness threat. 3,6 Though there are no military specific studies, in the United States, over 2 million people acquire antibiotic-resistant infections annually and 23,000 people subsequently die from these infections. 7 Over 250,000 illnesses and 14,000 deaths annually are due to Clostridium difficile alone. ...
Introduction
Penicillin allergy is the most common drug allergy reported. About 8–10% of individuals in the USA have a documented penicillin allergy, yet 90% are not truly allergic to penicillin. A penicillin allergy “label” results in increased antibiotic-related adverse reactions and increased health care costs, thus impacting the overall “readiness” of the military.
Materials and Methods
A review of the current literature and approaches to penicillin allergy and “de-labeling” a patient who reports penicillin allergy was conducted and future strategies to identify and assess military beneficiaries were outlined. Military allergists had a formal discussion at the Tri-service Military Allergy Immunology Assembly regarding the state of penicillin allergy testing in military allergy clinics.
Results
A PubMed search yielded 5,775 results for “penicillin allergy” and 484 results for “penicillin allergy testing.” There were two formalized penicillin testing programs in the military treatment facilities. In 2017, the military trained nearly 165,000 new recruits. If 5–10% reported a penicillin allergy and 90% were de-labeled, that would yield a $15–30 million cost savings annually. Further, de-labeling of the 9.4 million active duty, beneficiaries and retirees with a 90% success rate could result in even greater savings for the military health care system.
Conclusion
A penicillin allergy label is a risk to military readiness secondary to associated increases in the length of hospitalizations and emergency department and medical visits. Penicillin de-labeling is a simple intervention that can improve readiness, significantly decrease health care costs and prevent antibiotic resistance, as well as antibiotic-associated adverse events. The military allergist should be “front and center” providing expertise guidance and leadership for clinic and hospital-based penicillin de-labeling efforts which are nested within the antibiotic stewardship programs.
... Campylobacteriosis cases are primarly sporadic but outbreaks are not uncommon. In developing countries, in particular in Southeast Asia where C. jejuni is endemic, the incidence is estimated to be at least 10 times higher (6,7). This high incidence represents a concerning life threatening risk, especially towards the pediatric population in these endemic regions. ...
Campylobacter jejuni is one of the most common causes of human diarrheal disease worldwide. Campylobacteriosis cases are primarily sporadic, but outbreaks are not uncommon. In developed countries Campylobacteriosis cases are about 50/100,000 per year, but in developing countries, particularly in Southeast Asia, the incidence is estimated to be at least 10 times higher. In these endemic regions, this high incidence represents a life threatening risk, especially towards the pediatric population. C. jejuni is considered a zoonotic disease in which the major source of contamination is through the consumption of poultry. In humans, the infectious dose can be as low as 500-1,000 bacteria with symptoms being variable and dependent on the bacterial strain and host factors. Some patients only present mild abdominal pain and mild to no diarrhea, while the most severe cases are associated with severe abdominal cramping, accompanied with fever, headaches, myalgia, and large volumes of mucous and bloody diarrhea that can last for several days. If left untreated, severe C. jejuni cases can be lethal. C. jejuni infections have also been associated with the development of Guillain-Barré syndrome (an autoimmune disease triggered by C. jejuni lipooligosaccharide sub-structures that mimic glanglioside forms) inflammatory bowel syndrome, reactive arthritis and stunting in children from developing countries. In this piece, we describe the development of a C. jejuni vaccine candidate in which the protective antigens are the cell-surface capsular polysaccharides (CPSs), with focus on (i) CPS discovery highlighting the two key structural features of C. jejuni CPSs, 6-deoxy-heptoses of unsual configurations and variably linked O-methyl-phosphoramidate moities; (ii) conjugation of C. jejuni CPSs to carrier proteins using new methodology for CPS activation (TEMPO-mediated oxidation); and (iii) protection studies in a non-human primate model. Collectively, the data obtained has allowed us to advance our prototype C. jejuni CPS conjugate vaccine through cGMP production and onto an ongoing phase I human clinical trial.
... Campylobacteriosis cases are primarly sporadic but outbreaks are not uncommon. In developing countries, in particular in Southeast Asia where C. jejuni is endemic, the incidence is estimated to be at least 10 times higher (6,7). This high incidence represents a concerning life threatening risk, especially towards the pediatric population in these endemic regions. ...
... Introduction Shigella species are a leading cause of inflammatory diarrheal disease in endemic regions, and is especially problematic in children living in low-middle income countries, in refugees, travelers, and deployed military personnel [1][2][3][4]. Shigella are spread through fecal-oral transmission such as via contaminated food and water, and person to person contact, and has a low infective dose making it particularly challenging in settings of poor sanitation and overcrowding [5][6][7]. Globally, among children less than five years of age, mortality estimates approximate 54,900 deaths annually (95% uncertainty intervals: 27,000-94,700), accounting for 50% of the diarrhea-attributed deaths in this population [8]. In addition, Shigella are likely one of several pathogens that contribute to long-term adverse health outcomes including growth faltering [1,9]. ...
Background
Since 1946 the controlled human infection model (CHIM) for Shigella has been used to improve understanding of disease pathogenesis, describe clinical and immunologic responses to infection and as a tool for vaccine development. As the frequency and intent for use in vaccine comparisons increases, standardization of the primary endpoint definition is necessary.
Methods
Subject-level data were obtained from previously conducted experimental Shigella CHIM studies. Signs and symptoms severity were categorized consistently across all studies. Sign and symptom correlations were estimated and univariate models were utilized to describe the association between stool output and other Shigella-attributable signs and symptoms. Multiple correspondence and hierarchical clustering analyses were performed to describe the co-occurrence of signs and symptoms. A disease score is proposed based on the co-occurrence of these events.
Results
Data were obtained on 54 subjects receiving 800 to 2000 colony forming units (cfu) of S. flexneri. The median maximum 24 hour stool output was 514 ml (IQR: 300, 998 ml) with a median frequency of 6 (IQR: 4, 9). Subjects reported abdominal pain or cramps (81.5%), headache (66.7%) and anorexia (64.8%), 50.0% had a fever and 27.8% had gross blood in multiple loose stools. Multiple correspondence analyses highlighted co-occurrence of symptoms based on severity. A 3-parameter disease severity score predicted shigellosis endpoints and better differentiated disease spectrum.
Conclusion
Dichotomous endpoints for Shigella CHIM fail to fully account for disease variability. An ordinal disease score characterizing the breadth of disease severity may enable a better characterization of shigellosis and can decrease sample size requirements. Furthermore, the disease severity score may be a useful tool for portfolio management by enabling prioritization across vaccine candidates with comparable efficacy estimates using dichotomous endpoints.
Background:
Southeast Asia is attractive for tourism. Unfortunately, travelers to this region are at risk of becoming infected with Shigella. We conducted a meta-analysis to provide updates on Shigella prevalence in Southeast Asia, along with their serogroups and serotypes.
Methods:
We conducted a systematic search using PubMed, EMBASE, and Web of Science for peer-reviewed studies from 2000 and November 2022. We selected studies that detected Shigella in stools by culture or polymerase chain reaction (PCR). Two reviewers extracted the data using a standardized form and performed quality assessments using the Joanna Briggs Institute checklist. The random effects model was used to estimate the pooled prevalence of Shigella.
Results:
During our search, we identified 4376 studies. 29 studies (from six Southeast Asian countries) were included in the systematic review, 21 each in the meta-analysis of the prevalence of Shigella (Sample size:109545) and the prevalence of Shigella serogroups. The pooled prevalence of Shigella was 4% (95% CI: 4-5%) among diarrhea cases. Shigella sonnei was the most abundant serogroup in Thailand (74%) and Vietnam (57%), whereas Shigella flexneri was dominant in Indonesia (72%) and Cambodia (71%). Shigella dysenteriae and Shigella boydii were uncommon (pooled prevalence of 1% each). The pooled prevalence of Shigella was 5% (95% CI: 4-6%) in children aged <5 years. The pooled prevalence showed a decreasing trend comparing data collected between 2000 and 2013 (5%; 95% CI: 4-6%) and between 2014 and 2022 (3%; 95% CI: 2-4%). Shigella prevalence was 6% in studies that included participants with mixed pathogens versus 3% in those without. Shigella flexneri serotype 2a was the most frequently isolated (33%), followed by 3a (21%), 1b (10%), 2b (3%), and 6 (3%).
Conclusions:
This study provides compelling evidence for the development of effective Shigella vaccines for residents of endemic regions and travellers to these areas.
The controlled human infection model (CHIM) for enterotoxigenic Escherichia coli (ETEC) has been instrumental in defining ETEC as a causative agent of acute watery diarrhea, providing insights into disease pathogenesis and resistance to illness, and enabling preliminary efficacy evaluations for numerous products including vaccines, immunoprophylactics, and drugs. Over a dozen strains have been evaluated to date, with a spectrum of clinical signs and symptoms that appear to replicate the clinical illness seen with naturally occurring ETEC. Recent advancements in the ETEC CHIM have enhanced the characterization of clinical, immunological, and microbiological outcomes. It is anticipated that omics-based technologies applied to ETEC CHIMs will continue to broaden our understanding of host-pathogen interactions and facilitate the development of primary and secondary prevention strategies.
Background. Travelers’ diarrhea (TD) is the most common travel-related illness with an estimated 10 million people afflicted annually. Outcome measures to assess the efficacy of primary and secondary TD interventions were historically based on diarrhea frequency with ≥1 associated gastrointestinal symptom. Furthermore, efficacy determination is often made on the presence or absence of TD, rather than on TD illness severity. Current severity classifications are based on subjective consideration of impact of illness on activity. We sought to develop a standardized scoring system to characterize TD severity to potentially apply as a secondary outcome in future field studies.
Methods. Data on multiple signs and symptoms were obtained from a previously published multi-site TD treatment trial conducted by the US Department of Defense (TrEAT TD). Correlation, regression and multiple correspondence analyses were performed to assess impact on activity and a TD severity score was established.
Results. Numerous signs and symptoms were associated with impaired function; with malaise and nausea most strongly associated (OR 5.9–44.3, p < 0.0001 and OR 2.8–37.1, p < 0.0001, respectively). Based on co-varying symptomatology, a TD severity score accounting for diarrhea frequency in addition to several signs and symptoms was a better predictor of negative impact on function than any single sign/symptom (X2 = 127.16, p < 0.001). Additionally, there was a significant difference (p < 0.0001) in the mean TD severity score between those with acute watery diarrhea (3.9 ± 1.9) and those with dysentery or acute febrile illness (6.2 ± 2.0).
Conclusions. The newly developed disease severity score better predicted a negative impact on activity due to TD than did any single sign or symptom. Incorporating multiple parameters into the TD severity score better captures illness severity and moves the field towards current recommendations for TD management by considering symptoms with high functional impact. Further validation of this score is needed in non-military travelers and other settings.
Background
Travelers’ diarrhea (TD) is one of the most common illnesses affecting modern-day travelers, including military personnel. Previous work has shown that afflicted travelers may alter their itineraries and be confined to bed rest due to symptoms, and military personnel may become incapable of completing operational requirements. Examination of signs, symptoms, and severity of diarrheagenic pathogens can inform clinical diagnosis and prioritization of future surveillance and research activities.
Methods
Utilizing a global laboratory network, culture and molecular testing were performed in parallel at each site on a group of core pathogens, and definitions for acute diarrhea (AD), severe AD, acute gastroenteritis (AGE), and severe AGE were determined using data elements in the modified Vesikari scale. We included 210 cases of TD reporting all variables of interest in our severity assessment analysis. Results: Out of all cases, 156/210 (74%) met criteria for severe AD and 35/210 (17%) for severe AGE. Examination of severity by pathogen revealed that, at non-military sites, 17/19 (89%) of enteropathogenic Escherichia coli (E. coli) (EPEC) infections, 28/32 (88%) of enterotoxigenic E. coli (ETEC) infections, and 13/15 (87%) of Shigella/enteroinvasive E. coli (STEC) infections resulted in severe AD cases. At the military site, all infections of ETEC (6/6), STEC (4/4), and enteroaggregative E. coli (EAEC) resulted in AD. Norovirus infections at non-military and military sites resulted in 27% (14/51) and 33% (3/9) severe AGE cases, respectively.
Conclusions
This study found a high percentage of participants enrolled at both military and non-military sites experienced severe AD with high rates of hospitalization and reductions in performance. Since travelers with mild TD symptoms are less likely to present to health care workers than those with more severe TD, there is a potential selection bias in this study skewed towards more severe outcomes. Future research should examine other covariates among pathogen and host, such as treatment and comorbid conditions, that may contribute to the presence of signs and symptoms and their severity.
Enterotoxigenic E. coli (ETEC) are a common cause of diarrheal illness in military, travelers, and children living in low to middle income countries. Increased antibiotic resistance, the absence of a licensed vaccine and the lack of broadly practical therapeutics perpetuate the significant health and financial burden resulting from ETEC infection. A critical step in the evaluation of vaccines and therapeutics is pre-clinical screening in a relevant animal disease model that closely replicates human disease. We previously developed a diarrheal model of class 5a colonization factor (CF) CFA/I expressing ETEC in the New World owl monkey species Aotus nancymaae using ETEC strain H10407 . In order to broaden the use of the model, we report here on the development of A. nancymaae models of ETEC expressing the class 5b CFs CS17 and CS19 with strains LSN03-016011/A and WS0115A, respectively. For both models, we observed diarrheal attack rates of ≥ 80% after oral inoculation with 5 × 10 ¹¹ CFU of bacteria. These models will aid in assessing the efficacy of future ETEC vaccine candidates and therapeutics.
Recent efforts to develop an enterotoxigenic Escherichia coli (ETEC) vaccine have focused on the antigenically conserved tip adhesins of colonization factors. We showed previously that intranasal immunization with dsc 19 CfaE, a soluble variant of the in cis donor strand complemented tip adhesin of CFA/I fimbria, is highly immunogenic and protects against oral challenge with CFA/I ⁺ ETEC strain H10407 in the Aotus nancymaae non-human primate. We also reported a cholera toxin (CT)-like chimera (called dsc 19 CfaE-CTA2/CTB) in which the CTA1 domain of CT was replaced by dsc 19 CfaE that was strongly immunogenic when administered intranasally or orogastrically in mice. Here we evaluate the immunogenicity and protective efficacy of a refined and more stable chimera comprised of a pentameric B-subunit of ETEC heat-labile toxin (LTB) in lieu of the CTB pentamer and a donor strand truncation (dsc 14 ) of CfaE. The refined chimera, dsc 14 CfaE-sCTA2/LTB, was highly immunogenic in mice when administered intranasally or intradermally, eliciting serum and fecal antibody responses against CfaE and LTB, as well as strong hemagglutination inhibition titers, a surrogate for neutralization of intestinal adhesion mediated by CfaE. Moreover, the chimera was safe and highly immunogenic when administered intradermally to guinea pigs. In A. nancymaae , ID immunization with chimera + LT(R192G) elicited strong serum anti-CfaE and anti-LTB antibody responses and conferred significant reduction of diarrhea compared to PBS controls (PE = 84.1%, P <0.02). These data support the further evaluation of dsc 14 CfaE-sCTA2/LTB as an ETEC vaccine in humans.
Travelers’ diarrhea is the most common infectious disease in this subpopulation and usually develops within the first week of travel. This review presents summarized data on epidemiology and etiology of travelers’ diarrhea. Nonspecific precautions and medical treatments (antimicrobials, probiotics) to prevent this infection are described in detail. Current approaches to the treatment of travelers’ diarrhea (oral rehydration, probiotics, antidiarrheals, antimicrobials) in adults and children depending on disease severity are also considered.
This chapter focuses on the most common population at risk for travelers' diarrhea (TD), which is a traveler from an industrialized country traveling to a less developed region with higher rates of enteropathogens, particularly bacterial, than the traveler's country of origin. The clinical syndrome consists of both an increased frequency of bowel movements, along with a change in stool consistency to loose and/or liquid form. "Typical" TD represents a spectrum of illness from a fleeting mild diarrhea without associated symptoms or activity limitation to a serious dehydrating and/or febrile dysentery requiring hospitalization. Bacterial enteropathogens are the predominant etiologic agents associated with TD. The American College of Gastroenterology (ACG) guidelines classified pretravel counseling regarding high‐risk food/beverage avoidance to prevent TD as a conditional recommendation, though with very low‐level evidence of efficacy.
Background:
Well over 700,000 United States military personnel participated in the Persian Gulf War in which they developed chronic health disorders of undetermined etiology. Up to 25% of Veterans had persistent and chronic gastrointestinal (GI) symptoms, which they suspected were related to their military service in the Gulf.
Aim:
The overall aim of the current study was to evaluate intestinal permeability in previously deployed Gulf War Veterans who developed chronic GI symptoms during their tour in the Persian Gulf.
Methods:
To accomplish this, we evaluated intestinal permeability (IP) using the urinary lactulose/mannitol test. Measurements of intestinal permeability were then correlated with mean ratings of daily abdominal pain, frequency of bowel movements, and consistency of bowel movements on the Bristol Stool Scale in all Veterans.
Results:
A total of 73 veterans had documented chronic GI symptoms (diarrhea, abdominal pain) and were included in the study. A total of 29/73 (39%) of veterans has increased IP and had a higher average daily stool frequency (P<0.05); increased liquid stools as indicated by a higher Bristol Stool Scale (P<0.01); and a higher mean M-VAS abdominal pain rating (P<0.01). Pearson correlation coefficients revealed that there was a positive correlation between increased IP and stool frequency, Bristol Stool Scale, and M-VAS abdominal pain rating.
Conclusions:
Our study demonstrates that deployed Gulf War Veterans with persistent GI symptoms commonly have increased intestinal permeability that potentiates the severity of abdominal pain, diarrhea, and stool consistency. These new findings in our study are important as they may lead to novel diagnostic biomarkers for returning Gulf War Veterans who suffer from chronic functional gastrointestinal disorders. These advances are also important for an increasing number of veterans who are now serving in the Persian Gulf and are at a high risk of developing these chronic pain disorders.
The Department of Defense (DoD) Global Respiratory Pathogen Surveillance Program annually monitors the genetic diversity of influenza viruses circulating in DoD beneficiary populations. This program relies on a global network of partners across the DoD to submit respiratory specimens throughout the influenza season. In previous seasons, representative specimens for sequencing were chosen because of cost and time restrictions associated with reliance on Sanger-based sequencing technology. The effect of this specimen prioritization for sequencing has not been previously examined in the respiratory surveillance program. Here, specimen prioritization was simulated by iteratively subsetting sequencing data sets from 1 October 2013 through 15 March 2017 to determine how prioritizing affects common metrics of genetic diversity. Prioritization of specimens did not meaningfully affect calculations of average influenza genetic diversity within seasons or subtypes. Because of the high genetic diversity of influenza, prioritizing resulted in fewer unique viruses and less accurate measures of geographic relationships although it still provided relevant estimates. Given the advent of cost-effective next-generation sequencing approaches, all programs should carefully consider how best to prioritize influenza sequencing to recover meaningful information on the evolutionary dynamics of the virus.
The native Invaplex (InvaplexNAT) vaccine and adjuvant is an ion exchange-purified product derived from the water extract of virulent Shigella species. The key component of InvaplexNAT is a high-molecular-mass complex (HMMC) consisting of the Shigella lipopolysaccharide (LPS) and the invasin proteins IpaB and IpaC. To improve product purity and immunogenicity, artificial Invaplex (InvaplexAR) was developed using recombinant IpaB and IpaC proteins and purified Shigella LPS to assemble an HMMC consisting of all three components. Characterization of InvaplexAR by various methods demonstrated similar characteristics as the previously reported HMMC in InvaplexNAT. The well-defined InvaplexAR vaccine consistently contained greater quantities of IpaB, IpaC, and LPS than InvaplexNAT. InvaplexAR and InvaplexNAT immunogenicities were compared in mouse and guinea pig dose escalation studies. In both models, immunization induced antibody responses specific for InvaplexNAT and LPS while InvaplexAR induced markedly higher anti-IpaB and -IpaC serum IgG and IgA endpoint titers. In the murine model, homologous protection was achieved with 10-fold less InvaplexAR than InvaplexNAT and mice receiving InvaplexAR lost significantly less weight than mice receiving the same amount of InvaplexNAT. Moreover, mice immunized with InvaplexAR were protected from challenge with both homologous and heterologous Shigella serotypes. Guinea pigs receiving approximately 5-fold less InvaplexAR compared to cohorts immunized with InvaplexNAT were protected from ocular challenge. Furthermore, adjuvanticity previously attributed to InvaplexNAT was retained with InvaplexAR. The second-generation Shigella Invaplex vaccine, InvaplexAR, offers significant advantages over InvaplexNAT in reproducibility, flexible yet defined composition, immunogenicity, and protective efficacy.
Introduction:
Over 25% of Persian Gulf War (PGW) veterans with Gulf War Illness (GWI) (chronic health complaints of undetermined etiology) developed GI symptoms (diarrhea and abdominal pain) and somatic complaints.
Objectives:
Our study objective was to determine if veterans with GWI and GI symptoms exhibit heightened patterns of somatic pain perception (hypersensitivity) across nociceptive stimuli modalities.
Methods:
Subjects were previously deployed GW Veterans with GWI and GI symptoms (n=53); veterans with GWI without GI symptom (n=47); and veteran controls (n=38). We determined pain thresholds for contact thermal, cold pressor, and ischemic stimuli.
Results:
Veterans with GWI and GI symptoms showed lower pain thresholds (P<0.001) for each stimulus. There was also overlap of somatic hypersensitivities among veterans with GI symptoms with 20% having hypersensitivity to all 3 somatic stimuli. Veterans with GWI and GI symptoms also showed a significant correlation between M-VAS abdominal pain ratings and heat pain threshold, cold pressor threshold, and ischemic pain threshold/tolerance.
Discussion:
Our findings show that there is widespread somatic hypersensitivity in veterans with GWI/GI symptoms that is positively correlated with abdominal pain ratings. In addition, veterans with somatic hypersensitivity that overlap have the greatest number of extraintestinal symptoms. These findings may have a translational benefit: strategies for developing more effective therapeutic agents that can reduce and/or prevent somatic and GI symptoms in veterans deployed to future military conflicts.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/.
Background:
Travelers' diarrhea (TD) is a common illness experienced by travelers from developed countries visiting developing countries. Recent questionnaire-based surveillance studies reported that approximately 6-16% of travelers experienced TD while visiting Thailand; however, a majority of TD information was limited mainly to US military populations.
Methods:
A TD surveillance study was conducted at Bumrungrad International Hospital in 2012-2014 in Bangkok, Thailand. Enteropathogens were identified by conventional methods and TaqMan® Array Card (TAC) which employs real-time PCR for the simultaneous detection of multiple pathogens. Analyses to determine pathogen-disease and symptoms association were performed to elucidate the clinical relevance of each enteropathogen.
Results:
TAC identified more pathogens per sample than conventional methods. Campylobacter spp. were the most prevalent, followed by the diarrheagenic Escherichia coli, and norovirus GII. These agents had significant pathogen-disease associations as well as high attributable fractions (AF) among diarrheal cases. A wide range of pathogen loads for Campylobacter spp. was associated with TD, while heat-labile toxin enterotoxigenic Escherichia coli (LT-ETEC) was associated with an increased pathogen load. Most cases were associated with inflammatory diarrhea while Campylobacter spp. and Shigella spp. were associated with dysentery.
Conclusion:
A pan-molecular diagnostic method such as TAC produces quantifiable and comparable results of all tested pathogens, thereby reducing the variability associated with multiple conventional methods. This allows better determination of the clinical relevance of each diarrhea etiologic agent, as well as their geographical relevance in Thailand.
According to the 2015 Global Burden of Disease Study, diarrhea ranked ninth among causes of death for all ages, and fourth among children under 5 years old, accounting for an estimated 499,000 deaths in this young age group. It was also the second most common cause of years lived with disability (2.39 billion YLDs). The goal of the WHO/UNICEF Integrated Global Action Plan for the Prevention and Control of Pneumonia and Diarrhea (GAPPD) is to reduce deaths from diarrhea in children under 5 years of age to less than 1 per 1000 live births, by 2025. Development of new and improved vaccines against diarrheal infections is a fundamental element of the strategy towards achieving this goal.
Enterotoxigenic Escherichia coli (ETEC) and Shigella are enteropathogens that cause significant global mortality and morbidity, particularly in low- and middle-income countries. In 2016, WHO’s Product Development for Vaccines Advisory Committee (PDVAC) recommended that the WHO’s Initiative for Vaccine Research (IVR) engage in this area, based on PDVAC’s criteria of prioritizing the development of vaccines against pathogens that will address a major unmet public health need, and for which clinical candidates with a good probability of technical success are in the pipeline. As a first step, WHO’s IVR convened global subject matter experts to discuss the current global ETEC and Shigella disease burden estimates, including the current understanding of the long-term indirect effects of ETEC and Shigella infection, and how these data may affect future decision making on vaccine development for both pathogens.
The available global burden estimates for ETEC and Shigella differ with respect to the relative importance of these two pathogens. The mortality estimates vary between iterations published by the same group, as well as between estimates of different groups, although the uncertainty intervals are broad and overlapping. These variances are attributable to differences in the data available and incorporated in the models; the methods used to detect the pathogens; the modelling methodologies; and, to actual changes in the total number of diarrheal deaths over time. The changes in the most recently reported mortality estimates for these pathogens, as compared to previous iterations, has led to debate as to whether investment in development of stand-alone vaccines, rather than combined vaccines, is warranted from cost-effectiveness and vaccine impact perspectives. Further work will be needed to understand better the variances and uncertainties in the reported mortality estimates to support investment decision making, and ultimately policy recommendations for vaccine use. In addition, a comprehensive assessment of the value proposition for vaccines against these pathogens is needed and will be strengthened if the long-term health consequences associated with diarrhea and dysentery due to these pathogens are better defined.
To compare the safety and efficacy of loperamide used in combination with ciprofloxacin or ciprofloxacin alone for the treatment of travelers' diarrhea.
Double-blind, placebo-controlled, randomized clinical trial.
United States Army hospital in Egypt.
United States military personnel with travelers' diarrhea (n = 104) during a military exercise in November 1989. Persons who were noncompliant, had bloody diarrhea, or had received antidiarrheal medications before entry into the study were excluded.
All participants with travelers' diarrhea were treated with ciprofloxacin, 500 mg twice daily for 3 days. Fifty of these patients were randomly assigned to receive loperamide, a 4-mg first dose and 2 mg for every loose stool (as much as 16 mg/d), and 54 were randomly assigned to receive placebo.
Enterotoxigenic Escherichia coli was isolated from 57% of patients; Shigella and Salmonella, seen in 4% and 2% of patients, respectively, were not common.
After 24 hours, the symptoms of 82% of patients in the ciprofloxacin and loperamide group compared with 67% in the ciprofloxacin and placebo group had improved or fully recovered (odds ratio, 2.3; 95% CI, 0.8 to 6.3; P = 0.08). After 48 hours, the symptoms of 90% of both groups had improved or fully recovered. The mean number of stools for those receiving loperamide was not much lower than those who did not receive loperamide after 24 hours (1.9 +/- 0.2 [SE] compared with 2.6 +/- 0.2) or 48 hours (3.1 +/- 0.3 compared with 4.0 +/- 0.3) of treatment (P = 0.19).
In a region where enterotoxigenic E. coli was the predominant cause of travelers' diarrhea, loperamide combined with ciprofloxacin was not better than treatment with ciprofloxacin alone. Loperamide appeared to have some benefit in the first 24 hours of treatment in patients infected with enterotoxigenic E. coli. Both regimens were safe.
Norfloxacin, an oral fluoroquinolone (dose 400 mg daily), was compared to a placebo in a double blinded randomized trial for the prophylaxis of travelers' diarrhea. The study was of U.S. Navy and Marine Corps personnel on shore leave in Alexandria, Egypt. A total of 222 subjects were available (105 norfloxacin, 117 placebo). In the placebo group, 26% (30/117) developed acute diarrhea vs. 2% (2/105) in the norfloxacin group. There were no significant side effects in either group.
Acute gastroenteritis is a potential cause of substantial morbidity in U.S. military personnel during deployment. This study was conducted to evaluate enteric pathogens associated with diarrhea in a U.S. military population on deployment in Cairo, Egypt, during November 1993. Enteric pathogens found to be associated with cases of diarrhea included: enterotoxigenic Escherichia coli (ETEC), 27% (22% heat-stable [ST], 3% heat-labile [LT], and 2% ST/LT producers); Campylobacter spp., 3%; and Salmonella spp. 3%. Other enteric pathogens, namely Shigella, Aeromonas, Plesiomonas, Vibrio spp., Bacillus cereus, and enteric parasites, were not found in any of the 36 patients. Of the 8 patients who were ETEC-positive, three expressed colonization factor antigens (CFA)/II, and two expressed putative colonization factor antigen (PCF) 0159. All of the latter isolates produced ST. ETEC with different surface protein antigens were found to have surface hydrophobicity in the range of 0.2 M to greater than 2.0 M. Plasmid profiles of the ETEC strains showed no correlation with toxin production. In vitro susceptibility testing of the ETEC strain showed that 32% of the strains were resistant to three or more antimicrobial agents, whereas 24% showed 100% susceptibility. The enteropathogens tested were susceptible to norfloxacin, ciprofloxacin, and nalidixic acid, suggesting that the quinolones might be useful for the treatment of diarrheic patients.
The potential for widespread diarrheal disease was regarded as a substantial threat to U.S. troops participating in the early phases of Operation Restore Hope in Somalia. Outpatient surveillance of 20,859 U.S. troops deployed during the first eight weeks, however, indicated that a mean of only 0.8% (range 0.5-1.2%) of personnel sought care for diarrhea each week, and in three epidemiologic surveys, < 3% of troops reported experiencing a diarrheal illness per week. Despite these low overall attack rates, diarrhea accounted for 16% of 381 hospital admissions and 20% of 245 patients admitted with a temperature > or = 38.5 degrees C. Sixty-one specimens were obtained from inpatients and 52 were obtained from outpatients. Shigella sp. were isolated from 33%, enterotoxigenic Escherichia coli from 16%, Giardia lamblia from 4%, and rotavirus from 1% of 113 stool samples obtained from inpatient (61) and outpatient (52) troops with diarrhea. Bacterial isolates obtained in Somalia were resistant to doxycycline (78%), ampicillin (54%), and sulfamethoxazole (49%), but uniformly sensitive to ciprofloxacin. With the exception of 10 Shigella sonnei isolates that were linked epidemiologically to one eating facility, bacterial pathogens occurred sporadically and demonstrated a wide variation of serotypes and antibiotic sensitivity patterns. Additionally, three of 11 paired sera collected from persons with nausea, vomiting, and watery diarrhea demonstrated a four-fold or greater increase in titer to Norwalk virus antibody. These data indicate that large outbreaks of diarrheal disease did not occur; however, highly drug-resistant enteric bacteria, and to a lesser extent viral and parasitic pathogens, were important causes of morbidity among U.S. troops in Somalia.
British and Australian medical teams working in Northern Iraq in 1991 providing primary care to refugees and the war wounded were subjected to a descriptive retrospective survey, 5 weeks after arriving in Iraq. The aim was to document different rates of diarrhea in British and Australian troops. The British, who were not taking daily doxycycline and did not enforce a plate- and hand-washing routine, experienced higher rates of diarrhea (69% of British troops compared with 36% of Australian troops), which was more severe and of a longer duration (p < 0.001) and resulted in twice as many days being lost (p < 0.001) in spite of the British team being half the size of the Australian contingent, and the region having enteropathogens with a high rate of antibiotic resistance. Vigorous hand- and plate-washing routines along with doxycycline prophylaxis appear to significantly reduce incapacitation from diarrhea in this military setting and have an important implication for operational effectiveness.
This study investigated the microbial causes of diarrheal disease among U.S. troops deployed near Alexandria, Egypt, during October 1995. Bacterial causes associated with 19 cases of diarrhea included: enterotoxigenic Escherichia coli (ETEC), 42% (21% heat-stable, 11% heat-labile, and 11% heat-stable/ heat-labile producers); enteropathogenic E. coli (5.3%); and enteroadherent E. coli (42%). Four cases of diarrhea were associated with enteroaggregative E. coli based on probe analysis for enteroaggregative heat-stable enterotoxin 1. Protozoan causes included; Entamoeba histolytica (11%), E. hartmanni (5%), E. nana (5%), Blastocystis hominis (5%), Chilomastix mesnili (11%), Dientamoeba fragilis (5%), Entamoeba coli (5%), and Cryptosporidium (5%). Shigella, Aeromonas, Plesiomonas, Vibrio, Campylobacter, and Salmonella were not detected. Of the eight ETEC cases, one was colonization factor antigen (CFA)/I only, one was both CFA/I and CFA/III, three were CFA/II, two were CFA/IV, and two were CFA-negative. Antibiograms of the ETEC and enteroadherent E. coli strains showed that all isolates were susceptible to norfloxacin, ciprofloxacin, and nalidixic acid but resistant to ampicillin, tetracycline, chloramphenicol, and sulfamethoxazole.
To determine whether military personnel deployed outside the United States are at increased risk of Helicobacter pylori infection, we evaluated U.S. Army personnel who served in the Persian Gulf from August 1990 to April 1991. Of 204 subjects
from whom paired predeployment and postdeployment serum specimens were obtained, 76 (37%) were seropositive for IgG antibody
to H. pylori before deployment by an enzyme-linked immunosorbent assay. Of the 111 initially seronegative subjects evaluated before and
after a 7.5-month deployment, five (4.5%) seroconverted. The calculated annual seroconversion rate was 7.3%. In a postdeployment
questionnaire, 62% of soldiers reported an episode of diarrhea while deployed, but there was not an increased rate of diarrhea
or upper gastrointestinal symptoms in soldiers who were infected before deployment or in those who seroconverted. These data
suggest that the risk of H. pylori infection increases during long-term deployment and that acute infection is not distinguishable from other gastrointestinal
illnesses encountered during deployment.
Outpatient medical surveillance of U.S. troops was conducted during 11 different overseas missions between 1981 and 1990. In addition, at the end of each of 18 overseas missions during the same period, a sample of troops was queried regarding illnesses and exposures experienced in the preceding time overseas. Diarrhea was among the leading causes of morbidity during all of these short-term missions. Diarrhea incidence rates were found to be highest during summer months, and were higher during missions to Thailand (median = 25%, range = 20-29%), Latin America (median = 26%, range = 1-43%), and northeastern Africa and southwest Asia (median = 19%, range = < 1-52%). Rates were lowest in troops deployed to the Republic of South Korea (median = 16%, range = 8-27%). During April and May 1990, a focused surveillance and questionnaire study was conducted during a five-week, joint U.S.-Thai military training exercise in central Thailand. Among 2,600 U.S. personnel, diarrheal illness was found to be the most common medical problem for troops (estimated cumulative incidence = 29%). Travel outside of the base of operations and consumption of ice were found to be important risk factors. The 10-year database analyzed for this report is the largest, published summary showing the significant impact of diarrheal diseases on U.S. military forces during short-term deployments to less developed areas.
Travel to the farthest corners of any continent is available to many. The spectrum of problems encountered by the international traveler vary from upper respiratory infections to great scourges such as malaria, plague, and rabies. Health care of the international traveler starts with education and prevention and ends with evaluation for exposures to diseases not normally encountered in the country of origin. This rapidly changing field is well suited to the broad background of the family practitioner.
The second edition of this best-selling book has been thoroughly revised and expanded to reflect the significant changes and advances made in systematic reviewing. New features include discussion on the rationale, meta-analyses of prognostic and diagnostic studies and software, and the use of systematic reviews in practice.
Background: Journalists and relief workers participating in international relief efforts in Somalia following the intervention of outside armed forces in late 1992, were faced with a number of threats to their health. Principally these threats were from endemic infectious diseases and trauma.
Methods: In-patient, emergency clinic, and laboratory records of U.S. military field hospitals, which provided the only available sophisticated medical care in Somalia during most of the study period (December 15, 1992, to February 15, 1993), were reviewed to determine the number of workers evaluated and the causes of their illnesses. In addition, two questionnaire surveys were conducted to elucidate risk factors for illness in these groups.
Results: One hundred and thirty-eight journalists and relief workers, primarily from Europe and North America, were evaluated at a hospital for a variety of common travel-associated health problems, including diarrhea (33%), acute respiratory infection (21%), other febrile illnesses (11%), hepatitis (2%), major trauma (6%), and minor trauma (13%). Documented infectious disease pathogens included Plasmodium falciparum (7 cases), Shigella sp (3 cases), enterotoxigenic Escherichia coli (ETEC) (3 cases), dengue virus-2 (2 cases), and hepatitis E virus (3 cases). Two relief workers were killed by gunshot wounds. In the questionnaire surveys of 104 journalists and 98 relief workers, 84% of respondents reported that they had received some pretravel medical advice, but only 70% sought a medical consultation in person. Thirty-four percent were not receiving a recommended antimalarial chemoprophylaxis regimen, and only 10% obtained a fluoroquinolone antimicrobial drug for self treatment of diarrhea. Sixty-four percent of both groups combined, reported having had diarrhea, and 26% experienced a nondiarrheal febrile illness. Sixty-eight percent reported that their work performance was adversely affected by illness. In multivariate logistic regression analyses, factors associated with an increased risk of diarrhea were age < 35 years (OR 1.5, 95% CI 1.1–1.9); residence in Somalia for more than 21 days (OR 1.7, 95% CI 1.3–2.1); and regular consumption of local food and water (OR 3.8,95% CI 3.4–4.2). Factors associated with nondiarrheal febrile illness were age < 35 years (OR 1.4, 95% CI 1.1–1.8); residence in Somalia for more than 21 days (OR 1.8, 95% CI 1.4–2.2); and not having had an in-person pretravel medical consultation (OR 2.0, 95% CI 1.5–3.0).
Conclusions: These data indicate that journalists and relief workers who traveled to Somalia in response to the massive humanitarian crisis themselves experienced substantial health problems. Improved pretravel medical preparation might prevent or limit illness in these unique groups and improve the efficiency of future disaster response efforts.
Bacterial enteropathogens, the major cause of travelers' diarrhea, are customarily treated with antibacterial drugs. Rifaximin, a nonabsorbed antimicrobial was examined as treatment for travelers' diarrhea.
A randomized, prospective, double-blind clinical trial was carried out in 72 US adults in Mexico. Patients with acute diarrhea received one of three doses of rifaximin (200, 400 and 600 mg t.i.d.) or trimethoprim/sulfamethoxazole (TMP/SMX, 160 mg/800 mg b.i.d.) for 5 days. Results were compared with data from 2 placebo-treated historical control populations.
The shortest duration of treated diarrhea was seen in the group receiving 200 mg rifaximin t. i.d (NS). Clinical failure to respond to treatment occurred in 6 of 55 (11%) rifaximin-treated subjects versus 5 of 17 (29%) of TMP/SMX-treated subjects (NS). Sixteen of twenty (80%) of the enteropathogens isolated from the rifaximin-treated subjects and 7 of 7 (100%) from the TMP/SMX group were eradicated by treatment (NS). Sixteen of twenty-four (67%) enteropathogens identified were susceptible to TMP and all 24 were inhibited by</=50 microgram/ml of rifaximin. Rifaximin reduced the number of unformed stools passed during the first 24 h of treatment when compared with 2 control placebo groups (3.3 versus 5.1; p = 0.008 and 0.0001) and led to a reduced duration of post-enrollment diarrhea (mean values of 43.1 versus 68.1 and 81.9 h; p = 0.001).
Rifaximin shortened the duration of travelers' diarrhea compared with TMP/SMX and 2 earlier studied placebo-treated groups. A poorly absorbed drug if effective in treating bacterial diarrhea has pharmacologic and safety advantages over the existing drugs.
Recent epidemiologic data on travelers' diarrhea (TD) are essential for the evaluation of conventional and future prophylactic and therapeutic measures.
To determine the epidemiology, including risk factors, impact and quality-of-life evaluation of TD, a cross-sectional survey was conducted over 12 months at the airports of Mombasa (Kenya), Goa (India), Montego Bay (Jamaica) and Fortaleza (Brazil) by distributing questionnaires to visitors just prior to their flying home. The study period was March 1996 to July 1998.
Overall, 73,630 short-term visitors completed a questionnaire. The total diarrhea attack rate varied between a high of 54.6% in Mombasa and a low of 13.6% in Fortaleza, but only between 31.5% and 5.4% of all travelers had classic TD. The 14-day incidence rates varied between 19.5% and 65.7%. Few travelers meticulously avoided potentially dangerous food items, although in India and Kenya most travelers avoided those considered most dangerous. Risk factors were stays exceeding 1 week, age between 15 and 30 years, and residence in the UK. The impact, measured as incapacity or quality-of-life scores, was very considerable.
TD continues to affect vacationers and business travelers as frequently as it did some 20 years ago. Compliance with recommendations to reduce exposure to pathogens by avoiding dangerous food items is poor among travelers from all countries. Implementation of food safety education programs may be difficult to achieve.
Detailed knowledge of anticipated casualties is essential for the medical officer preparing to support a mission. To accurately describe the injuries inflicted upon the 2/75th Ranger Battalion involved in Operation Just Cause, 471 (75.5%) Rangers were personally interviewed. The average Ranger was 23 years old, an E-4 with 3 years of active duty service, and in a good to excellent fitness category. The majority went into battle with little sleep or food. Injuries forced 9.5% out of combat, and limited another 9.9%. The overall unit casualty rate was 35%, with 217 Rangers suffering 281 injuries. Most of the injuries were musculoskeletal (sprains) and non-surgical, with 90% occurring during the insertion. The lower extremity, particularly the ankle, was the most frequently injured area. It is hoped that this study will assist those who are planning to support future, similar nighttime parachute operations.
Travellers' diarrhoea is a syndrome of diverse aetiology. So far, its epidemiology and microbiology have been most closely investigated in United States visitors to Mexico: it is not yet clear to what extent the results of these studies can be applied elsewhere. Enterotoxigenic E. coli are important causes but other agents undoubtedly remain to be discovered; they may include strains of E. coli whose pathogenicity is due neither to invasiveness nor to toxin production as detected by current methods. As the diagnostic net extends to include additional likely pathogens, multiple infections are likely to be recognized more frequently than at present and single 'causes' of the syndrome may become more difficult to identify both in individuals and groups. We still lack reliable immunological markers of infection, and we need to know much more more about the nature of immunity to travellers' diarrhoea among long-stay and resident populations. Prevention is still a distant goal. Chemoprophylaxis cannot be generally recommended at the moment, though in some areas doxycycline appears to be useful in the prevention of illness due to sensitive strains of E. coli. Although toxoid vaccines induce only temporary immunity against cholera such vaccines might be effective against travellers' diarrhoea caused by E. coli infections, since exposure to these organisms is usually short-lived. Because there are a number of microbial causes of diarrhoea in travellers, pharmacological methods of control have great potential. Prostaglandin inhibitors and drugs interfering with the activation of cyclic AMP may eventually prove to be effective agents for both prophylaxis and treatment.
A retrospective study on the treatment of diarrhea in a U.S. Air Force Wing deployed to Egypt during Operation Desert Storm was conducted. Two groups of patients were compared for treatment efficacy. One group was treated with norfloxacin 800 mg as a single dose with the onset of symptoms. The other group was treated conservatively. The group treated with norfloxacin was noted to become asymptomatic in one-fourth the time of the group treated conservatively. This was highly significant, statistically, and in practice. It is recommended that diarrhea be treated aggressively during deployments to third world countries.
To determine the efficacy of loperamide given with long- and short-course quinolone therapy for treating traveler's diarrhea,
142 US military personnel were randomized to receive a single 750-mg dose of ciprofloxacin with placebo, 750 mg of ciproftoxacin
with loperamide, or a 3-day course of 500 mg of ciprofloxacin twice daily with loperamide. Culture of pretreatment stool specimens
revealed campylobacters (41%), salmonellae (18%), enterotoxigenic Escherichia coli (ETEC, 6%), and shigellae (4%). Of the participants, 87% completely recovered within 72 h of entry. Total duration of illness
did not differ significantly among the three treatment groups, but patients in the 3-day ciprofloxacin plus loperamide group
reported a lower cumulative number of liquid bowel movements at 48 and 72 h after enrollment compared with patients in the
singledose ciprofloxacin plus placebo group (1.8 vs. 3.6, P = .01; 2.0 vs. 3.9, P = .01). While not delivering a remarkable therapeutic advantage, loperamide appears to be safe for treatment of non-ETEC
causes of traveler's diarrhea. Two of 54 patients with Campylobacter enteritis had a clinical relapse after treatment that was associated with development of ciprofloxacin resistance.
In this double-blind study with 232 patients, 300 mg of ofloxacin given orally twice daily for 5 or 3 days was compared with placebo for the treatment of acute diarrhea in U.S. students visiting Guadalajara, Mexico. The 3-day regimen of ofloxacin was found to be as effective as the 5-day regimen in producing a clinical and microbiologic cure. Clinical cures for patients who received ofloxacin for 5 days occurred in 59 of 66 (89%) subjects, whereas clinical cure occurred in 77 of 81 (95%) of those who received ofloxacin for 3 days and in 56 of 79 (71%) of those who took placebo (P = 0.0001). When the duration of diarrhea after therapy was begun was compared in subgroups, a significant (P less than 0.05) shortening of posttreatment illness occurred in comparison with that in the placebo group for the following groups: for 5 days of ofloxacin, cases of shigellosis (32 versus 98 h); for 3 days of ofloxacin, all cases (28 versus 56 h), cases of enterotoxigenic Escherichia coli diarrhea (26 versus 66 h), cases of shigellosis (24 versus 98 h), all cases of illnesses associated with a bacterial enteropathogen (28 versus 69 h), and cases of illnesses in which numerous leukocytes were found in stool by microscopy (22 versus 49 h). Microbiologic eradication rates were 75 of 78 (96%) for patients who received ofloxacin and 37 of 46 (80%) for patients who received placebo (P = 0.009). There was no significant difference in the number of adverse events reported by patients in either of the treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)
A randomized treatment trial of travelers' diarrhea was carried out among U.S. military personnel participating in routine exercises in several port cities in South America and West Africa. A 5-day, twice daily course of either norfloxacin (400 mg) or trimethoprim/sulfamethoxazole (TMP/SMX, 160/800 mg) was given to 142 volunteers. At the end of 5 days of treatment, diarrhea had resolved in 100% of 73 patients receiving norfloxacin and 97.1% (67/69) receiving TMP/SMX. A probable bacterial pathogen was determined in 44% of 142 subjects: 49% of the norfloxacin group and 39% of the TMP/SMX group. The most common pathogens detected were enterotoxigenic Escherichia coli in 20% of cases and rotavirus in 15%. Resistance to TMP/SMX was present in 20 (27%) bacterial isolates, while no resistance to norfloxacin was found. Eight of 10 patients in the TMP/SMX treatment group who had TMP/SMX-resistant bacterial enteropathogens improved clinically. Both norfloxacin and TMP/SMX were clinically effective in the treatment of travelers' diarrhea in this military population.
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.
Between September and December 1990, stool cultures for enteric pathogens were obtained from 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.
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.
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.
The etiology of travelers' diarrhea was studied in 579 adult Finnish tourists participating in two packaged tours to Morocco in the winter (n = 233) and fall (n = 346) of 1989. A research team accompanied the travelers, and a laboratory for enteric pathogens was established in Agadir. At least one pathogen was found in 62% of the 60 diarrhea cases in winter and in 58% of the 111 diarrhea cases in fall. Multiple pathogens were found less often in winter (8%) than in fall (21%, P less than .05). Campylobacter strains were the leading cause of travelers' diarrhea in winter, found alone or with other pathogens in 28% of the cases (but in only 7% in fall), whereas enterotoxigenic Escherichia coli (ETEC) was the most common pathogen in fall, present in 32% of the cases (8% in winter). Both differences are highly significant (P less than .001). Salmonella enterica was almost as common as ETEC in fall (25% of diarrhea cases) but rare in winter (10%, P less than .05). Thus, the etiology of travelers' diarrhea varied according to the season in the same tourist destination. This finding has relevance to both antimicrobial treatment and prophylaxis.
A study was conducted of travelers' diarrhea in a United States military population on deployment in Cairo, Egypt, during July and August 1987. Acute diarrhea requiring medical attention developed in 183 (4%) of 4,500 troops. A possible etiologic agent was identified in 49% of all diarrhea cases. Enteric pathogens associated with cases of diarrhea included: Enterotoxigenic Escherichia coli (17% ST-producers, 13% LT-producers, and 3% LT/ST-producers); Shigella (9%); Campylobacter spp. (2%); Salmonella (2%); and Vibrio cholerae non-01 serogroup (2%). Other enteric pathogens isolated from one episode each of diarrhea included Aeromonas hydrophila group, Plesiomonas shigelloides, and Bacillus cereus. Yersinia enterocolitica, enteroinvasive E. coli, intoxications by Clostridium perfringens and Clostridium difficile, and pathogenic enteric parasites were not found in any of the 183 patients with diarrhea. A survey of military personnel not requesting medical care indicated that up to 40% of troops may have had diarrhea during this deployment. Acute gastroenteritis is a potential cause of substantial morbidity in U.S. military personnel deployed to Egypt.
During 1984-1989, 655 diarrheic and 287 nondiarrheic stool specimens from adult U.S. citizens living in Lima, Peru were tested for presence of bacterial enteropathogens. Frequencies of isolation among diarrheic specimens were: Shigella 9.8%; Campylobacter 6.1%; enterotoxigenic Escherichia coli (ETEC) 6.0%; Plesiomonas 2.0%; Salmonella 1.4%; and Vibrio 0.6%. Isolates recovered from non-diarrheic stools were: Shigella 4.5%; Campylobacter 2.1%; Salmonella 1.0%; ETEC 0.7%; Plesiomonas 0.7%; and Vibrio 0.3%. Aeromonas, an unproven cause of diarrhea, was isolated from 9.2% of cases and 3.5% of controls. Disease occurrence was strongly associated with isolation of Shigella, ETEC, Campylobacter, or Aeromonas (p less than or equal to 0.01). During the 6-year period of study, shifts in the dominant phenotypes of Shigella and Campylobacter occurred which may have important implications for vaccine development and intervention strategies.
The incidence and etiology of travelers' diarrhea was studied in a crew of 1,914 sailors and marines aboard a U.S. Navy ship during a western Pacific deployment. Questionnaires completed by 301 troops indicated that 52% had at least one episode of diarrhea during the deployment; however, only 5% of the ship's company sought treatment. Enterotoxigenic Escherichia coli was the most commonly identified pathogen (23%), followed by Giardia lamblia (6%), Salmonella (3%), rotavirus (2%), and Shigella, Campylobacter jejuni, and Entamoeba histolytica (1% each). In 66% of the episodes no etiologic agent was found. None of the risk factors thought to be associated with travelers' diarrhea could be statistically associated with the diarrhea group in comparison to questionnaire respondents who denied having had the illness.
A double blind study of daily doxycycline (100 mg) vs. weekly mefloquine (250 mg) was performed on United States soldiers training in Thailand to assess the effect of doxycycline malaria prophylaxis on the incidence of gastrointestinal infections. During a 5 week period, 49% (58/119) of soldiers receiving doxycycline and 48% (64/134) of soldiers receiving mefloquine reported an episode of diarrhea. Infection with bacterial enteric pathogens was identified in 39% (47/119) of soldiers taking doxycycline and 46% (62/134) of soldiers taking mefloquine. Forty-four percent (59/134) of soldiers receiving mefloquine and 36% (43/119) of soldiers receiving doxycycline were infected with enterotoxigenic Escherichia coli (ETEC), while 9% (12/134) of soldiers receiving mefloquine and 4% of soldiers receiving doxycycline were infected with Campylobacter. Side effects from either medication were minimal. After 5 weeks in Thailand, the percent of non-ETEC strains resistant to greater than or equal to 2 antibiotics increased from 65% (77/119) to 86% (95/111) in soldiers on mefloquine and from 79% (84/106) to 93% (88/95) in soldiers on doxycycline. Doxycycline prophylaxis did not prevent or increase diarrheal disease in soldiers deployed to Thailand where ETEC and other bacterial pathogens are often resistant to tetracyclines.
Each year 12 million persons travel from an industrialized country to a developing country in the tropics or subtropics. These
travelers experience a high rate of diarrhea caused by a wide variety of enteric pathogens acquired by ingestion of contaminated
food or water. One or more pathogens can be found in the stool of a majority of ill individuals. Enterotoxigenic Escherichia coli generally are the most frequently identified pathogens, having been found in a median of 42% of travelers' diarrheal episodes
in studies in Latin America, 36% in Africa, and 16% in Asia. Other pathogens that cause diarrhea in a smaller fraction of
ill travelers include Shigella species, Salmonella species, Campylobacter jejuni, Vibrio, Aeromonas hydrophila, Entamoeba histolytica, Giardia lamblia, rotavirus, and 27-nm viruses, including Norwalk virus. Other organisms that may cause a fraction of the episodes of travelers'
diarrhea include Plesiomonas shigelloides, enteroadherent E. coli, adenovirus or other viruses, and Cryptosporidium. Mixed infections of two or more of these pathogens also occur.
A prospective study of acute diarrhoea was performed during 15 months 1981/1982 and included 731 patients and 240 controls. 43% had been infected abroad. A cluster of travellers with bacterial pathogens was diagnosed in July-August. The following pathogens were found: Campylobacter (18%), enterotoxigenic E. coli (6%), Salmonella spp. (5%), rotavirus (4%), Yersinia enterocolitica (3%), Giardia lamblia (3%), Shigella spp. (2%), Clostridium difficile (2%), enteroviruses (2%) and Entamoeba histolytica (less than 1%). More than 90% of the bacterial or parasitic enteropathogens were detected in the first stool sample. Only 10% of the patients needed hospital treatment and for 97% oral fluids were sufficient. The median duration of diarrhoea was 9 days. No fatal cases occurred and only 2 cases of chronic bowel disease were detected.
This paper examines eight published reviews each reporting results from several related trials. Each review pools the results from the relevant trials in order to evaluate the efficacy of a certain treatment for a specified medical condition. These reviews lack consistent assessment of homogeneity of treatment effect before pooling. We discuss a random effects approach to combining evidence from a series of experiments comparing two treatments. This approach incorporates the heterogeneity of effects in the analysis of the overall treatment efficacy. The model can be extended to include relevant covariates which would reduce the heterogeneity and allow for more specific therapeutic recommendations. We suggest a simple noniterative procedure for characterizing the distribution of treatment effects in a series of studies.
An assessment was conducted of the impact of infectious diseases on the 697,000 U.S. troops deployed to the Persian Gulf during
1990–1991 in Operations Desert Shield and Desert Storm. The incidence of nonbattle injuries, including infectious diseases,
during this conflict was lower than during previous wars involving U.S. military personnel. The major reported causes of morbidity
were generally mild cases of acute diarrheal and upper respiratory disease. The most unexpected outcome was the lack of arboviral
infections, particularly sandfly fever, and the occurrence among U.S. troops of 12 cases of visceral leishmaniasis due to
Leishmania tropica. The fact that infectious diseases were not a major cause of lost manpower, in sharp contrast to the experience among military
personnel in World War II, can be attributed to a combination of factors: the presence of a comprehensive infrastructure of
medical care, extensive preventive medicine efforts, and several fortuitous circumstances. Beneficial conditions that may
not be present in future conflicts in this region include isolation of most combat troops to barren desert locations during
the cooler, winter months, which provided the least favorable conditions for transmission of arthropod-borne diseases.
Traveler's diarrhea is usually a short, self-limiting illness lasting on average 3-5 days. The illness may present either as (1) acute watery diarrhea, (2) diarrhea with blood (dysentery) or (3) chronic diarrhea, often with clinical evidence of fat or carbohydrate malabsorption. The majority of cases of traveler's diarrhea are due to intestinal infection and resolve without specific treatment. Antibiotics can reduce the severity and duration of the illness and are always indicated for dysenteric shigellosis and amoebiasis. Oral rehydration therapy is the mainstay for managing water and electrolyte depletion.