Diarrhea Part II: The Immunosuppressed Patient Jonathon Sullivan MD, PhD Dept of Emergency Medicine Wayne State University

FOR SOME WEIRD REASON… Ayesha thinks I know more about this than you do. Ayesha thinks I know more about this than you do. Disclaimer follows. Disclaimer follows.

Agenda Review Review The Bug Parade The Bug Parade Usual pathogens Usual pathogens Opportunistic pathogens Opportunistic pathogens Weird pathogens Weird pathogens Organ Transplants Organ Transplants Bottom line: call attending and/or admit. Bottom line: call attending and/or admit. HIV Diarrhea HIV Diarrhea Infectious Infectious Drug-Related Drug-Related Secondary Secondary Approach to HIV+Acute Diarrhea Approach to HIV+Acute Diarrhea

REVIEW OF BASIC SQUIRTOLOGY A quick reprise of some of the high (and low) points of Diarrhea Part I. A quick reprise of some of the high (and low) points of Diarrhea Part I. r‘mber Me?

Causes of Morbidity and Mortality Dehydration, Dehydration, Dehydration Dehydration, Dehydration, Dehydration Electrolyte depletion and malnutrition Electrolyte depletion and malnutrition Bacteremia/Sepsis Bacteremia/Sepsis Perforation, megacolon Perforation, megacolon Underlying condition Underlying condition

The Runs Come in 4 Flavors Secretory Secretory Cholera, viral gastroenteritis Cholera, viral gastroenteritis Inflammatory Inflammatory Dysentery (eg, She-Gella, Amy the Ameba) Dysentery (eg, She-Gella, Amy the Ameba) Chemo Chemo IBD IBD Radiation poisoning Radiation poisoning Osmotic Osmotic Congenital Congenital Drugs Drugs Lactose intolerance and other dietary causes Lactose intolerance and other dietary causes Motility Motility

Inflammatory Diarrhea Results from damage to intestinal mucosa. Results from damage to intestinal mucosa. Unable to resorb water, electrolytes, proteins. Unable to resorb water, electrolytes, proteins. Loss of fluid, lytes and blood. Loss of fluid, lytes and blood. Includes the dysenteries, in which the organism adheres to lining. Blood and white cells in stool. Includes the dysenteries, in which the organism adheres to lining. Blood and white cells in stool.

Secretory Diarrhea Active secretion of water and electrolytes (primarily chloride) into the gut lumen. Active secretion of water and electrolytes (primarily chloride) into the gut lumen. Results from increased cellular permeability. Results from increased cellular permeability. Toxins Toxins Viral damage Viral damage Minimal if any blood, no leukocytes Minimal if any blood, no leukocytes May nevertheless be severe. May nevertheless be severe.

Osmotic Diarrhea Water and electrolytes are pulled into the lumen due to a high osmotic load. Water and electrolytes are pulled into the lumen due to a high osmotic load. This osmotic load can be due to: This osmotic load can be due to: Certain laxatives: Glycerin suppositories, Sorbitol, Lactulose, and Polyethylene glycol (PEG). Certain laxatives: Glycerin suppositories, Sorbitol, Lactulose, and Polyethylene glycol (PEG). Malabsorption: pancreatic disease, celiac disease, etc. Leaves nutrients (osm load) in the lumen. Malabsorption: pancreatic disease, celiac disease, etc. Leaves nutrients (osm load) in the lumen.

Hypermotility Not enough time for nutrients to be absorbed before they shoot out. Not enough time for nutrients to be absorbed before they shoot out. Vagotomy Vagotomy Diabetic neuropathy Diabetic neuropathy Menstruation Menstruation Prokinetic drugs Prokinetic drugs Idiopathic Idiopathic Diagnosis of exlusion. Diagnosis of exlusion.

Or, If You Prefer, These 4 Flavors ViralProtozoan, Rota, adeno, enterovirus, Norwalk CMV, Rota, adeno, enterovirus, Norwalk, Giardia, Amy the Ameba, Cryptosporidium “Invasive”Toxicogenic/Secretory E. Coli 0157:H7, E. Coli 0157:H7, Shigella, Vibrios, Low-Backed Her, Salmonella, Vibrios, Campy Low-Backed Her, Your Sin Yee-Hah Staph, noninvasive E. Coli, Be Serious,, Cholera Staph, noninvasive E. Coli, Be Serious, C. Difficile, Cholera *lumps together invasive, inflammatory, non-amebic dysenteries, etc.

Invasive vs. Noninvase “INVASIVE”“NONINVASIVE” Heme Positive Heme Negative Shigella and Salmonella ETEC, EPEC Campylobacter Cholera (V. cholerae) Entameba histolytica Other Vibrios Yersinia enterocolitica Clostridium perfringens EHEC Be Serious! NorwalkGiardia Cryptosporidia Rota, parvovirus, Rota, parvovirus, weird protists

Approach to the Runny Patient ABCs, resuscitation if necessary. ABCs, resuscitation if necessary. Fluids, electrolytes, EKG, accucheck, temp control Fluids, electrolytes, EKG, accucheck, temp control History: History: Diet: uncooked meat, fish, unpasteurized dairy, sick contacts, last meal, etc. Diet: uncooked meat, fish, unpasteurized dairy, sick contacts, last meal, etc. Stool frequency, consistency, odor, blood, mucus, etc. Stool frequency, consistency, odor, blood, mucus, etc. AP, bloating, N/V, F/C, urinary frequency, etc. AP, bloating, N/V, F/C, urinary frequency, etc. MEDICATIONS, especially HAART and recent antibiotic use. MEDICATIONS, especially HAART and recent antibiotic use. History of opportunistic infections History of opportunistic infections Travel Travel

Physical Exam: Physical Exam: VS: tachycardia, hypotnesion, fever VS: tachycardia, hypotnesion, fever Volume status: turgor, sunken eyes, mucus membranes, cap refill Volume status: turgor, sunken eyes, mucus membranes, cap refill Abdominal exam Abdominal exam Rectal (yes, everybody): blood, pus, associated rectal and perirectal lesions Rectal (yes, everybody): blood, pus, associated rectal and perirectal lesions Contraindications: Contraindications: neutropenia neutropenia No consent No consent No rectum No rectum No finger No finger Approach to the Runny Patient

OUR CAST OF CHARACTERS aka The Bug Parade Three Categories: Three Categories: The Usual Suspects The Usual Suspects Crass Opportunists Crass Opportunists Pathogens From Another Galaxy Pathogens From Another Galaxy

Usual Pathogens Our Old Friends: Our Old Friends: She-Gella She-Gella Sal Monella Sal Monella Campy Lo-Backed Her Campy Lo-Backed Her Be Cereus! Be Cereus! Gee, Our Diarrhea (Lambia) Gee, Our Diarrhea (Lambia) Amy the Ameba Amy the Ameba Your Sin, Yee-Ha! Your Sin, Yee-Ha! Si Difficile Si Difficile

Opportunistic Pathogens Cyto Megaton Virus Cyto Megaton Virus Adenovirus Adenovirus HSV HSV MAC MAC Tales from the Tales from the Cryptosporidium and Isospora and Cyclospora

Pathogens from Another Galaxy Balantidium coli Blastocystis hominis Encephalitozoon intestinalis

Most Common Infectious Causes of Diarrhea in Immunocompromised HIV: HIV: Shigella Shigella Salmonella Salmonella Campylobacter Campylobacter Acute Post-Transplant (w/in 6 mos) Acute Post-Transplant (w/in 6 mos) CMV, CMV, CMV CMV, CMV, CMV Giardia Giardia Cryptosporidium Cryptosporidium

Shigella! Shi sure is.

Invasive and Inflammatory Diarrhea Shigella Shigella Highly communicable Highly communicable Toxic patient with high fever, very loose, bloody, watery stools, +/- pus Toxic patient with high fever, very loose, bloody, watery stools, +/- pus febrile seizures. febrile seizures. Straining at stool Straining at stool Reactive arthritis Reactive arthritis Incubation from 2-7 days. Incubation from 2-7 days. Cipro, TMP/SMX Cipro, TMP/SMX Some association with HUS (Shigatoxin) Some association with HUS (Shigatoxin)

Don’t Confuse Them: Sal Mineo Salmonella No Treatment Treatment Required

Invasive and Inflammatory Diarrhea Salmonella Salmonella Eggs, reptiles and amphibians, chickens, improperly treated foods, Pizza Papalis in Mod 5, esp w. reptile toppings. Eggs, reptiles and amphibians, chickens, improperly treated foods, Pizza Papalis in Mod 5, esp w. reptile toppings. Typhoid (meaning “typhus-like”) fever: Typhoid (meaning “typhus-like”) fever: Relative bradycardia Relative bradycardia Abdominal pain, borborygmi Abdominal pain, borborygmi Leukopenia with eosinophilia Leukopenia with eosinophilia Rash Rash Hepatosplenomegaly Hepatosplenomegaly +/- diarrhea +/- diarrhea Vaccine Vaccine Trivia points: what causes typhus? Trivia points: what causes typhus?

Campylobacter!

Invasive and Inflammatory Diarrhea Campylobacter Campylobacter Most common bacterial squirtosis Most common bacterial squirtosis Most common route: fecal-oral Most common route: fecal-oral In a perfect world, these two words would never go together. In a perfect world, these two words would never go together. Improper food preparation Improper food preparation Beef, pork etc. But mostly it tastes…just like chicken. Beef, pork etc. But mostly it tastes…just like chicken. Associated with HUS, TTP, and Guillan-Barre (!) Associated with HUS, TTP, and Guillan-Barre (!)

Backpackers Beware! Cockpit Cargo Hold Diarrhea Ray Warp Drive Engines

Giardia Lambia Most common intestinal parasite in N. America Most common intestinal parasite in N. America Rivers, streams, ponds, pools, daycare Rivers, streams, ponds, pools, daycare Fecal-oral, anal receptive intercourse. Fecal-oral, anal receptive intercourse. Long incubation: up to two weeks. Long incubation: up to two weeks. Nonbloody, noninflammatory diarrhea Nonbloody, noninflammatory diarrhea Target the warp drive nacelles: Flagyl. Target the warp drive nacelles: Flagyl.

Tales from the Cryptosporidium! Cthulhu Lives!

Cryptosporidium Crytposporidium sux. Crytposporidium sux. Multiple species. Multiple species. Contaminated water, travelers. Contaminated water, travelers. Spores are highly resistant to chlorination and some disinfectants. Spores are highly resistant to chlorination and some disinfectants. Young children and immunocompromised are at high risk. Young children and immunocompromised are at high risk. Dx: serology, acid-fast staining of stool oocytes, intestinal biopsy. Dx: serology, acid-fast staining of stool oocytes, intestinal biopsy. No proven therapy. Paromomycin may help. May require reduction of immunosuppression. No proven therapy. Paromomycin may help. May require reduction of immunosuppression.

Amy!

Amy the Ameba is Not Your Friend Kills 70,000/yr worldwide. Kills 70,000/yr worldwide. Amebiasis may be asymptomatic, or present with mild diarrhea or full-blown dysentery with blood and mucus Amebiasis may be asymptomatic, or present with mild diarrhea or full-blown dysentery with blood and mucus Liver and CNS abscesses, pericarditis(!). Liver and CNS abscesses, pericarditis(!). Fecal-oral, anal receptive, water contamination. Reason # 527 to wash your hands. Fecal-oral, anal receptive, water contamination. Reason # 527 to wash your hands. Pt may be colonized and asx until Amy penetrates mucus and enzymes damage gut wall. Pt may be colonized and asx until Amy penetrates mucus and enzymes damage gut wall. Dx: Serology, assay kits, microscopy. Dx: Serology, assay kits, microscopy. Metronidazole, paromycin (16S rRNA binder), iodoquinol. Metronidazole, paromycin (16S rRNA binder), iodoquinol.

Si, Difficile!

Pseudomembranous Enterocolitis Overgrowth of toxin-producing C. Difficile Overgrowth of toxin-producing C. Difficile 7-10 days after antibiotics 7-10 days after antibiotics Patients often look toxic, febrile Patients often look toxic, febrile ELISA ELISA Stop antibiotics Stop antibiotics Flagyl or vanc, hydration, etc. Flagyl or vanc, hydration, etc. Let ‘em squirt. DO NOT poison these patients with antimotility drugs Let ‘em squirt. DO NOT poison these patients with antimotility drugs Because you’ll kill them. Because you’ll kill them.

C. Difficile Be Difficile Half of transplant patients who get Abx will develop C. Diff enterocolitis. Half of transplant patients who get Abx will develop C. Diff enterocolitis. Full clinical spectrum: Full clinical spectrum: Uncomplicated diarrhea Uncomplicated diarrhea Enterocolitis Enterocolitis Toxic Megacolon Toxic Megacolon Transplant + Diarrhea + Abdominal Pain = Xrays Transplant + Diarrhea + Abdominal Pain = Xrays

Cyto Megatron Virus! I DON’T FEEL SO GOOD. Megatron’s diarrhea comes out here.

CMV AKA Human Herpesvirus 5 or HCMV AKA Human Herpesvirus 5 or HCMV 50-80% of the population has α-CMV Ig, indicating latent infection % of the population has α-CMV Ig, indicating latent infection. Immunocompromised: acute infection vs. reactivation of latent virus. Immunocompromised: acute infection vs. reactivation of latent virus. Most common infection causing symptoms after transplant (esp intestinal transplants). Most common infection causing symptoms after transplant (esp intestinal transplants). Tx: Tx: ganciclovir, valganciclovir, foscarnet, cidofovir ganciclovir, valganciclovir, foscarnet, cidofovir BTW: These all. Good luck, doctor. BTW: These all cause diarrhea. Good luck, doctor. supportive care. supportive care.

Isospora!

Isospora Belli Protist of the coccidia subclass. Protist of the coccidia subclass. Closely related to Toxoplasma gondii and cryptosporidium. Closely related to Toxoplasma gondii and cryptosporidium. Dogs are an important reservoir. Dogs are an important reservoir. Fecal-oral transmission. Fecal-oral transmission. Diarrhea, bloating, misery. Diarrhea, bloating, misery. TMP-SMX. Response varies. TMP-SMX. Response varies.

Cyclospora!

Cyclospora cayetanensis Related to Isospora spp. Related to Isospora spp. Frequent cause of traveller’s diarrhea or “yuppie diarrhea” (organic raspberries from the co-op, anyone?) Frequent cause of traveller’s diarrhea or “yuppie diarrhea” (organic raspberries from the co-op, anyone?) Dx: good luck. Try PCR, serial stool samples, phase-contrast microscopy. Dx: good luck. Try PCR, serial stool samples, phase-contrast microscopy. TMP-SMX. TMP-SMX.

Pathogens from Another Galaxy! GREETINGS, EARTHLING. YOUR BOWEL HABITS, AS YOU HAVE KNOWN THEM, ARE NOW OVER. Encephalitozoon Blastocystosis Balantidium

Intergalactic Squirtosis Balantidium coli. Ciliated protozoan. Balantidium coli. Ciliated protozoan. Fecal-oral route. Fecal-oral route. Tetracycline or diiodohydroxyquin. Tetracycline or diiodohydroxyquin. Blastocystis hominis. Single-celled parasite (order Blastocystida) Blastocystis hominis. Single-celled parasite (order Blastocystida) Implicated in IBS (aka Mountain Girl syndrome) Implicated in IBS (aka Mountain Girl syndrome) Multiple animal reservoirs. Multiple animal reservoirs. TMP-SMX? TMP-SMX? A very primitive fungus among us (order Microsporidia). Encephalitozoon intestinalis. A very primitive fungus among us (order Microsporidia). Forms a in the host cell. Forms a multinucleate plasmodium in the host cell. You don’t have to know exactly what this means to know you don’t like it. You don’t have to know exactly what this means to know you don’t like it. Just weird. Don’t even have mitochondria. Just weird. Don’t even have mitochondria. Dx: Good luck. Special PCR techniques. Dx: Good luck. Special PCR techniques. Tx: Good luck. Try antifungals, fluoroquinolones. Tx: Good luck. Try antifungals, fluoroquinolones. Your sophisticated drugs are no match for our primitive biology!

Organ Transplants 30,000 per year 30,000 per year Diarrhea is a common complication Diarrhea is a common complication Can result in badness. Can result in badness. Differential: Differential: Infection Infection GVH (BMT) GVH (BMT) Std vs. Opportunistic spp. Std vs. Opportunistic spp. Antibiotic effect Antibiotic effect Immunosuppressant effect Immunosuppressant effect

Organ Transplants Up to 6 months after transplant, or during rejection or increased immunosuppression: Up to 6 months after transplant, or during rejection or increased immunosuppression: Opportunistic and viral infections Opportunistic and viral infections Giardia Cryptosporidium CMV Isospora Isospora Cyclospora Cyclospora Microsporidium Microsporidium Strongyloides Strongyloides

Organ Transplants After 6 months, if graft takes well: After 6 months, if graft takes well: More typical, comm-acquired etiologies: More typical, comm-acquired etiologies: C. Difficile Yersinia Salmonella Campy-Low-Backed-Her Campy-Low-Backed-Her Listeria Listeria

Approach to the Post-Transplant Patient with Acute Diarrhea ABCs, supportive care (fluids, fluids, fluids) ABCs, supportive care (fluids, fluids, fluids) Consider isolation protocol Consider isolation protocol Strongly consider C. Difficile (esp if recent abx) and CMV. Strongly consider C. Difficile (esp if recent abx) and CMV. Stool for Cx, O&P Stool for Cx, O&P Call Transplant Surgeon and PMD! Call Transplant Surgeon and PMD! Most cases require admission Most cases require admission

ACUTE DIARRHEA IN HIV DISEASE 50-90% of all AIDS patients % of all AIDS patients. Multiple etiologies: Multiple etiologies: Infectious Infectious Drug-related Drug-related HIV enteropathy HIV enteropathy lymphoma, GI Kaposi’s lymphoma, GI Kaposi’s Hydration, sample collection, strongly consider admission, consult with ID. Hydration, sample collection, strongly consider admission, consult with ID.

ACUTE DIARRHEA IN HIV DISEASE Infectious: Infectious: Most common: Shigella, salmonella, campylobacter, cryptosporidium, Isospora, CMV, MAC, and C.Difficile. Most common: Shigella, salmonella, campylobacter, cryptosporidium, Isospora, CMV, MAC, and C.Difficile. Bacterial: more fulminant Bacterial: more fulminant Viral and parasitic: more indolent Viral and parasitic: more indolent Unlike “normal” patients, patients with HIV + diarrhea usually require testing aimed at isolating the pathogen (or lack thereof). Unlike “normal” patients, patients with HIV + diarrhea usually require testing aimed at isolating the pathogen (or lack thereof).

ACUTE DIARRHEA IN HIV DISEASE Drug-related Drug-related Anti-retroviral therapy (all except Indinavir), especially HAART (mitochondrial suppression with adenosine- based ARVs--check lactate) Anti-retroviral therapy (all except Indinavir), especially HAART (mitochondrial suppression with adenosine- based ARVs--check lactate) Antibiotic therapy Antibiotic therapy Atovaquon Atovaquon Macrolides Macrolides Ganciclovir, Foscarnet Ganciclovir, Foscarnet Antifungalls Antifungalls Post-antibiotic therapy Post-antibiotic therapy C. Difficile C. Difficile Analgesics Analgesics NSAIDS NSAIDS Narcotics (!) Narcotics (!)

ACUTE DIARRHEA IN HIV DISEASE HIV/AIDS enteropathy HIV/AIDS enteropathy Severe, high-volume, watery diarrhea. Severe, high-volume, watery diarrhea. Typically end-stage patients. Typically end-stage patients. No pathogen identified. No pathogen identified. Admission almost always required. Admission almost always required. Octreotide may help. Octreotide may help.

Management ABCs! ABCs! A: Avoid introducing diarrhea into the airway. A: Avoid introducing diarrhea into the airway. B: Avoid breathing in the diarrhea. B: Avoid breathing in the diarrhea. C = replace that volume loss! C = replace that volume loss! Oral vs. IV Oral vs. IV IV NS vs. Juice vs. Soup n’ crackers. IV NS vs. Juice vs. Soup n’ crackers. Sucrose? Worse or better? Sucrose? Worse or better? Replace electrolytes Replace electrolytes Endpoints: improve in clinical hydration status, improve symptoms, make pee-pee. Endpoints: improve in clinical hydration status, improve symptoms, make pee-pee.

ACUTE DIARRHEA ASSESS FOR PERF (THINK S. TYPHII) LAB: CBC, LYTES, CD4, O&P, Cx, FECAL LEUKOCYTES. CONSIDER SMEAR FOR MALARIA. CONSIDER WIDAL TEST OR TYPHIDOT. ABDOMINAL PAIN? FEVER? FLUIDS, OBSERVE hr. CIPRO; BACTRIM + FLAGYL FURROW BROW; GO TO NEXT SLIDE

ACUTE DIARRHEA + HIV + ABD PAIN AND/OR FEVER = ADMIT HYPOTENSION ACUTE ABD NO PO’S? 1.FREAK OUT 2.CALL SURG 3.IVFs ARE GOOD. 4.THINK SAL, SHIG AND S. TYPHII 5.CEFTRIAX + FLAGYL OR CIPRO 6.XRAYS 7.EGDT IF NEC O & P POSITIVE? TENESMUS OR BLOODY STOOL? TREAT FOR AMY THE AMEBA: FLAGYL TREAT FOR GIARDIA: FLAGYL BLOATING OR FLATULANCE? TX FOR COCCIDIA, etc. BACTRIM 14d Tx FOR SAL, SHIG, CAMPY, YERS. BACTRIM or CIPRO 14d Y N Y N Y N YN

DISPOSITION DISCHARGE CRITERIA: DISCHARGE CRITERIA: Nontoxic. Nontoxic. No abdominal pain upon presentation or subsequently. No abdominal pain upon presentation or subsequently. No fever. No fever. Euvolemic. Euvolemic. Normal vital signs. Normal vital signs. Able to tolerate liquids and take medications. Able to tolerate liquids and take medications. Able to GET medications. Able to GET medications. CLOSE FOLLOWUP ARRANGED. CLOSE FOLLOWUP ARRANGED. ADMISSION CRITERIA: Opposite of the discharge criteria. Duh. ADMISSION CRITERIA: Opposite of the discharge criteria. Duh. ALWAYS discuss patient with primary if available; arrange CLOSE follow up for discharged patients. ALWAYS discuss patient with primary if available; arrange CLOSE follow up for discharged patients. No primary? STRONGLY consider admission No primary? STRONGLY consider admission

? Gimme. No good data. Sullydog approves, provided you dilute to 1/3 with water.