update on infectious enterocolitides -...
TRANSCRIPT
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Update on Infectious Enterocolitides and the Diseases That They Mimic
Laura W. Lamps, M.D.Professor and Vice-Chair for Academic AffairsUniversity of Arkansas for Medical Sciences
Little Rock, AR
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GI Infectious Diseases are Common Throughout the World
• Transplant patients• Immunocompromised patients• Immigration/international travel• Food/water supply issues
Enteric infectious diseases are second leading cause of deathworldwide, after cardiovascular disease
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Naturally Occurring Foodborne Diseases CDC Estimates for USA, 2010-11
• 47.8 million illnesses/year• 128,000 hospitalizations/year• 3000 deaths/year• Many food-borne outbreaks and
sporadic cases unrecognized
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Naturally Occurring Foodborne Diseases CDC Estimates for USA, 2010-11Cases with Identified Pathogens
• 47.8 million illnesses/year– 9.4 million illnesses/year
• 128,000 hospitalizations/year– 55,961 hospitalizations/year
• 5000 deaths/year– 1351 deaths/year
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Common Etiologic Agents of Infectious Gastroenteritis in USA
• Food-associated– Salmonella– S.aureus– Shigella– Campylobacter– C. perfringens– B.cereus– EHEC
• Water-associated– Giardia– Shigella– Norwalk Virus
(norovirus)– Salmonella– Campylobacter– C. parvum– EHEC
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Top Domestically-Acquired Pathogens Contributing to Foodborne Illness,
Hospitalization, and/or Death
Foodborne Illness Foodborne illness-associated hospitalization
Foodborne illness-associated death
Norovirus Norovirus Norovirus
Salmonella (nontyphoid) Salmonella (nontyphoid) Salmonella (nontyphoid)
C. perfringens Campylobacter Listeria
Campylobacter Toxoplasma Campylobacter
Toxoplasma
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Foods Commonly Associated with GI Infection
Raw Dairy Shellfish Meat
Salmonella Vibrio Salmonella
Campylobacter Hepatitis A Campylobacter
Brucella Norwalk virus Yersinia
E. coli Rotavirus
Listeria Salmonella
Adapted from Fang et al Inf Dis Clin N Amer 5:681-701, 1991
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Naturally-Occurring Food-Borne Outbreaks
• (2010) Salmonella + salami: 184 infections; 1.2 million lbs. recalled
• (2009) E. coli + ground beef: 26 infections in 8 states; 545,699 lbs. recalled
• (1998) Listeria + hotdogs: 17 deaths; 30 million pounds recalled
• (1990s) Raspberries + Cyclospora: 2500 infections in 21 states
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Enteric Infections Acquired from Animals (rare!)
Birds Cats Dogs Goats Ham-sters
Mon-keys
Sheep Snake Tur-tle
Aeromonas x xCampylobacter x x x x x x
Salmonella x x x x x x xYersinia x x xCrypto-sporidium x x x x
Giardia x xStrongyloides x
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Challenges for Pathologists When Evaluating a Specimen for an Infectious Process
• Everything is in formalin– No cultures– Possibly no molecular
• Available resources/techniques that aid in diagnosis may be limited/unavailable, expensive, or unknown to pathologist
• Lack of pertinent history
• Patient given abx before biopsy procedure
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Challenges for Pathologists When Evaluating a Specimen for an Infectious Process
• The training that most of us get in ID pathology is at odds with the worldwide frequency of infectious diseases
– Most pathology training in infectious diseases is in microbiology and divorced from examination of tissue sections
• Ideal diagnostic environment involves morphology, microbiology, and often molecular tests
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Anatomic Pathologist’s Goals When Evaluating a Specimen for Infectious Processes
• Distinguish infectious processes from other processes (ischemia, chronic idiopathic inflammatory bowel disease)
• Try (enthusiastically!) to identify infectious organism or pattern of infection– Biopsy often out long before culture result– Tissue often not preserved for other studies
• Be aware of resources/techniques that aid in diagnosis
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Why should surgical pathologists care about bugs?
• Many can’t be cultured-must recognize patterns of disease in tissue– HIV– HCV– Hantavirus– SARS– Pneumocystis jiroveci (carinii)– Coccidians
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Aids to Diagnosis
• Immunostains– Availability
• Special histochemical stains– Gram: hard to tell enteric pathogens from
normal commensals– Silver impregnation: high background
• Culture– Organism may be fastidious– Can’t tell virulent from nonvirulent strains– Patient may have gotten abx
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Aids to Diagnosis
• Serologic studies– Many cross-reactive organisms– Need acute and convalescent titers– False negatives in immunocompromised,
very old, or very young patients
• Molecular testing– Formalin fixation limits yield– Block may be exhausted
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ID Molecular Testing and FFPE Tissue
• Can be done • Targets must be SMALL (<500 base
pairs)• Primers should target genes exclusively
present in pathogenic strains• Molecular testing must be correlated
with histologic findings
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Responsibilities of the Anatomic Pathologist
• Optimize opportunities to intervene and guide the workup:– Get material for culture, molecular studies– Rapid evaluation techniques
• Frozen section• Touch preps • Air dried smears• Smears, touch preps, and frozens can be used
for same-day special stains
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Responsibilities of the Anatomic Pathologist
• Formulate final anatomic diagnoses that correlate clinical history with – Histology– Special stains– Immunologic studies– Molecular studies– Cultures (if possible)
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Helpful History
• Travel• Food intake• Work/environmental exposure• Animal exposure/zoonoses• Tick, other vector exposure• Sexual practices• Immune status
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General Classification of Histologic Patterns in Infectious Enterocolitides
• Minimal or no inflammation• Acute infectious-type enterocolitis/ASLC• More specific or suggestive patterns:
– Pseudomembranes– Granulomas– Diffuse histiocytic infiltrate– Architectural distortion– Viral inclusions or other visible organisms
Histologic pattern directs diagnostic algorithm
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Infections Producing Minimal or No Inflammation
• Vibrio and non-Vibrio cholerae• Enteropathogenic and Enteroadherent
E. coli• Spirochetosis• Neisseria species• Many enteric viruses
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Spirochetosis
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HIV Enterocolopathy
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Infections Producing ASLC/AITC Pattern
• Campylobacter species• Shigella• Aeromonas• Syphilis (+/- plasma cells)• Occasionally:
– Yersinia– C. difficile– Non-typhoid Salmonella
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•PMN infiltrate•Intact architecture
•+/- crypt abscesses•No basal plasma cells•Surface damage
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• Most common histologic pattern in enteric infections
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Resolving Infection
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Infections Producing More Specific Diagnostic Features
Pseudo-membranes
Granuloma Formation
Diffusehistiocytic Architectural
Distortion
Inclusions/Organisms Visible on H&E
C. difficile Yersinia R. equi Salmonella CMV/HSV
EHEC M. Tb MAI Shigella EAEC
Rarely Shigella
Fungi Whipple’s Disease
Amoeba Spirochetosis
Actino-mycosis
Sometimes Aeromonas
Fungi
Amoeba
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GI Infectious Diseases That Mimic Other Processes
Mimics of Crohn’s
Mimics of UC Mimics of Ischemia
Mimics of Normal
Salmonella Salmonella EHEC CoccidiansShigella Shigella Aspergillus HistoplasmosisYersinia E. histolytica Mucor EAECCampylobacter LGV CMVAeromonas Syphilis C. perfringensE. histolytica C. difficileCMVM. tuberculosis
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Specific GI Infectious Disease Examples
• Commonly encountered– Responsible for majority of food-related
illnesses worldwide
• Mimic other inflammatory conditions
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Campylobacter species
• Most common stool isolate in USA
• Contaminates meat, poultry, water, milk– Fecal-oral transmission also possible
• Common pathogen associated with focal active colitis pattern
Schneider, Havens, Goldblum, et al. AJSP 30: 2006
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Common Enteric InfectionsClinical Features
Fever Diarrhea Infective Dose
Prognosis Pattern Other
Campylobacter Usually Yes, +blood, WBC
500 bugs Usually self-limited; relapse common
AITC Arthropathy, GBS
Salmonella(Typhoid)
Yes, high
Yes, at 2-3 weeks
1000 Need abx; may cause sepsis
IBD mimic
Rash, leukopenia, HSM
Salmonella (non-Typhoid)
Yes Yes 1000 Good with abx
AITC;rarely mimics IBD
Milder illness
Shigella Yes Yes, +blood, mucus, pus
10-100 Need abx; may causesepsis, perforation
AITC or IBD mimic
Constitutional sx; HUS
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• Lamina proprianeutrophils– More
prominent superficially
• +/- Cryptitis and crypt abscesses
• Preservation of crypt architecture
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Campylobacter
• Diagnosis:– Culture is mainstay
• Patients often on empiric abx therapy prior to biopsy
– Darkfield examination of stool smears– Campy antigens on immunoassay– Molecular testing
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Salmonella speciesClinical
• Typhoid (S. Typhi or Paratyphi)– Rising fever– Abdominal pain– Rash– Leukopenia– Hepatosplenomegaly– Diarrhea @ 2-3
weeks
• Non-typhoid serotypes (Enteritidis, Muenchen,
• Typhimurium)– Milder illness– Nausea– Vomiting– Milder fever– Watery diarrhea
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Common Enteric InfectionsClinical Features
Fever Diarrhea Infective Dose
Prognosis Pattern Other
Campylobacter Usually Yes, +blood, WBC
500 bugs Usually self-limited; relapse common
AITC Arthropathy, GBS
Salmonella(Typhoid)
Yes, high
Yes, at 2-3 weeks
1000 Need abx; may cause sepsis
IBD mimic
Rash, leukopenia, HSM
Salmonella (non-Typhoid)
Yes Yes 1000 Good; +/-abx
AITC;rarely mimics IBD
Milder illness; nausea and vomiting
Shigella Yes Yes, +blood, mucus, pus
10-100 Good with abx; may causesepsis, perforation
AITC or IBD mimic
Constitutional sx; HUS
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Salmonella speciesGross Pathology
• Favors ileum, appendix, right colon
• Thickened wall, raised nodules over Peyer patches
• Ulceration and necrosis
• Mesenteric adenopathy
• Milder findings in non-typhoid species, but considerable overlap
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Ulcers typically occur over Peyer’s patches, with necrosis of mucosa
Courtesy Dr. Brian West
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Architectural distortion, crypt abscesses
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Histiocytes and mononuclear cells are most prominent, with fewer neutrophils
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Salmonella
• Features that mimic CIIBD:
– Apthous, linear, and/or deep ulcers
– Crypt distortion
– Right side distribution with ilealinvolvement may mimic Crohn’s in particular
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Non-typhoid Salmonella
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Salmonella speciesDifferential Diagnosis
• Stool cultures help resolve!• Other enteric pathogens
– Longer incubation period (10-15 days)– Neutrophils less prominent– Granulomas unusual
• Idiopathic IBD– Can see significant crypt distortion
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Shigella species
• Invasive, virulent bacteria• Typically from contaminated water• Fecal-oral transmission also possible
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Common Enteric InfectionsClinical Features
Fever Diarrhea Infective Dose
Prognosis Pattern Other
Campylobacter Usually Yes, +blood, WBC
500 bugs Usually self-limited; relapse common
AITC Arthropathy, GBS
Salmonella(Typhoid)
Yes, high
Yes, at 2-3 weeks
1000 Need abx; may cause sepsis
IBD mimic
Rash, leukopenia, HSM
Salmonella (non-Typhoid)
Yes Yes 1000 Good; +/-abx
AITC;rarely mimics IBD
Milder illness; nausea and vomiting
Shigella Yes Yes, +blood, mucus, pus
10-100 Good with abx; may causesepsis, perforation
AITC or IBD mimic
Constitutional sx; HUS
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Shigella speciesPathologic Findings
• Favors left colon
• +/- pseudomembranes
• Early shigellosis has AITC pattern
• Later in the disease there is often significant mucosal damage, architectural distortion
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Shigella
• Features that mimic CIIBD– Mucosal destruction with significant
architectural distortion – Left side distribution can mimic ulcerative
colitis in particular
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from Riddell, Lewin, and Weinstein:Gastrointestinal Pathology and Its
Clinical Implications
Shigellosis with marked architectural distortion
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PseudomembranousShigellosis
Courtesy Dr. John Hart
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Yersinia (enterocolitica and pseudotuberculosis)
• One of the most common causes of bacterial enteritis in N. America and Europe
• Wide variety of acute and chronic GI manifestations
• Contaminates meat, shellfish, poultry, milk and dairy, water
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Chitterlingsalso Chitlins or Chitlings
• “The small intestines of pigs, especially when cooked and eaten as food.”– Probable diminutive of Old English cieter,
intestines• American Heritage Dictionary of the English
Language, 3rd ed, 1996.
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The Chitterling DataTauxe et al
• CDC studied a group of children in Atlanta in 1990 with gastroenteritis secondary to YE (by stool isolate)
• Outbreaks clustered around holidays
• More than 50% exposed to raw pork intestines during household chitterling preparation
• Similar data acquired in Belgium where eating raw and undercooked pork is common
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YersiniaGross Pathology
• Involves ileum, right colon,and appendix preferentially
• Thickened wall with apthous and linear ulcers
• Associated lymphadenopathy
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Granulomatous Appendicitis
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Yersinia enterocolitica
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YersiniaMimic of Crohn’s Disease
• Yersiniosis– Isolated appendiceal
involvement– More acute clinical
onset
• Crohn’s– Disease in multiple
sites– Creeping fat– Fistulae– Histologic changes
of chronicity
Lamps, Madhusudhan, Greenson et al. AJSP 25: 2001Lamps Madhusudhan, Havens et al. AJSP 27: 2003
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Aeromonas species
• Originally recognized as pathogen in turtles and other water dwelling creatures, but only recently in humans– A. hydrophila, A. veronii, and A. sobria now
recognized as important to human GI disease
• Associated with water sources, fish, seafood, veggies, raw milk, ice cream, meat
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Aeromonas sp.
• Particularly a problem in young children (< one year of age), the elderly, and immunocompromised patients, but can affect anyone
• Summer peak• Pleisiomonas species probably
emerging as similar pathogen
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Clinical Findings
• Bloody diarrhea, often mucoid• Nausea, vomiting, crampy abdominal
pain• May have fever and fecal WBCs• Duration of symptoms may range from
days to much longer
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Pathologic Findings
• Often segmental distribution• Edema, friability, erosions, exudate,
loss of vascular pattern– DDx: Ischemia, Crohn’s disease
• Usually shows AITC pattern– Ulceration, focal architectural distortion
may be seen, mimicking IBD
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Aeromonas-ileocecal ulceration
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Aeromonas
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Aeromonas species
• Aeromonas is now an accepted cause of infectious enterocolitis in humans
• Cultures are key to diagnosis
– Some recommend culturing all new onset IBD patients, especially kids
– Molecular testing also available
• May mimic Crohn’s both grossly and histologically
Lindberg, Havens, Lauwers, et al. Mod Pathol 21: 127A, 2008
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E. histolytica
• Infects 10% of world population• Clinical: ranges from asymptomatic to
fulminant colitis• In USA, associated with homosexual
population and unsanitized water
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E. histolytica
• Typical– Flask shaped
ulcers– Right sided
involvement
• Atypical– Pseudomembranes– Toxic megacolon– Crohn’s-like
• Skip lesions• Linear or geographic
ulcers• Architectural distortion• Organisms may be
mistaken for macrophages
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E. histolytica: architectural distortion and skip lesions mimic Crohn’s disease
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Courtesy Dr. David Owen
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•Foamy cytoplasm
•Pale, round, eccentric nuclei
•Ingested red cells are pathognomonic of E. histolytica
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Enterohemorrhagic E. coli
• Usually serotype 0157:H7 • Causes “ischemic-pattern” colitis
– Shiga-like toxins cause thrombosis• Contaminates meat, produce, water• Children and elderly at increased risk
– TTP, HUS
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Enterohemorrhagic E. coliClinical Features
• Crampy pain, watery and/or bloody diarrhea
• Right sided colitis• Mild or no fever• Rare fecal leukocytes
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•Hemorrhagic necrosis•Ulceration with fibrinopurulent exudate•Variably present pseudomembranes, microthrombi
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Enteric Viruses
• Rarely biopsied• Adenovirus, rotavirus, coronavirus,
enterovirus• Diagnosis usually made by stool
culture/immunoassay
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Courtesy Dr. Joel Greenson
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Diagnosis of GI Infectious Diseases
• Many infectious entities are underdiagnosed– HIGH INDEX OF SUSPICION!
• Cultures may not be useful/available– Patient already got antibiotics– Everything is in formalin
• Serologies– False negatives– Cross-reactivity
• Molecular testing
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Utility of Special Stains in Evaluation of Biopsies for GI Infections
• Monkemuller et al, AJCP 2000– HIV patients– 28 months– Sensitivity and specificity for CMV diagnosis
on H&E were 97% and 100%– AFB/GMS stains did not identify previously
diagnoses infection in any patient– Long-term follow-up revealed no missed
infections on H&E– Stains doubled cost
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Big unexplained ulcer
? Elderly Pt
Yes
CMV
No
Get history, tailor workup to that
Immunocompromised Pt
Yes
CMV?HSVGMS?AFB
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Essentially Normal Bx in Immunocompromised Patient
Increased apoptotic
epithelial cells
CMVAdenovirus
Don’t overlook spirochetosis, coccidians, or
Giardia!
Are they severely immunocompromised?
No
Done!
Yes
Get history, consider GMS,
CMV
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Summary
• Infectious (including food-borne) gastrointestinal disease is common, and probably underdiagnosed
• Microbiological and molecular techniques are invaluable partners to biopsy
• Infectious processes may mimic other types of IBD
• Pathologists and lab workers are essential to evaluating food-borne outbreaks
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It’s a great party until someone ends up outside wearing a lampshade on their head.