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Gastroenteri*s and H. pylori infec*ons
Joanne Engel, M.D., Ph.D. Professor
Depts of Medicine and Microbiology/Immunology
UCSF
"What the?...This is lemonade!Where's my culture ofamoebic dysentery?"
Outline
• Overview of diarrhea/gastroenteri4s • Viral diarrhea incl norovirus • Bacterial diarrhea • Traveler’s diarrhea • H. pylori • C. difficile will be covered by Dr. Jacobs
Diarrhea: a global cause of disease
• 2nd leading cause of morbidity/mortality worldwide
• In the US – 200-‐375 million episodes/year
– 73 million physician visits
– 1.8 million hospitaliza4ons
– 5000 deaths – Each person has 1-‐2 diarrheal illnesses/yr
Case I • 32 yo female calls your office c/o diarrhea x 2 days. She notes 8 loose stools in the past 24 hrs. She has a low grade temp, mild nausea, and has vomited x 2. She denies bloody stools, recent travel, inges4on of unsual foods. No sick contacts.
Issues
• Differen4al diagnosis? • Does the pa4ent need to be seen? • Should abx be given? • Is it safe to give an4-‐mo4lity agents? • Should stool tests be sent? • For which organisms?
Differen4al Dx
• Infec4ous • Ischemic
• IBD • Iatrogenic/Osmo4c • Malabsorp4on
Foodborne illnesses* EID 17:2011
• 31 pathogens acquired in US caused 9.4 million episodes of foodborne illness
• 55,961 hospitaliza4ons • death
*not all cause gastroenteritis!
0 10 20 30 40 50 60 70
Norovirus
Salmonella
C. perfringens
Campylobacter
% episodies of
food
borne illne
s
0 5
10 15 20 25 30 35 40
Salmonella
Norovirus
Campylobacter
T. gondii
% hospitaliza*
ons
0
5
10
15
20
25
30
Salmonella T. gondii Listeria Norovirus
% deaths
E4ology of severe acute gastroenteri4s in adults in ER
• Prospec4ve mul4center ER-‐based study (JID 205:1374)
• Serum, rectal swabs, whose stool
• Pathogens found in 25% • Whole stool more sensi4ve
than rectal swab
0
5
10
15
20
25
30
Norovirus
Rotavirus
Salmonella
C. diff
Campylobacter
Iden
*fie
d pa
thogen
s in ER visits
The players aka “The dirty laundry list” Viral Bacterial Protozoal Calicivirus (Norwalk, Norovirus,Sapovirus)
Salmonella 16.1* Giardia
Rotavirus Campylobacter 13.4* E. histoly4ca
Adenovirus Shigella 10.3* Cryptosporidium 1.4*
CMV Yersinia Microsporidium
Astrovirus E. Coli 1.7* Cyclospora
Small round virus C. difficile
Corona virus C. perfringens
HSV S. aureus
Bacillus
Vibrio
Listeria
Chlamydia *cases per 100,000
N. gonorrhea
Who should be seen: Inflammatory vs non-‐inflammatory?
Take a good history! • When & how illness began • Stool characteris4cs • Frequency & quan4ty • Presence of dysenteric symptoms • Symptoms of volume deple4on
• Associated symptoms • Epidemiologic clues
Be a Sherlock Holmes • Travel to developing area • Day-‐care center akendance or employment • Consump4on of raw meats, eggs, unpasteurized milk/cheese, swimming in or drinking from untreated fresh water
• Farm or zoo animals, rep4les • Exposure to other ill persons • Medica4ons, esp an4bio4cs • Underlying medical condi4ons • Recep4ve anal intercourse or oral/anal contact • Food-‐handler or caregiver
Norwalk Rotavirus
Viral diarrhea
• Usually resolves ≤ 3 days
Norovirus
Rotavirus • Rotavirus
– Infants protected up to age 3 mos by maternal an4bodies – Usually affects children age 6-‐24 mos – At least once before age 5 – Mul4ple serotypes – Immunity incomplete
• Morbidity and Mortality – 25 million clinic visits – 2 million hospitaliza4ons (60,000 in US) – Kills ~ 600,000 children annually in developing countries (37 in
US) – Most disease caused by 4 serotypes
• Dx: stool rapid an4gen
Two vaccines NEJM Jan 2006
• Both are live oral vaccines intended to be given to infants at same 4me as DPT – Rotateq (Merck): age 2m 4m 6 mos
– Rotarix (GSK): age 2, 4 mos
• ACIP recommends rou4ne vaccina4on of infants w/either vaccine
Just a likle stomach flu…
Norovirus
• Single stranded, noneveloped RNA virus • Caliciviridae family
• 6 genogroups-‐>34 genotypes-‐>many strains – GI, GII, GIV cause most human infxns – GII.4 strains predominant since 1990’s
– New GII.4 Sydney strain reported – Rapidly spread across world (CDC)
• Replicates only in GI tract • Persists in environment
• Humans are the only reservoir
Glass et al, NEJM, 2009" Sx
• Inc 24-‐48 hrs • Diarrhea, vomi4ng, abd pain, malaise, low grade fever
• Usually self-‐limited, resolves ≤ 3 d – Prolonged and severe sx in elderly, very young – Prolonged asymptoma4c shedding
• Up to 8 wks in healthy pts • Up to 1 yr in severely IC pts
Dx
• Not culturable • Older techniques: EM, stool ELISA
• Gold standard: RT-‐PCR (since early 1990’s) – 68% sensi4ve – 99% specific – Avail at public health depts, state, na4onal labs, Viracor (2-‐5 d turnaround)
Evolving epidemiology • Most common cause of gastroenteri4s
• 35% of cases of sporadic gastroenteri4s of known cause • 5-‐31% of pts hospitalized for gastroenteri4s • 5-‐36% of clinic visits for gastroenteri4s • Est 71,000 norovirus-‐associated hospitaliza4ons cos4ng $493 million/
yr (CID 2011: 52, 466)
• Greatly under-‐reported – Only 1/1562 cases iden4fied
• Increasing outbreaks • An4genic shit and drit (like influenza)
– Change in viral capsid affects binding to GI tract oligosaccharides – New variant-‐>new epidemic wave – New pandemic strain every 2-‐4 yrs
Increasing outbreaks Evolving epidemiology
• Increased outbreaks in nursing homes and long-‐term care facili4es – 30-‐50% of outbreaks occur in closed facili4es – 28% in restaurants/catered meals – 16% cruise ships – 8% day care centers – Commonly cause by GII.4 strain
• Increased illness severity – Associated with poor outcome in older pts
• Longer illness • Acute renal failure, arrhythmias, hypokalemia, chronic diarrhea
Why is norovirus so difficult to contain?
• Highly transmissable: a likle goes a long way… – ID50: 10-‐100 virions
– Facile 2˚ spread • Viral shedding precedes clinical illness in >30% of pts • Prolonged shedding
– Up to 8 wks in healthy hosts – Up to 1 yr in IC hosts
• Asymptoma4c shedders
– Withstands wide range of temps and persists in environment
– Immunity is short-‐lived and not cross-‐protec4ve against an4genic variants
Why is norovirus so difficult to contain?
• Mul4ple modes of transmission – Food
• Globaliza4on of food distribu4on • Increased # of people who handle the food we eat • Increased consump4on of food at risk of contamina4on (fresh vegetables and
fruit)
– Water
– Airborne via vomitus • Suscep4bility correlates w/distance from vomi4ng event
– Contact w/contaminated surfaces
– Fomites – Person-‐person contact – Resistant to many disinfectants
Interrup4ng transmission
• Disinfec4on – Wipe surface w/detergent to remove par4cle debris
followed by household bleach (5-‐25 Tbsp/gallon) as disinfectant
– Other disinfectants less efficient: (quanternary ammonium compounds, alcohols)
– Alcohol-‐based disinfectants are insufficient • Wash hands for 1 min w/soap & water, rinse for 20 sec, dry w/disposable towels
• Ins4tu4onal sewngs – Cohort pts and staff – Minimize transport, visitors – Isola4on, contact precau4ons for sick pts (48 hrs ater sx resolve) – Sick staff stay home un4l 48 hrs ater sx resolve – Alcohol in, soap& water out
Pa4ent educa4on Planning your next cruise….
Cdc vessel sanitation site!
Case IIa • 32 yo female calls your office c/o diarrhea x 4 days. She notes 8 loose stools in the past 24 hrs. She has a low grade temp, mild nausea, and has vomited x 2. She denies bloody stools, recent travel, inges4on of unsual foods. No sick contacts.
What would you do? 1. Tell her to drink plenty of fluids, take lomo4l as
needed, and that her sx will likely resolve on their own
2. Treat her empirically with a 3 day course of levofloxicin
3. Treat her empirically with a single dose of azithromycin
4. Have her come into your office with plans to send stool for culture, O&P, with plans to start her on levofloxicin
Major bacterial pathogens in the US
Campylobacter Salmonella Shigella
E. coli O157:H7
Dis<nguish from viral diarrhea by dura<on of sx (> 3 days)
Deaths associated with foodborne-‐bacterial pathogens 1996-‐2005
JID 2011:204, 263 • Case fatality rate overall 0.5% of which – Listeria 17%
– Vibrio 5.8%
– EHEC 0.8%
– Salmonella 0.5%
– Campylobacter 0.1%
– Shigella 0.1%
• >65 yo had highest mortality rate
• Obtain cultures early in illness (1st 3 days) • Up to 2 cultures cost-‐effec4ve – Diagnos4c yield 1.5-‐5.6% – Cost ~$1000/posi4ve culture – Be selec4ve-‐
• limit to > 1d dura4on of symptoms • Definitely get for inflammatory diarrhea
• Send to lab ASAP (prevent prolifera4on of normal flora)
• Negligible yield if pt hospitalized > 3 days – Except if HIV+, immunocompromised, age >65, +comorbid illness (Annals of Internal Med 2006)
Bacterial Stool cultures • Special requests for – Vibrio (TCBS media)
– Yersinia – EHEC – Aeromonas
– Pleisiomonas
– C. diff
Vibrio
Tests for parasites Branda et al, CID, 2006
• Negligible yield if hospitalized > 3d prior to onset of diarrhea
• Par4cularly relevant if sx > 7 d, camping, exposure history • DFA for Giardia and Cryptosporidium faster, but misses
other pathogens seen by O&P; 95% sensi4vity • O&P
– Send up to 3 specimens (1 specimen: 71% Sensi4vity) – Send or run 2nd specimen if pt s4ll sx or high index of suspicion
• 2nd specimen adds ~6% sensi4vity • 3rd specimen adds ~3% sensi4vity
– Consider if HIV+ or if cyclospora or microsporidium a serious considera4on
Treatment
• Fluids, Fluids, Fluids • Abx-‐only under special circumstances – Diarrhea will resolve on its own
• An4mo4lity agents (loperamide) – Risk of exacerba4ng disease
• Bismuth subsalicylate • BRAT diet
Role of An4bio4cs • Decrease fecal excre4on (ie Shigella, Giardia, Cholera) – Prolongs excre4on of Salmonella?
• Prevent bacteremia in suscep4ble groups (neonates, IC, HIV, age > 50 ASHD, joint disease, cardiac valvular or endovasc abnl)
• Resolve persistent or life-‐threatening infec4ons – Giardia, amebiasis, cholera
• Hasten recovery 1-‐2 days – Traveler’s diarrhea – “Domes4cally acquired” diarrhea
• Weigh benefits vs drug resistance issues
Which an4bio4cs? • Fluoroquinolones
– Persistent or extra-‐intes4nal salmonella
– Shigella – E. coli (ETEC) in travelers – Prolonged campylobacter – Yersinia – Aeromonas – Pleisiomonas – Vibrio (some4mes) – Resistance increasing
• Azithromycin
• TMP-‐sulfa (kids) – Bacterial, cyclospora,
microsporidium – Resistance is problema4c
• Metronidazole – Persistent giardia – E. histoly4ca – C. difficile
• STD-‐assoc diarrhea
Drug resistance • Mul4drug resistance – Common in Salmonella DT104 (CAM, Septra, Tet, Amp) – Recently reported for Shigella (MMWR 2010 59:1619)
• 3 cases of Shigella in a family that was resistant to cetaz, cefepime, Amp, aztreonam, cefotaxime, cetriaxone, CAM, cipro, NA, strept, sulfisozazole, tet, TMS/Sulfa involving interna4onal adop4on
• Cephalosporin resistance – Salmonella (<0.5%)
• Cipro resistance – Salmonella enterica serotype Kentucky ST198 (Africa-‐>middle
east-‐>European and US travelers (JID 2011)
–
Drug resistance • Quinolone resistance – Campylobacter-‐longer dura4on of infec4on, greater risk of death or invasive disease
– Salmonella spp • Non-‐typhoidal isolates in US:nalR Incr from 1.6% to >2.3% 1996-‐2003
• Typhoidal isolates in US (travelers): 40-‐90% nalR • Most nalR isolates showed decr suscep4bility to ciprofloxicin • Unknown if all ciproR isolates are nalR • Many studies show increased morbidity/mortality in drug resistant salmonella typhimurium infec4ons
– Shigella • 20 cases reported (80% with travel to southeast asia, south asia) • An4microbial Agents and Chemotherapy, April 2011, p. 1758-‐1760, Vol. 55, No. 4
Salmonella outbreaks Case IIB • 32 yo female calls your office c/o diarrhea x 3 days. She notes 8 loose stools in the past 24 hrs. She has a low grade temp, mild nausea, and has vomited x 2. She denies bloody stools. She returned 2 days ago from a 2 week trip to India.
What would you do 1. Tell her to drink plenty of fluids, take lomo4l as
needed, and that her sx will likely resolve on their own
2. Treat her empirically with a 3 day course of levofloxicin
3. Treat her empirically with a single dose of azithromycin
4. Have her come into your office with plans to send stool for culture including Cholera, O&P, with plans to start her on azithromycin
Traveler’s diarrhea • Most common illness in travelers
• Onset usually 5-‐15 days ater arrival • Usually resolves spontaneously 3-‐5 d • 40-‐60% incidence during 2-‐3 wk vaca4on in persons from industrialized countries-‐>developing regions
Traveler’s diarrhea:crikers • Occurs in naïve/non-‐immune hosts – ETEC most common
– Also enteroaggrega4ve E. coli – Campylobacter>Shigella, Salmonella
• Incr FQ resistance in Campylobacter
– Aeromonas, Pleisiomonas, V. cholera, V. parahaemoly4cus
– Rotavirus – Parasites (prolonged diarrhea: E. histoly4ca, Giardia, Cryptosporidium)
– Blastocys4s hominus unlikely to be a pathogen
– 20-‐30% have no iden4fiable cause
Traveler’s diarrhea: Px
• Avoid tap water, ice, bokled noncarbonated beverages
• Avoid raw veggies, unpeeled fruits, raw meat, and seafood
• Ab prophylaxis rarely required
Prophylaxis op4ons • If traveler cannot tolerate few days of illness
• Achlorhydria, IC, underlying chronic GI disease, CRF, DM, ostomies
• Rifamixin-‐effec4ve against ETEC • Peptobismol 2 tabs QID effec4ve in preven4ng ETEC (bacteriosta4c) – ~60% efffec4ve – Side effects: black tongue & stool, mild 4nnitus – Avoid if allergic to salicylates or on salicylates or an4-‐coagulants
– Not to exceed 3 weeks
Traveler’s diarrhea: Rx • Oral rehydra4on usually sufficient • An4mo4lity agents – Loperamide 4 mg followed by 2 mg q loose stool (<16 mg/day) – Not recommended if sx of dysentery (high fever, bloody stool)
• Dysentery: – Levofloxicin 500 mg qd un4l sx resolve or 3 days – Azithro (1000 mg) or 500 mg qd x 3d (preferable in SE & India 2/2 high rate of Cipro-‐R Campylobacter • Tribble et al CID 2007: • 96% cure single dose azithro • 95% cure 3D azithro • 71% cure levo • Cure rate related to levo resistant Campy
– Reduce dura4on of sx ~1 d
Prac4cal approach:
• Have pt fill prescrip4on for quinolone or azithro prior to travel – take if pt gets mod-‐severe diarrheal illness
• Have pt bring loperamide – take if pt has mild diarrheal illness or more severe illness if NO bloody diarrhea
Ini4al management (prior to culture results)
• Mild sx: Non-‐inflammatory diarrhea – Developed country: hydrate & observe, ±an4mo4lity agent – Traveler’s diarrhea: hydra4on, an4-‐mo4lity agent, single dose of levofloxicin or azithromycin
• Mod Sx: Inflammatory diarrhea – Levofloxicin or Azithromycin 1-‐3 d unless C. diff suspected – Loperamide if no bloody diarrhea – Flagyl if C. difficile or E. histoly4ca suspected – If no improvement in 48 hrs, seek medical evalua4on
• To culture or not to culture…that is the ques4on
What about EHEC?
• 95% of pts have bloody stools at least some 4me during their illness
• Abx shown to exac illness (Wong et al NEJM 2000) – Likely by decreasing nl flora and/or enhancing toxin produc4on
• How to dis4nguish dysentry from EHEC – Rely on case epidemiology-‐if returning travel to 3rd world countries, more likely shigella
– If domes4cally acquired, concern for EHEC • Send stool cultures if in first 6 d of illness and await results before prescribing abx
What would you do 1. Tell her to drink plenty of fluids, take lomo4l as
needed, and that her sx will likely resolve on their own
2. Treat her empirically with a 3 day course of levofloxicin (not good for travel to India or SE asia 2˚ to increasing resistance in Campylobacter)
3. Treat her empirically with a single dose of azithromycin
4. Have her come into your office with plans to send stool for culture, O&P, with plans to start her on levofloxicin
Case IIc • 32 yo female calls your office c/o diarrhea x 3 days. She notes 8 loose stools in the past 24 hrs. She has a low grade temp, mild nausea, and has vomited x 2. She denies bloody stools. She returned 2 days ago from a 2 week trip to Hai4.
Vibrio cholera: a life threatening illness in travelers
• Suspect V. cholera in all travelers with severe diarrhea in or returning from 3rd world
• Death can occur within 24 hrs due to profound dehydra4on
• Massive fluid replacement required
• An4bio4cs are an adjunct
Cholera-‐Hai4 2010 A disaster wai<ng to happen
• Unprecedented natural disasters in a poor country – Jan 12, 2010: earthquake
• 250,000 deaths, 300,000 injured, >1.3 million homeless
– November 2010: severe flooding
• World’s worst water system – ranked 147/147 in water poverty index in 2002 – 27% country has basic sewage – 70% households have rudimentary toilets none at all
• Occurred in rural Hai4 rather than displaced-‐person camps near Port-‐au-‐prince
• No cases of cholera in preceding 100 years – No natural immunity
What was the source Chin et al, NEJM Jan 2011
• Prevailing hypothesis was importa4on from South America
• Rapid sequence of isolates from Hai4, South America 1991 outbreak, SE asia (2002, 2008)
• Most resembled variant El Tor 01 strains isolated from Bangladesh
• Likely introduced by human from distant geographic source
Advice for pts w/diarrhea returning from cholera-‐epidemic countries
• Obtain travel hx!!! • If cholera suspected, aggressive rehydra4on • Doxycycline or azithromycin for hospitalized pts • Report to DPH • While risk of person-‐person transmission is low, do not return to work un4l sx subside if food handler, involved in child care, or HCW
Probio4cs • Beneficial microorganisms (lactobacillus or S. boulardii)
• Possible mechanisms – Lactose diges4on – Produc4on of an4-‐microbial agents – Compe44on for space or nutrients – Immune modula4on
• Possible uses-‐no clear indica4ons – Pediatric viral gastroenteri4s – C. difficile & an4bio4c associated diarrhea – Traveler’s diarrhea???
Main refs
• Said et al, CID 2008:47:1202-‐1208 • Glass et al, NEJM 361:18, 2009
hkp://www.cdc.gov/ncidod/dvrd/revb/gastro/norovirus.htm
Blastocys4s CID 2012; 54, 105
• Most frequently isolated stool parasite • Mul4ple species – Zoonosis – human-‐adapted species
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