Presentation on theme: "Infectious Diarrhea in Travel and Military"— Presentation transcript:
1 Infectious Diarrhea in Travel and Military COL Kent E. KesterOctober 2013
2 Definition of Travelers’ Diarrhea Cramps, nausea, vomiting, fever, blood in stoolsClassic – passage of > 3 unformed stools in 24 hours plus at least one of above symptomsModerate: 1-2 unformed stools in 24 hours plus one of above symptomMild: passage of one or two unformed stools in 24 hours without other symptomsTypically acquired within first few weeks of travel/ deployment.
3 Impact of Diarrheal Diseases in Modern Military Campaigns World War II: ‘A few months of the year, malaria would cause more man-days lost, but on the calendar-year average, gastrointestinal infections were well ahead.’1Vietnam War: Diarrhea/dysentery largest single disease threat, leading to 4 times more hospitalizations than malaria2OIF: Acute enteric illness was leading cause of hospital admission among British forces during first 12 months of operations in Iraq31) Ward, TG: History of Preventive Medicine, U. S. Army Forces in the Middle East, 19Oct Jun44, Vol [Official record.](2) Wells RF, GI Diseases: Background and Buildup. In: Internal Medicine in Vietnam Vol II: General Medicine and ID, US Army Medical Dept 0:(3) Grange, C: J Royal Army Medical Corps, 2005:151(2):(4) Matson, David O: Infect Dis 2005:40;526-7.(1) Ward TG: History of Preventive Medicine, US Army Forces in the Middle East, 19Oct Jun44, Vol [Official record.](2) Wells RF, GI Diseases: Background and Buildup. In: Internal Medicine in Vietnam Vol II: General Medicine and ID, US Army Medical Dept 0:(3) Grange, C: J Royal Army Medical Corps, 2005:151(2):
4 clinical presentations Force Health ImpactsAfghanistanVomiting onlyIraqSevere diarrheaDysenteryDiarrhea with fever13-14%5-15%21-27%2-8%9-25%clinical presentationsMissed patrolIV fluidsHospitalizedConfined to bedrest Job performance9-13%12%15-17%13%45%2%GroundedFecal incontinenceBack-fill needed6-12%32%operational impact-When we look at what has been reported from current operations in Iraq and Afghanistan we see: [first panel]-Furthermore, [next panel] we identify important impacts in terms of duty lost, decreased performance, and operational impacts. Among troops reporting diarrhea illness during the first 2 years of operations in Iraq, nearly a third reported not being able to find a latrine facility quickly enough. [next panel]-Here is a photo from a soldier's blog which also describes the potential impact on morale and welfare these frequent infections might have. [next panel]-While diarrhea does not directly result in mortality of individuals, one can imagine the hypothetical contribution that a severe infection might have on an individual where he or she is afflicted with such an illness, may be sleep deprived because of the frequent awakenings to use the facilities, and because of this does not recognize the trip wire to a roadside improvised explosive device, or through lapsed attention walks into a booby trap.
5 Incidence Rates of Travelers’ Diarrhea per 2-week Stay
6 Epidemiology 90% of travelers’ diarrhea caused by bacteria Most occur between 4-14 days after arrivalHighest risk area Asia (except for Singapore), Africa (outside South Africa), South and Central America, MexicoStress of travel and hot temperature may make symptoms less tolerableMost are self limited, dehydration is main cause of morbidity
7 Epidemiology in Children Major cause of morbidity and mortality> 10 illness per child per yearAsia, Africa, Latin America – 4 million deaths per yearUp to 50% of childhood deaths
11 Etiology of Diarrheal Diseases: U.S. Military on Deployment ETEC22%EAEC13%C jejuni10%Norovirus8%Shigella7%Salmonella5%Rotavirus4%Other/no pathogen31%29%6%3%9%38%Latin America, Caribbean12%25%4%11%Southeast Asia13%23%17%1%7%2%28%37%Middle EastMS Riddle et al. Am. J. Trop. Med. Hyg., 74(5), 2006
12 Clinico-pathological Considerations: Acute Travelers’ Diarrhea Watery diarrheaDysenteryGastroenteritisMechanismNon-inflammatory (enterotoxin)Inflammatory (invasion or cytotoxin)Villus blunting (delayed gastric emptying)LocationProximal small bowelColon or distal small bowelSmall bowelUsual PathogensAll causative pathogens; most commonly ETEC, EAECC. jejuniShigella spp.Salmonella (non-typhi)EHECNorovirus Rotavirus
14 Risk Factors Crowding and poor sanitation Lower gastric acid secretion Epidemic diarrheaShigella dysenteriaeVibro choleraeLower gastric acid secretionThose taking histamine blockers and PPIThose with altered upper GI anatomyImmunocompromised hostHIV, steroids, autoimmune condition
15 Types of E.coli E. coli consists of a diverse group of bacteria. Pathogenic E. coli strains are categorized into pathotypes.Six pathotypes are associated with diarrhea1). Enterotoxigenic E.coli (ETEC)2). Shiga toxin-prod. E. coli (STEC) / Enterohemorrhagic E. coli (EHEC).3). Enteroaggregative E. coli (EAEC)4). Enteroinvasive E. coli (EIEC)5). Enteropathogenic E. coli (EPEC)6). Diffusely adherent E. coli (DAEC)
16 Enterotoxigenic E. coli (ETEC): Features Transmissionfoodborne (food, water)inoculum sizeHigh (≥ 5x106 organisms)infants, LDC; travelers to endemic regionspopulations at riskEstimated no. cases annually200 million worldwide; > 500,000 under five death per yeartypical clinical syndromewatery diarrhea; dehydration in moderate-severe diseasephenotypic diversity2 enterotoxins; > 20 fimbrial typesphysical and cognitive retardation; malnutritionsequelae
17 Escherichia coli Common in Travelers ETECEAECSTEC / EHECFimbrial colonization factors mediate enterocyte adherenceElaboration of secretory heat-labile (LT), heat- stable (ST) enterotoxinsEnterocyte adherence and biofilm formationElaboration of secretory enterotoxins and cytotoxinsInduction of attaching and effacing (AE) lesions in the colonic epitheliumElaboration and absorption of Shiga toxin (STx)adapted from Kaper JB et al Nat Rev Microbiol 2004
21 Shigellosis: Features transmissionperson-to-person; foodborne (food, water)inoculum sizelow ( organisms)reservoirshumans onlytoddlers living in and travelers to LDC; crowding, poor sanitation (e.g., day care, institutions)populations at high riskserotypic diversityOver 50 different serotypes (determinant, LPS)invasion, spread, inflammatory response; cytotoxicity (S. dysenteriae type 1, Shiga toxin)key pathogenic processestypical clinical syndromedysentery (most commonly)natural immunityMedium-term, serotype-specific immunityReiter’s syndrome; reactive arthropathy; hemolytic uremic syndromesequelaeLDC, less developed countries
22 Differential Morbidity Associated with Major Bacterial Pathogens of Travelers’ Diarrhea Pathogen profileGlobal prevalence (%)Illness duration after treatment (mean, d)Probability of causing incapacitation (%)Illness duration w/o treatment (mean, d)10 (5-15)22 (17-28)7 (3-10)C jejuniETECShigella8.03.67.14721-2756-922.51.01.2
23 Salmonella Typhoidal Salmonella Non-typhoidal Salmonella S. typhi or S. paratyphiTyphoid or Enteric feverColonized humans, fecal-oral transmissionSystemic illness with very little or no diarrhea (small bowel disease)Non-typhoidal SalmonellaSeveral speciesNot common cause of traveler’s diarrheaAnimal or human fecal materialPoultry, petsInvasive, bloody stools
24 Virbrio cholerae Toxigenic serogroups 01 or 0139 Free living organisms in brackish waterEpidemics throughout human historySpreads quicklyAcute watery diarrheaFood or water contaminated with human fecal materialCholera enterotoxinStimulates secretory mechanism of intestinal mucosa1/5 infected will have severe disease, diagnose by cultureRehydration is keyTetracyclines, doxycycline, ciprofloxacin reduces illnessOral vaccine available (not in U.S)Incomplete, short protection
26 Comparison of clinical feature of epidemic dysentery and cholera Causative organismShigella dysenteriae type 1Vibrio cholerae O1(Vibrio cholerae O139)Infective dose10 to 100 organisms1000 to 1,000,000 organismsClinical featuresBloody diarrheaAbdominal crampsFeverRectal painWatery diarrheaDehydrationVomitingComplicationsSeizuresRectal prolapseHemolytic-uremic syndromeSepsisSevere hypovolemia/shockElectrolyte abnormalitiesTreatmentAntibioticsRehydrationTransmissionFood and waterPerson-to-personCase fatality rate10 to 20 percent (untreated)5 percent (treated)40 percent (untreated)<1 percent (treated)Regina C LaRocque, MD, MPH, and Mark Pietroni, MA, MBBChir, FRCP, DTM&H.
27 Noroviruses: Features transmissionfoodborne (food, water); person-to-person (crowding)inoculum sizelow (as few as 10 viral particles)reservoirshumans only; hardy virus, persists on fomitesAll age groups; outbreak potential in semi-closed populations – military populations, including shipspopulations at high riskgenotypic diversity3 genogroups, and ≥ 25 genotypesLimited to small intestine, broadening/blunting of proximal intestinal villi; transient malabsorptionkey pathogenic processesSudden onset of vomiting and non-inflammatory diarrhea; duration typically ≤72 hourstypical clinical syndromeShort-term homologous immunity; possible long-term immunity with repeated exposurenatural immunitysequelaeNo evidence of serious long-term sequelae
28 Acute Water DiarrheaWatery stools of <14 days duration, with no visible blood constitutes acute watery diarrhea.(A) Green watery stool. Green colored stool, often seen in rotavirus gastroenteritis.(B) Rice water stool. White colored stool characteristic of severe cholera.
29 Clinical and Diagnostic Evaluation Assess for dehydrationMild (3-5%): dry mouth, decreased sweat and urine outputModerate (6-9%): orthostasis, skin tenting, sunken eyesSevere (>10%): hypotension, tachycardia, confusion, shockConsider setting of illnessHost factorsEnvironment, geographic regionPathogenDefine the clinical syndromeWatery diarrheaDysenteryGastroenteritis with recurrent vomitingPersistent diarrhea
30 Considerations for Laboratory Work-up With military deployments, available laboratory capabilities may be austereSeveral common pathogens are not detectable with routine laboratory diagnostic testsDiarrheagenic E. coli (ETEC, EAEC, EIEC)NorovirusDifferentiate inflammatory vs. non-inflammatory diarrheaClinical indicators of inflammatory disease include fever, tenesmus, visible blood in stoolGross and microscopic examination of stool for blood and fecal leucocytes
31 Considerations for Laboratory Work-up (level III) Stool culture: clinical indicationsSevere diarrhea (≥ 6 loose/liquid stools/24 hrs, incapacitating illness)Febrile enteritis and/or dysenteryPersistent diarrhea (≥ 14 days duration)Bloody diarrhea (at risk for Shigella, STEC)Inflammatory enteritis (by stool diagnostics)Stool parasitology: clinical indicationsDiarrhea in traveler returning from known high risk regionStool microbiology available at Level III facility (CSH).
33 Therapeutics: Water and Electrolyte Replacement Cornerstone of diarrhea treatmentMilitary settings, insensible fluid losses increased with high ambient temperature, intense physical activityOral rehydrationPhysiological principle: Integrity of coupled transport of Na+ (plus H2O and other electrolytes) with glucose or amino acidsEffective in majority of patientsIntravenous rehydrationSevere dehydrationAltered sensoriumIntractable vomiting
34 Oral Rehydration Therapy Mild dehydrationPotable water or appropriate ORSModerate-severe diseaseORS (Oral Hydration Salts)WHO ORSPedialyteRehydration FormulasGatoradePoweradeSports DrinksRed BullApple JuiceOther fluidsChicken BrothCHO g/LNa mmol/LCHO:NaK mmol/LOSM mOsm/kg13.5254560-801086907520~103532501.23.113~6~3230-328245330601500For ORS, ideal solutions have an osmolarity that is < plasma (~300 mOsm/L); sufficient Na to replace deficit; ratio of glucose to Na between 1:1 and 1:2 to achieve maximum absorption; added K to replace stool losses (20 mmol/L).Emergency solutions: CDC recommendation – add 1 tsp salt and 2-3 tblsp sugar or honey per L water. Lacks HCO3 but will work.Compliance can be improved by use of commercial flavor packets.Rule of thumb: replace each fluid bowel movement with 2 glasses of fluid.Osmolarity and electrolyte content of WHO ORS is optimal for rehydration. Fluids with high glucose and high osmolarity are not ideal but are better than nothing. Highly sweetened drinks (e.g., apple juice) can increase intestinal fluid losses. Sports drinks are better balanced but have higher carbohydrate content and lower electrolyte replacement capability. Energy drinks (e.g., Red Bull) are poor choices for rehydration – high in carbohydrate, lower sodium than desired and higher osmolarity.
35 Non-Antibiotic Therapy Consider with mild diarrhea for symptomatic reliefLoperamide (imodium): antimotility agent of choiceSlows down peristalsis, intestinal transitIncreased fluid and salt absorption4 mg by mouth, then 2 mg after each liquid movement (up to 16 mg per day)Okay to use for non-bloody, non-febrile diarrhea.Bismuth subsalicylate (Pepto Bismol)Reduces number of passes stoolsDoes not limit duration of disease525 mg (2 tabs) every 30 min for 8 dosesContraindicated in persons on salicylates, warfarinCan interfere with doxycycline absorption (malaria prophylaxis)
36 Empiric Antibiotic Therapy Indicated for patients with moderate to severe diarrhea/dysenteryCombination of antibiotic PLUS loperamide leads to rapid resolution of illnessRe-evaluate patient if no improvement after 1 wkAntibiotic (po)Dosage (adult)ConsiderationsFluoroquinolonesNorfloxacin800 mg once or 400 mg bidRe-evaluate h after single dose. Continue for up to 3 d if diarrhea not resolvedCiprofloxacin750 mg once or 500 mg bidOfloxacin400 mg once or 200 mg bidLevofloxacin500 mg once or 500 qdAzithromycin1000 mg once or 500 mg bid x 3dUse when C. jejuni suspectedRifaximin200 mg tidEffective for non-invasive E coli
37 Effectiveness of Antibiotics, and Additive Effect of Loperamide) Placebo vs antibiotics alone (outcome: cure at 72 hours)Bruyn G et al Cochrane Collab 2004Antibiotics alone or plus loperamide(outcome: cure at 24 hours)Riddle MS et al, CID 2008Favors Placebo Favors AntibioticsTLUS ~ 12 hoursDuPont,1982Ericsson, 1983Mattila, 1993Salam, 1994Steffen, 1993Wistrom, 1989Total13.96 [5.47,35.65]10.52 [3.43,32.28]3.34 [149,7.48]5.73 [1.14,28.92]4.63 [2.20,9.75]4.72 [1.96,11.39]5.90 [4.06,8.57]However first I want to briefly summarize the evidence in terms of antimicrobial treatment of travelers diarrheaIn this systematic review by the Cochrane collaboration we see that among 6 randomized double-blinded placebo controlled trials which evaluated antibiotic therapy against placebo and looking at clinical cure at 72 hours, we see that all studies demonstrated a statistically significant increased odds of clinical cure with antibiotics. Time to last unformed stool was noted to range between 24 – 36 hours.In a more recent meta-analysis conducted we looked at what was the added advantage of adding an antimotility agent to this antibiotic regimen. We considered clinical cure at 24 hours as the primary outcome.[click]What we found that among 6 studies which compared antibiotic alone compared to the same antibiotic combined with loperamide that there was a statistically significant increase odds of clinical cure among combined regimens. You will note that the 3rd study down showed no effect. This was the Petrucelli study in Thailand which tested a single dose of Ciprofloxacin. Given what we know about the predominance of Campylobacter, the prolonged duration of illness, despite appropriate therapy, and the potential issue of resistance to fluoroquinolones, one might have predicted that no effect would be seen in this study.However, it appears that at least for non-invasive watery diarrhea (which is most commonly encountered) a combined strategy may have significant advantages, particularly in a deployment environment where the austere environment, operational requirements and risk for dehydration would favor rapid resolution of symptoms.While there were no important safety issues reported in use of combined regimens, we do need to consider these in moving forward with treatment recommendations on individual and population levels.[next slide]TLUS = 24 – 36 hours
38 Increasing Fluoroquinolone Resistance among Campylobacter in Travelers No. resistant isolatesResistance rate (%)No. resistant isolatesResistance rate (%)RegionNo. isolatesNo. isolatesAfrica1622213.61143631.6Asia2087435.6956770.5Caribbean, Central & So. America361027.8332060.6Use Azithromycin in SE ASIA, mg x 1 may be enoughStudy site: Travel clinic, Antwerp, BelgiumErythromycin resistance showed modest increase over same period to 8.6% resistance in 2006Vlieghe ER et al, J Travel Med 2008;15:419-25
40 Complications of Bacterial Diarrhea Associated Bacterial AgentsComplicationClinical ConsiderationsAny bacterial pathogenMost important complication of watery diarrheaDehydrationSalmonella spp., C. fetusCertain conditions predispose to systemic Salmonella infectionBacteremiaHemolytic-uremic syndrome (HUS)STEC, S. dysenteriae type 1Pathogenesis due to shiga toxin absorption and damageGuillain-Barré syndromeCampylobacter jejuni40% cases of GBS caused by C. jejuni; molecular mimicry LOSC. jejuni, Salmonella, S. flexneriOccurs in 2.1 per Campylobacter infectionsReactive arthritisIrritable bowel syndromeMost bacterial pathogens≤ 10% incidence following bacterial enteric infection
41 Antibiotic associated GI problems Any antibiotic can cause upset stomach, loose stoolsClostridium difficile infection happens when normal bacteria are killedC.difficle patients have high fever, highly elevated WBC’s, large volume smelly stools, and appear sick (not always).C.difficile may be ‘community onset’Treatment is metronidazole
43 Postinfectious Irritable Bowel Syndrome (PI-IBS) First described among British Forces during WWII (Stewart. Br Med J 1950; 1(4650):405–9)Approx. 1 in 12 people develop PI-IBS after infectious diarrheaHigher risk associated with prolonged illness and invasive pathogensOnset usually occurs within 6 months after infectionCan persists 5-6 years in % of peopleHalvorson et al, Am J Gastroenterol. 2006; 101:
44 Persistent Travelers’ Diarrhea Travelers’ diarrhea is often self-limited, resolving in the majority of cases after several daysIllness lasting >1 week: 10% of casesIllness lasting >1 month: 2% of casesEtiological considerations with persistent diarrheaEAEC (occasionally, Campylobacter, Salmonella)Parasitic diarrheaGiardia lambliaCryptosporidium parvumCyclospora cayatanensis
45 Giardiasis: Life Cycle Giardia lamblia: Protozoan flagellate
46 Giardiasis: Features transmission contaminated water; infected food handlersinoculum sizelow (as few as cysts)antigenic variationon-off switch of variant specific surface proteins (VSP)key pathogenic processesAttachment to intestinal epithelium via ventral disc; flagellar motility; VSP switching evades IgAtypical clinical syndromewatery diarrhea; epigastric abdominal pain, bloating, malabsorption, nausea, weight losssequelaeFunctional gastrointestinal disorders (IBS)reservoirsHumans and other mammalspopulations at high risktreatmentSelf-limited. Metronidazole, tinidazolebackpackers; young children LDC; higher risk with travel to Russia, Mexico, SE Asia, South AmericaGiardia lamblia: Protozoan flagellate
47 Cryptosporidium: Features transmissioncontaminated water and food; person-to-personinoculum sizelow (as few as 10 oocysts)species diversitymajority of human cases due to C. hominis, C. parvumkey pathogenic processesLocalizes in parasitophorous vacuoles in intestinal epithelium; distal small intestine; villous atrophytypical clinical syndromewatery diarrhea, abdominal cramps, vomiting, mild fever, and loss of appetitesequelaeintractable diarrhea in immunocompromised patientsreservoirshumans and other mammals (including livestock)populations at high risktreatmentSelf limited. None great, nitazoxanideHIV/AIDS; urban populations, municipal water contamination; children in LDC; travelersCryptosporidium, protozoan pathogen of the Phylum Apicomplexa
48 Cyclosporiasis: Features transmissioncontaminated food and water; no person-to-personinoculum sizeundefinedspecies diversityC. cayatanensis found only in humanskey pathogenic processesnot well understood; localizes to small intestinal epithelium, partial villous atrophy, crypt hyperplasiatypical clinical syndromepersistent diarrhea, anorexia, nausea/vomiting, abd cramps, flatulence, low grade fever, weight losssequelaeChronic diarrhea in immunocompromised patientsreservoirsenvironmental; may be host species-specific typespopulations at high risktreatmentSelf-limited, Trimethoprim-sulfamethoxazole (TMP/SMX)young children in LDC; travelers (especially Peru, Nepal, Haiti, Guatemala (*); immunocompromisedCryptosporidium, protozoan pathogen of the Phylum ApicomplexaFigure. Life cycle of Cyclospora cayetanensis. Unsporulated oocysts differentiate into sporulated oocysts, which undergo the excystation process.Sporozoites infect cells to form type I merozoites, and these form type II merozoites. The sexual-stage microgametocyte fertilizes the macrogametocyteto become a zygote and thus to differentiate as an unsporulated oocyst. Appears that both asexual and sexual reproduction can occur in same host.
49 Amebiasis Protozoan parasite Entamoeba histolytica Not common traveler’s diarrhea pathogenLonger stays in tropical endemic areaFecal oral spreadMost infections (90%) have no symptoms or mild diarrheaAmebic dysentery is severe infectionFever, bloody stoolsLook for trophozoite in stoolMay be confused with non-pathogenic speciesLiver abscess and systemic infectionTreatment: iodoquinol, paromomycin, metronidazole
56 Prevention – Food and Water Boil it, cook it, peel it, or forget itAvoid iceWash hand when possibleCondiments on table can be contaminatedIt is difficult to do …. but have to mention it
57 Rifaximin and Chemoprophylaxis of Travelers’ Diarrhea ProsConsPoorly adsorbed oral antibioticAbsent side effectsLow levels of rifaximin resistance among enteric pathogensProphylaxis against travelers’ diarrhea for short-term travelersETEC predominant regions≥70% protection conferredLimited studies to dateGeographically delimitedPredominance of ETEC/EAECShort duration travelImpact of widespread usage for prophylaxis unknownAlong these lines, I would like to turn your attention to a more frequent post-infectious sequela that has been observed and that is of post-infectious irritable bowel syndrome.In this meta-analysis of observational studies which included an infectious gastroenteritis exposed group matched with a control, it is observed that having an infectious gastro enteritis increases your risk of developing PI-IBS by about 7 fold.It is noted that higher risk occurs in prolonged illness and with invasive pathogens, and can occur for a number of years after onset.IBS is the leading cause of visits to GI physicians in the United States and results in considerable morbidity and health-care costs.[next slide]
58 Prevention of Enteric Diseases in Deployed Personnel Pre-deployment counseling of troopsAvoid exposure to pathogens transmitted by soiled food and drinkSeek early treatment with diarrheaAdminister appropriate enteric vaccinesTyphoid vaccines (oral or IM)Hepatitis A vaccine [Havrix, Avaxim]; Hepatitis B vaccineProbioticsNo official recommendationAntibiotic chemoprophylaxisNot recommended for routine travel or deploymentHepatitis A vaccine: Hepatitis A is the most common vaccine-preventable virus acquired during travel, so people travelling to places where the virus is common like the Indian Subcontinent, Africa, Central America, South America, the far East, and Eastern Europe should also be vaccinated.