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Gastrointestinal Manifestations of HIV-infected Children Nuthapong Ukarapol, M.D. Division of Gastroenterology Department of Pediatrics Chiang Mai University.

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Presentation on theme: "Gastrointestinal Manifestations of HIV-infected Children Nuthapong Ukarapol, M.D. Division of Gastroenterology Department of Pediatrics Chiang Mai University."— Presentation transcript:

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2 Gastrointestinal Manifestations of HIV-infected Children Nuthapong Ukarapol, M.D. Division of Gastroenterology Department of Pediatrics Chiang Mai University

3 Introduction GI involvement : one of most common complications in the HIV-infected patientsGI involvement : one of most common complications in the HIV-infected patients Thea DM et al. reported that 37% of HIV- infected infants experienced diarrhea. ( N Engl J Med 1993; 329: )Thea DM et al. reported that 37% of HIV- infected infants experienced diarrhea. ( N Engl J Med 1993; 329: )

4 GI immunity and pathogenesis of diarrhea Altered GI immunity decreased IgA secretion decreased IgA secretion decreased gastric secretion decreased gastric secretion altered GI motility altered GI motility Predispose GI tract to Opportunistic infections Opportunistic infections Neoplasms Neoplasms

5 Common gastrointestinal symptoms & signs Diarrhea Abdominal pain Dysphagia and Odynophagia Gastrointestinal bleeding Weight loss and anorexia

6 DiarrheaDiarrhea

7 Thea DM, et al. N Engl J Med 1993; 329:

8 HIV infection CD4-infected cells cross endothelium into the GI lamina propria HIV is uptaken by macrophage Dormant in the mesenteric lymph nodes Decreased IgA Increased CD8 and lymphoid population in the lamina propria Bacterial overgrowth Increased enodtoxin T cell activation (CD4) Villous atrophy Crypt hypoplasia Decreased CD4 population Accelerate viral replication Villous atrophy Crypt hyperplasia Decreased lactase and disaccharidase activity Fat malabsorption Mucosal injury Malabsorption Diarrhea Malnutrition Any opportunistic or non- opportunisticGI infection TNF, IFN anorexia malnutrition Pathogenesis of diarrhea in HIV-infected patients

9 Etiology of diarrhea in HIV-infected patients

10 Microsporidia, Isospora belli, and Cryptosporidium parvum infection : the first 3 most common pathogens detected in the HIV-infected patients with chronic diarrhea. (Kelly P Q J Med 1996; 89:813-7.) Etiology of diarrhea in HIV-infected patients

11 Isospora belli Microspora Cryptosporidium

12 CMV MAI Cryptococcus neoformans Penicillium TB Miller TL, et al. J Pediatr 1997; 130: Rene E, et al. Dig Dis Sci 1989; 34:

13 Diagnosis: Diarrhea & HIV infection

14 Predictive factors for positive findings in EGD in the HIV-infected patients with diarrhea 1. AIDS stage 2. Serious bacterial infection 3. Many GI symptoms Miller TL, et al. J Pediatr 1997; 130:

15 No gross abnormalities : NPV for normal histologic study:83% esophagus,79% stomach,65% duodenum Miller TL, et al. J Pediatr 1997; 130: Diagnosis: Diarrhea & HIV infection Only 9.3 % of normal endoscopic findings were associated with histologic abnormalities Lim SG, et al. Gut 1993; 34: did not recommend routine surveillance biopsy in the patients who still have CD4 count over 200 /cumm, except in the patients with diarrhea recommended that tissue biopsies and cultures should be carried out while doing endoscopy

16 CMV colitis with chronic diarrhea

17 Stool examination and cultures Endoscopy Diagnosis: HIV-infected children with diarrhea Penicillium marneffei infection, Mycobacterium tuberculosis, and Mycobacterium avium- intracellulare Ultrasound CT abdomen

18 Diagnosis: Diarrhea & HIV infection Randin DR. AJR 1991; 156:

19 Ultrastructure of Intestinal Biopsy in HIV- infected patients without identifiable pathogen Irregular microvilliIrregular microvilli joined bases microvillijoined bases microvilli shortened and broadened microvilli shortened and broadened microvilli tubuloreticular inclusions in the endothelium cellstubuloreticular inclusions in the endothelium cells –immune function disturbances and viral infections Fontana M, et al. J Pediatr Gastroenterol Nutr 1993; 17:255-9.

20 A 6 m/o HIV infected infant presented with chronic diarrhea. After extensive investigations, no specific causes could be identified. Irregular microvilli joined bases microvilli shortened and broadened microvilli

21 stop medication Restart medication start medication Rx: antiretroviral agents Outcomes: 1. Diarrhea stopped 2. Weaning off special formula 3. Gaining weight AIDS enteropathy AZT & Lamivudine

22 Abdominal pain

23 Thuluvath PJ, et al. Q J Med 1991; 78:

24 Abdominal pain & HIV infection Other possibility : Penicillim marneffei mesenteric lymphadenitis Ukarapol N, et al. J Med Assoc Thai 1998; 81:

25 Penicillim marneffei mesenteric lymphadenitis Ukarapol N, et al. J Med Assoc Thai 1998; 81: Report 3 cases of HIV-infected children with fever and abdominal pain: mimic acute abdomen Physical signs of peritonitis were noted. The first 2 patients were diagnosed as acute ruptured appendicitis and had an operation done. The last patient was diagnosed as sepsis.

26 case 1 case 2case 3 Investigations Hb/Hct9.7/ /239.4/30 ( gm% /%) WBC(/x10 -6 l) Plt(/ x10 -6 l)

27 case 1 case 2case 3 Initial Tx exploratomy exploratomy Ceftriazone I.V. laparotomy laparotomy laparotomy laparotomy Operative normal appendix normal appendix not done findings multiple and enlargement of findings multiple and enlargement of matted mesenteric mesenteric nodes matted mesenteric mesenteric nodes and paraaortic and paraaortic LN enlargement LN enlargement U/S abdomen not donemultiple small * Matted enlarge round hypoechoic multiple LN around lesions at porta celiac artery and hepatis(LN) mesenteric vessels

28 Penicillium marneffei mesenteric lymphadenitis Abdominal ultrasound History of acute abdomen with signs of peritonism

29 case 1 case 2case 3 mesentericP. marneffei P. marneffei not done LN biopsy BM smear P. marneffei P. marneffei P. marneffei Skin smearnot done P. marneffei not done BM culture P. marneffei P. marneffei P. marneffei Hemoculture P. marneffei P. marneffei P. marneffei

30 Conclusion I. This report presented clinical manifestrations of P. marneffei infection which are different from previous reports including - abdominal pain - clinical signs which mimic peritonitis

31 II. We suggest things that might help to correct diagnosis. 1. history of HIV infection 2. skin lesions of P. marneffei infection 3. anemia, leukopenia and thrombocytopenia 4. abdoninal ultrasound 5. skin and bone marrow smear 6. blood and bone marrow culture 7. Endemic area of P. marneffei

32 Abominal pain Peritonitis Prolonged fever Pancytopenia Skin lesion Blood culture Smear skin lesion Bone marrow exam&culture Ultrasound abdomen P marneffei Explor yes no yesno CBC, UA, stool exam&c/s serum amylase, lipase, LFTs plain abdomen Upper abdominal pain Lower abdominal pain EGD ERCP BE Colonoscopy Diagnosis No diagnosis CT abdomen, liver biopsy

33 Dysphagia/ Odynophagia

34 Dysphagia & Odynophagia in HIV- infected patients Esophagitis, Esophageal ulcer –Candida albicans –Cytomegalovirus –Herpes simplex virus

35 Ulcer Upper endoscopy: at the EG junction Erythema,Friability,Ulcer CMV Esophagitis

36 Upper endoscopy: White plaques on the esophageal mucosa Candida Esophagitis

37 Dysphagia & Odynophagia in HIV- infected patients Stoane JM, et al. Radiol Clin North Am 1996; 34:

38 GI bleeding

39 GI bleeding & HIV infection Non-infectious causes Infectious causes e.g. salmanella, shigella, Campylobacter, E. coli, E. histolytica, CMV ileitis and CMV colitis Penicillium marneffei Mycobacterium tuberculosis, Mycobacterium avium-intracellulare Diffuse infiltrative lymphocytosis syndrome in the stomach

40 Penicillium marneffei : duodenal biopsy Penicillium marneffei Colitis

41 Diffuse infiltrative lymphocytosis: in the stomach in the stomach Diffuse infiltrative lymphocytosis: in the stomach in the stomach

42 Gastrointestinal cytomegalovirus disease in AIDS children Nuthapong Ukarapol 1, Wattana Chartapisak 1, Nirush Lertprasertsuk 2, Lumduan Wongsawasdi 1, Vinaisak Kattipattanapong 3, Jesda Singhavejsakul 3, Virat Sirisantana 1 1 Department of Pediatrics, 2 Department of Pathology, 3 Department of Pediatric Surgery Faculty of Medicine, Chiang Mai University, Thailand

43 Patients & Methods patients with histologically confirmed gastrointestinal CMV infection were retrospectively reviewed.

44 Results: 6 of 8 < 1 year old median age 4.5 months (2 months-8 year 7 months)

45 Clinical manifestations

46 Laboratories

47 2 patients had a CD4 count done: with severe immunosuppression in 1 patient. – CD 4 count (cells/µl) : 1080 (33%), 490 (16%) 2 patients were diagnosed as CMV retinitis 1 patient also had CMV pneumonitis 1 patient was suspected having CMV hepatitis Laboratories

48 4 colonoscopy 3 EGD 1 flexible sigmoidoscopy Endoscopic findings: Indications 1. Lower GI hemorrhage 2. Chronic diarrhea 3. Odynophagia

49 Endoscopic findings mucosal edema loss of normal vascular pattern patchy erythema friability multiple ulcers Included

50 GI location

51

52

53 Immunochemistry stain with polyclonal antibody to CMV Ag

54 Outcome 6 patients died (4-bowel perforation, 1-massive lower GI bleeding, 1-chronic diarrhea) Two patients with fever, chronic diarrhea, and lower GI bleeding developed first remisssion after being treated with a 14-day course of ganciclovir (10 MKD I.V.). After the completion of ganciclovir therapy, zidovudine and didanosine were started.

55 Relapse occurred 6 weeks and 2 weeks after first remission in these two patients. A second course of ganciclovir was reintroduced with a short-period of remission in one case (2 weeks). Hepatotoxicity from combination of 3 antiviral drugs was suspected in 1 patient. The medicines were then discontinued. Outcome

56 Discussion the virus can infect all parts of the GI tract, however, the colon and esophagus are the most common sites. (In contrast to our study= colon&small bowel: small kids?) In this report, chronic diarrhea and fever are the most common clinical presentations.

57 Vasculitis, caused by CMV infection in the endothelial cells, has been postulated as playing a major role in the development of GI mucosal ulceration following thrombosis and local ischemia. or Primary CMV infection in the epithelial cells of the gastrointestinal tract can also result in mucosal erosion and ultimately ulceration. Discussion Pathogenesis : results from either

58 Discussion DiagnosisDiagnosis should rely exclusively on the finding of typical intranuclear and intracytoplasmic inclusion bodies in the gastrointestinal biopsy. Endoscopy is crucial.

59 Discussion Maintenance therapy for gastrointestinal CMV disease has not been established. At present, the restoration of the immune system by antiretroviral agents seems to be the best in preventing the relapse. gastrointestinal CMV disease in AIDS patients is known to relapse within 3-4 months. (2-6 weeks in this study) If relapse occurs, the second course of ganciclovir or other alternative drugs such as foscarnet was suggested in adult AIDS patients.

60 Conclusion Regarding patients with an unidentified cause of chronic diarrhea, fever, and lower GI bleeding, an early diagnosis using GI endoscopy might be useful to establish diagnosis accuracy and provide appropriate medical treatment. Ganciclovir treatment might be of benefit, but relapses are frequently noted.

61 Hepatobiliary disease

62 Hepatobiliary tract diseases & HIV infection Jaundice, RUQ pain, nausea, vomiting, abnormal LFTs (transminases, alkaline phosphatase)Jaundice, RUQ pain, nausea, vomiting, abnormal LFTs (transminases, alkaline phosphatase) Neither clinical symptoms & signs nor LFTs could definitely predict the etiology and liver pathology of the HIV-infected patientsNeither clinical symptoms & signs nor LFTs could definitely predict the etiology and liver pathology of the HIV-infected patients

63 Etiology of hepatobiliary tract diseases InfectionInfection DrugsDrugs MalignancyMalignancy

64 Infection: most common cause – Mycobacterium avium-intracellulare, Mycobacterium tuberculosis, salmonella, Cryptoccoccus neoformans, Candida albicans, Histoplama, Coccidioides immitis, CMV, Herpes simplex, viral hepatitis, Pneumocystis carinii, Cryptosporidium, Microsporidia, and HIV Mycobacterium avium-intracellulare, Mycobacterium tuberculosis, salmonella, Cryptoccoccus neoformans, Candida albicans, Histoplama, Coccidioides immitis, CMV, Herpes simplex, viral hepatitis, Pneumocystis carinii, Cryptosporidium, Microsporidia, and HIV Etiology of hepatobiliary tract diseases Cappell MS. Am J Gastroenterol 1991; 86:1-15.

65 Increased risk of HBV infection associated with IVDU & homosexualIncreased risk of HBV infection associated with IVDU & homosexual Increased risk of chronic hepatitis B infectionIncreased risk of chronic hepatitis B infection Increased risk of HDV coinfectionIncreased risk of HDV coinfection Increased incidence of HCV infectionIncreased incidence of HCV infection Viral hepatitis v.s. HIV

66 CMV & Cryptosporidium associated with sclerosing cholangitis, papillitis, acalculous cholecystitis, stonesCMV & Cryptosporidium associated with sclerosing cholangitis, papillitis, acalculous cholecystitis, stones ERCP with biopsy is helpful for diagnosis.ERCP with biopsy is helpful for diagnosis. Treatment can be provided by ERCP.Treatment can be provided by ERCP. Sclerosing cholangitis Yabut B,et al. J Pediatr Gastroenterol Nutr 1996; 23:624-7.

67 5 y/o girl with HIV infection gradual onset of jaundice gradual onset of jaundice epigastric pain pale-colored stools hepatomegaly (span 9cm) LFTs albumin 3.2 gm%, globulin 5.5 gm%, alkaline phosphatase 1022 Cholesterol 392 mg%, AST/ALT 450/350 IU/L, TB/DB 7.95/4.88 mg% Cholesterol 392 mg%, AST/ALT 450/350 IU/L, TB/DB 7.95/4.88 mg% GGT 180 GGT 180

68 HBs Ag negative, HCV antibody negative CMV IgM negative, CMV IgG >3200 Ultrasound: mild dilatation of intrahepatic bile duct with diffuse thickening of bile duct wall CT: Bile duct dilatation Liver pathology: Moderate mixed inflammatory cells infiltration at the portal tracts, AFB negative. Investigation: Continue

69 ERCP Irregularity of bile ducts Stenosis & dilatation Bead-like appearance Dx: Sclerosing cholangitis

70 Etiology of hepatobiliary tract diseases Bonacini M. Am J Med 1992; 92:

71 MalignancyMalignancy Etiology of hepatobiliary tract diseases Kaposi’s sarcoma Non-Hodgkin lymphoma

72 Jonas MM,et al. J Pediatr Gastroenterol Nutr 1989; 9:73-81.

73 Liver pathology in HIV-infected children Giant cell transformation: associated with CMV, Kaposi’s sarcoma, NHL Nonspecific findings –portal inflammation –steatosis –pericentral necrosis –lymphoma

74 Jaundice, RUQ pain, abnormal liver function tests History - drugs and infection Initial investigation Serology for CMV, HAV, HBV, HDV, HCV Serology for CMV, HAV, HBV, HDV, HCV Blood culture for bacteria, Mycopbacterium, funguses, viruses Blood culture for bacteria, Mycopbacterium, funguses, viruses Bone marrow aspiration Bone marrow aspiration Ultrasound and CT abdomen Focal lesion Dilated bile duct ERCP Diagnosis No diagnosis Liver biopsy with special stains and cultures Diagnostic approach to an HIV-infected patients suspected having hepatobiliary diseases

75 17% in HIV-infected children ( Miller TL, et al. J Pediatr 1992; 120:223-7.) Associated with CMV, Cryptosporidium, Mycobacterium avium-intracellulare, and P carinii infection Risk factor –Exposure to Pentamidine –Low CD4 count Pancreatitis & HIV infection

76 Other drugs:Other drugs: –Trimethoprim-sulfamethoxazole, ddI Serum amylase is much less sensitive than serum lipaseSerum amylase is much less sensitive than serum lipase Poor prognosisPoor prognosis Pancreatitis & HIV infection

77 Thank you


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