CASE #1. 39M with HIV/AIDS (CD4 24, VL 93,000) rarely taking HAART or OI prophylaxis for several months

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1 CASE #1 39M with HIV/AIDS (CD4 24, VL 93,000) rarely taking HAART or OI prophylaxis for several months Presented with acute onset abdominal pain Diffuse, constant, non-positional Reported nausea/vomiting and watery diarrhea x 1-2 months No melena/hematochezia, no fevers/chills 20 lb weight loss over prior 2 months PMH: HIV/AIDS: dx 1993 HSV encephalitis 2001 Peri-appendiceal abscess and SBO s/p LOA and appendectomy 11/2006 CNS toxoplasmosis x 2 in , s/p Clinda/Pyramethamine PCP pneumonia 7/09 s/p 21 days Atovaquone Chronic HBV PPD+ s/p six months of INH Bilateral hip AVN Allergies and Intolerances: Bactrim -> rash Multiple ARVs and OI prophylactic medications, including clindamycin, pyramethamine, atovaquone Meds: (very poor adherence) Epzicom 1 tab PO daily (since 6/09) Raltegravir 400mg PO bid (since 6/09) Dapsone 100mg PO daily Famotidine 40mg PO daily Ibuprofen 800mg PO tid prn Off all HAART x 6 months since self-d/c ing Denies drug use. No recent travel or new exposures.

2 Physical Exam: T: 98.0F, BP: 124/73, HR: 91, RR 16, SaO2: 100% RA GEN: NAD, A&O x 3 HEENT: No scleral icterus CV: RRR, nl S1 and S2 ABD: voluntary guarding, firm, nondistended, diffusely TTP, + rebound RECTAL: Guaiac neg EXT: no c/c/e Basic Labs wbc: 9.2 (76%N, 18%L, 5%M) hct: 37.8, plt: 485 ALT: 52, AST 60, Alk phos: 102, Tbili: 0.8 Abdomen/Pelvis CT: The stomach is markedly distended with contrast with large gastric airfluid level seen. Oral contrast is not seen distal to the stomach and most of the duodenum is collapsed. Findings are concerning for gastric outlet obstruction. No discrete mass is seen in the proximal duodenum. What is your diagnosis 1) Duodenal ucler with obstruction 2) Lymphoma with obstruction 3) MAI 4) Cryptosporium 5) Helicobacter pylori

3 Admitted to surgical service, managed conservatively with NGT decompression and TPN Further lab studies: Stool negative for C. diff, Giardia, Isospora, Microsporidia Serum CMV VL negative Mycolytic blood culture negative EGD: Pylorus appeared deformed with contact bleeding, able to pass scope with difficulty to 3 rd duodenum, which appeared normal Pathology of Pylorus and Gastric Antrum: Stool positive for Cryptosporidium 1. Marked chronic active gastritis. 2. Spherical organisms -approximately 3-5 microns in diameter- attached to epithelial surface of gastric pits, consistent with Cryptosporidium parvum.

4 Hospital Course Started on nitazoxanide 1000mg PO bid for cryptosporidiosis Intermittently able to tolerate meds due to N/V No initial improvement in diarrhea On 12/07, started to develop rising alk phos ALT AST Alk Phos Tbili 12/ / / / / / GGT 364 Hospital Course RUQ Ultrasound: No CBD dilation, focal liver lesions, or gallbladder abnormalities ERCP: Normal major papilla. No ductal abnormalities or filling defects Cholestasis improved as TPN transitioned to enteral feeds Hospital Course Treated with nitazoxanide 1000mg PO bid Gradual improvement in diarrhea, but not in upper GI symptoms Intermittently able to swallow pills, HAART held G-J tube placed endoscopically, after which HAART restarted A week later, developed worsening pain and N/V Repeat CT demonstrated new high-grade SBO in RLQ No reported cases of cryptosporidial-associated SBO Felt to be too high risk to take to OR, attempted to manage medically with NGT decompression and NPO Only intermittently able to tolerate feeds and meds via G-J tube Bridged to hospice, died a week later

5 Take Home Points Always consider infectious causes of bowel obstruction in patients with AIDS Cryptosporidiosis in advanced AIDS still exists Still can be fatal Still no proven anti-parasitic therapies in patients with advanced AIDS HAART is only reliable treatment option Cryptosporidium should be considered in patients with AIDS and cholestasis Gastric involvement is common histologically Always proximal spread from duodenum/jejunum Normal endoscopic appearance does not rule out gastric involvement Variable relationship between oocysts and severity of symptoms True gastric outlet obstruction uncommon, but does occur Clinical Manifestations Immunocompetent: Ranges from asymptomatic infection to severe enteritis Incubation period generally 7-10 days Watery diarrhea, often with N/V, anorexia, malaise, crampy abdominal pain Typically resolves without therapy in days Immunocompromised/HIV: More severe and protracted course Sexual behavior as risk factor less common in women, IVDU than MSM Can lead to significant wasting, especially with CD4 < 100 Can have occasional extra-intestinal manifestations: Gastric Biliary (acalculous cholecystitis or sclorosing cholangitis) Pulmonary oocysts isolated from respiratory tract, unclear significance Hunter & Nichols, Clin Microbiol Rev 2002 Gastric Cryptosporidiosis Three pathology/autopsy reviews Among HIV patients with cryptosporidial diarrhea: Gastric involvement ranged from 27% - 89% on histology All cases were from antral or pyloric biopsies, never found more proximally All cases had concurrent small bowel involvement, though not vice versa Lends credence to theory of proximal spread Stomach had normal endoscopic appearance in 31-93% cases Rivasi et al, 1999 Histological analysis of 8 cases of gastric cryptosporidiosis Parasites seen in areas of altered and inflamed gastric mucosa Intensity of infestation appeared related to degree of pathologic changes All cases had evidence of small bowel or colonic involvement, or both 50% of cases had no changes on gross endoscopy, despite altered histology or high parasite burden Some correlation between upper GI symptoms and severity of gastric involvement Godwin et al. Hum Path 1991;22: ; Rossi et al. Gut 1998;43:476-7 Lumadue et al. AIDS 1998;12: ; Rivasi et al. Histopath 1999;34:405-9

6 Garone et al 1986 Forester et al 1994 Irribarren et al 1997 Moon et al 1999 Cryptosporidiosis and Gastric Outlet Obstruction Initial Presentation CD4 Diagnosis Treatment Outcome 32 yo MSM, 2 months refractory crypto diagnosed with stool modified AFB, p/w worsening N/V/epigastric pain 28 yo MSM with several weeks fever and severe diarrhea, developing severe N/V 32M, IVDU with crypto diarrhea x 1 week, with RUQ pain, U/S with biliary dilation and thickened GB 8F with congenital HIV, 2 months of crypto diarrhea on Azithro, p/w severe N/V? EGD: erythematous and edematous pylorus, difficult to intubate duodenum Biopsies: crypto, inflammation? EGD: 11mm antral stricture, inability to intubate duodenum Biopsies: crypto, chronic gastritis 15 ERCP: Antral narrowing and friability, inability to intubate duodenum Biopsies: crypto, inflammation 10 EGD: pyloric edema, difficult to intubate duodenum Biopsies: Crypto, inflammation Spiramycin Paromomycin x 3 weeks Azithromycin, paromomycin No improvement, died 4 months later Improvement in symptoms and stricture on UGI Clinical improvement, but no improvement of stricture on UGI 3 months later Paromomycin Deteriorated, died 2 months later Garone et al, Am J Gastro 1986, Forester et al, Am J Gastro 1994, Iribarren et al. J Clin Gastro 1997, Moon et al. J Ped Gastro Nutr Biliary Cryptosporidiosis Along with CMV, most common cause of AIDS cholangiopathy Of 20 AIDS patients with cholangitis in British study, 13 had cryptosporidiosis Of 43 AIDS pateints with cryptosporidial diarrhea in Spanish study, 8 had biliary involvement (acalculous cholecystitis on CT or biliary stenosis on ERCP) Clinical Picture: RUQ/epigastric pain, diarrhea, N/V Cholestatic LFT pattern, with average alk phos and elevated GGT Bilirubin and AST/ALT mildly elevated RUQ Ultrasound has good negative predictive value Diagnosed by ERCP Papillary stenosis Intra and extrahepatic sclerosing cholangitis with beading Managed mainly endoscopically Sphincterotomy Endoscopic stenting for CBD strictures Up-to-Date Ursodeoxycholic acid: some evidence of efficacy in small trials Forbes et al, Gut 2003 Lopez-Velez et al, Eur J Clin Microbiol Infect Dis 1995 Treatment of Cryptosporidiosis HAART and subsequent immune reconstitution is the most reliable treatment option, with significantly reduced prevalence since mid-1990s IRIS with cryptosporidiosis not well-recognized entity No anti-parasitic treatment has proven efficacy in immunocompromised host Multiple agents studied Spiramycin Bovine hyperimmune colostrum Azithromycin Paromomycin Nitazoxanide Paromomycin and nitazoxanide only agents subjected to well-designed trials which initially showed some degree of efficacy Carr et al. Lancet 1998 MMWR 58(RR-4) 2009