1. Tropical diseases and the Gastrointestinal system Ahmed Laving ESPGHAN Post Graduate Course 2013

2. Case 1 3 yr old girl from Western Kenya c/o diarrhoea for 6 wks Stools x6-10/day (x3 at night), mucoid, occasionally bloody, foul smelling, tenesmus Intermittent fevers, mouth sores, rashes, joint pains but no joint swelling No h/o contact with PTB Weight gain appropriate

3. Case 1 (..2) PMH: first episode of mucoid stools at 6 months of age; intermittent symptoms Repeated courses of antibiotics, metronidazole Positive family h/o atopy and had multiple food allergies (milk, wheat, bananas) Had been on elemental milk with initial response but with periodic flares Diagnosis?

4. Case 1: (..3) Fair GC, P°, J°, afebrile, not dehydrated Wt: 14 kg, Ht: 91 cm, MUAC 17.5 cm Aphthuous mouth sores, healed skin lesions, perianal erythema, no anal tags or fissures Hb: 10.1, MCV 60, ESR 28, Eos: 6%, Albumin 40 Stool: occult blood +ve, few pus cells + RBC’s, Campylobacter sensitive to azithromicin Endoscopy: oesophagitis, gastritis, pancolitis (non- specific, normal eosinophil counts)

5. Case 1: Diagnosis? Infectious enteropathy (Campylobacter) Allergic enteropathy ?Inflammatory Bowel Disease (IBD)

6. Case 1: Final diagnosis Management: – Azithromicin: no response, repeat stool c/s -ve – Dietary elimination of dairy, wheat products – Prednisone (tapered off), sulfasalazine (?IBD) Recurring episodes of fever, bloody, mucoid stools (compliant to dietary elimination, drugs) Inadvertent finding: Father of child on ARV’s! Elisa for HIV: positive Child started on ARV’s with resolution of symptoms Final Diagnosis: HIV enteropathy

7. Tropical diseases and GIT HIV and the GIT Malnutrition associated enteropathy Tropical sprue Sickle cell hepatopathy Amoebic liver abscess Schistosomal liver disease

8. HIV and the GIT

9. Uncommon if CD4 >200 Oropharynx: Thrush, hairy leukoplakia, ulcers Oesophagus: Candida, HSV, CMV Small/large intestines: chronic diarrhoea – Bacterial: Salmonella, Shigella, Campylobacter, TB – Fungal: Histoplasma, Coccidiomycosis – Protozoa: Cryptosporidia, Microsporidia, Isospora – Others: CMV colitis, C. difficile, bacterial overgrowth Rectum: Kaposi’s Sarcoma, HSV, condylomata, Non-Hodgkins lymphoma

10. Oesophagus Oesophagitis-Burning retrosternal pain, odynophagia. Candida HSV-Multiple small ulcers CMV-Solitary large ulcer

11. Oesophagitis

12. HIV: Small/Large Intestine disease Usual presentation: diarrhoea with colicky abdominal pain ± fever and weight loss Bacterial causes are common Salmonella – 20x more likely to get non-typhoid salmonella – Severe disease with relapses – Long term ciprofloxacin may be necessary Shigella, Campylobacter, Mycobacteria (MAC)

13. Protozoal Infections Usually manifest with fever, watery diarrhea, nausea, vomiting, abdominal pain, dehydration, weight loss Cryptosporidia 1% per yr in those with CD4< 300 50% respond to Nitazoxanide (long courses) Microsporidia May require stool EM, intestinal aspirate or biopsy Extra-intestinal features: eye, muscle and liver Isospora Peripheral eosinophilia Septrin, Ciprofloxacin Giardiasis: chronic diarrhoea with malabsorption

14. Other Causes of Diarrhoea CMV colitis – Nonbloody diarrhoea – Endoscopy: multiple ulcerative lesions – Biopsy: intranuclear inclusion bodies – May induce vasculitis in the colon/distal small bowel resulting in GI bleeding. Clostridium difficile- drugs Neoplastic disease: Kaposis/NHL Small bowel bacterial overgrowth

15. Bacterial Overgrowth A syndrome of diarrhoea with attendant malabsorption Uncommon in immuno-competent individuals Predisposing factors: Impaired intestinal immunity, motility and gastric hypoacidity Rx: broad spectrum antibiotics Duration of Rx unknown

16. HIV Enteropathy Syndrome of non-infective diarrhoea Possible pathogenetic mechanisms: – direct infection of the enterocyte by HIV – infection of the lymphoid tissue of the GIT with dysregulation of local cytokine production – Secondary damage due to opportunistic infections Prevalence and impact of diarrhea on health-related quality of life in HIV-infected patients in the era of highly active antiretroviral therapy. Siddiqui U, Bini EJ, Chandarana K, Leong J, Ramsetty S, Schiliro D, Poles M J Clin Gastroenterol. 2007;41(5):484. **A prospective study of diarrhea and HIV-1 infection among 429 Zairian infants.Thea DM, St Louis ME, Atido U, Kanjinga K, Kembo B, Matondo M, Tshiamala T, Kamenga C, Davachi F, Brown C N Engl J Med. 1993;329(23):1696

17. HIV Enteropathy (2) Diagnostic workup: – Stools: mcs, AAFB staining (cryptosporidia, cyclospora), trichrome staining (microspora) – Blood cultures: if suspect disseminated disease – Endoscopy: colitis, multiple ulcers, lymphoma – CT abdomen >50% of diarrhoeal illnesses in HIV-infected individuals no identifiable pathogen *Physiological effects of HIV infection on human intestinal epithelial cells: an in vitro model for HIV enteropathy.Asmuth DM, Hammer SM, Wanke CA AIDS. 1994;8(2):205 **Diagnostic strategies in HIV-infected patients with diarrhea. Mayer HB, Wanke CA AIDS. 1994;8(12):1639.

18. HIV Enteropathy: Treatment Antiretroviral therapy: early initiation with reduced incidence of diarrhoea Empiric antimicrobial use: nitazoxanide, metronidazole, ciprofloxacin (2-3 weeks) Specific Rx: antivirals, pyrimethamine ?Antimotility agents, ?probiotics Zinc supplementation not shown to alter duration or severity in adults *Malabsorption and wasting in AIDS patients with microsporidia and pathogen-negative diarrhea.Lambl BB, Federman M, Pleskow D, Wanke CA AIDS. 1996;10(7):739. **Randomized controlled trial of zinc supplementation for persistent diarrhea in adults with HIV-1 infection. Cárcamo C, Hooton T, Weiss NS, Gilman R, Wener MH, Chavez V, Meneses R, Echevarria J, Vidal M, Holmes K J Acquir Immune Defic Syndr. 2006;43(2):197

19. Malnutrition Associated Enteropathy (Environmental Enteropathy)

20. Malnutrition and Diarrhoea Reduced food input Malnutrition Reduced immunity Diarrhoeal disease Increased nutritional demand Convalescent period not enough to catch up nutrients

21. Infant Diets Review of 42 infant feeding studies published 1996-2006: (Dewey and Adu-Afarwuah, 2008) Children who received interventions gained 0-760 g more weight (0.0 – 0.76 WAZ) 0 – 1.7 cm taller (0.0 – 0.64 LAZ) The very best of these interventions produced a 0.7 Z-score improvement BUT, the average growth deficit of African and Asian children is –2.0 Z-score At best, diet solved 1/3 of the problem

22. Environmental Enteropathy (EE) A major cause of child undernutrition may be a subclinical inflammation of small intestine EE: Chronic inflammation of the gut, characterised by: – Villous flattening – Modest malabsorption – Inflammatory cell infiltrate – Increased permeability – Bacterial overgrowth

23. Environmental enteropathy (2) Starved infants pass frequent green liquid stools of small volume (less than 10 grams) Pathogenesis – Impaired development and function of the immune system, therefore increase in enteric infection – generalized increase in inflammatory mediators – impaired tissue repair mechanisms – Specific nutrient deficiencies, such as vitamin A and zinc deficiencies

24. EE: Management Inpatient or outpatient management of malnutrition Multivitamin (and zinc) supplementation Empiric use of antibiotics Improve hygiene and sanitation Role of anti-inflammatory agents (?mesalamine)

25. Tropical Sprue

26. Tropical sprue A syndrome of acute or chronic diarrhoea, weight loss and malabsorption. Occurs in the tropics and subtropics Aetiology unknown, but intestinal microbial infection may cause the initial insult Coliform bacteria (E.coli, Klebsiella, Enterobacter) usual organisms isolated

27. Tropical sprue (2) Pathogenesis: – Infection results in enterocyte injury, intestinal stasis and possible bacterial overgrowth – Results in malabsorption with deficiencies of Iron, Folate, B12 Affects people who live in areas with sprue as well as travellers who stay for > 1 month

28. Tropical sprue (3) CBC: megaloblastic anaemia, Iron deficiency Diagnosis: endoscopy – Tropical sprue involves the entire small bowel – Gross findings at endoscopy include flattening of duodenal folds and "scalloping” – Histology: shortened, blunted villi and elongated crypts with increased inflammatory cells Must rule out other causes of diarrhoea, especially infective

29. Tropical Sprue: Management Antibiotics for 3-6 months Folate, Vitamin B12, Iron supplements No role for antibiotic prophylaxis to prevent sprue

30. Giardiasis (2) clinical manifestations*: – 50 %: asymptomatic and clear the infection – 5 to 15% asymptomatic shed cysts – 35 to 45% of individuals have symptomatic infection: Acute disease Chronic disease Diagnosis: – Stool microscopy * 2012 UpToDate,Release: 20.9 - C20.24

31. Amoebic Liver Abscess

32. Epidemiology Amoebic liver abscesses (ALA) most common extraintestinal site of infection of E histolytica occur in fewer than 1% infections ALA is 10 times more common in adult males than females while colonic infection is identical in males and females

33. Pathogenesis: Amoeba cysts ingested and Trophozoites released Infect intestines and cause necrosis with formation of flask shaped ulcers Gain access to the portal vein system and liver Cause necrosis of the hepatocytes which results in abscess formation

34. Clinical Presentation: Subacute fever Right upper quadrant pain May have protracted diarrhoea, abdominal pain, with weight loss Up to 50% patients have evidence of colonic disease Jaundice – uncommon, presence suggests multiple abscesses/severe disease

35. Investigations: laboratory Hemogram: – Increased WBC (≤75% cases), no eosinophillia Liver Enzymes: – Increased liver transaminases (≤ 75% cases) Stool microscopy: – Neither sensitive nor specific Serology: – Up to 90% positive after 1 week of symptoms

36. Investigations: Imaging Ultrasonography 90% sensitivity – user dependant CT scan Usually solitary involve right lobe of the liver

37. Treatment: Metronidazole 35-50mg/kg/d for 7-10 days Luminal amoebicide to control intestinal cysts (diloxanide furoate, iodoquinol) – present in ≤ 60% patients following treatment of ALA Cure rates of up to 90% with metronidazole No advantage of percutaneous drainage of an uncomplicated abscess

38. Schistosomal liver disease

39. Schistosomal liver disease (2) One of the most common causes of noncirrhotic portal hypertension in the world S. Japonicum, S. Mansoni and S. Hematobium Schistosomal eggs induce periportal fibrosis, by inducing chronic inflammation once they are trapped in terminal portal veins Clinical features: of portal hypertension, and of growth retardation Hepatic schistosomiasis. Dunn MA, Kamel R Hepatology. 1981;1(6):653. 2012 UpToDate,Release: 20.9 - C20.24

40. Schistosomal liver disease (3) Underlying hepatic function remains preserved Diagnosis – detection of schistosomal ova in the stool – biopsies of the rectal mucosa or the liver – immunologic assays Treatment – Praziquantel (20mg/kg/dose TID for 1 day) in acute stage – Treating complications of portal hypertension Immunopathogenesis of schistosomiasis. Wynn TA, Thompson RW, Cheever AW, Mentink-Kane MM Immunol Rev. 2004;201:156. Praziquantel side effects and efficacy related to Schistosoma mansoni egg loads and morbidity in primary school children in north-east Ethiopia. Berhe N, Gundersen SG, Abebe F, Birrie H, Medhin G, Gemetchu TActa Trop. 1999;72(1):53.

41. Sickle cell hepatopathy

42. Sickle cell hepatopathy (2) Clinical syndrome characterized by marked hyperbilirubinaemia, not explained by severe haemolysis, viral hepatitis, hepatic sequestration or extra-hepatic obstruction Classified into two categories: – a milder self-limited form without severe hepatic dysfunction – a severe form characterized by fulminant liver failure with coagulopathy and encephalopathy Pediatr Blood Cancer 2005;45:184-190

43. Sickle cell hepatopathy (3) Complications Due to disease itself: – Sickle cell vasculopathy – Pigment gall stones due to chronic haemolysis – Acute hepatic crises – Hepatic sequestration Due to treatment : – Chronic blood transfusions: iron overload 2012 UpToDate,Release: 20.9 - C20.24

44. Sickle cell hepatopathy (4) Evaluation recommended in any child with jaundice > 13 mg/dl ( >220 μmol/L) without evidence of acute severe haemolysis complete blood count coagulopathy panel viral hepatitis serology appropriate imaging (abdominal ultrasound or CT scan) to r/o biliary sludge, stones Renal function (hepato-renal syndrome)

45. Sickle cell hepatopathy - biopsy

46. Sickle cell hepatopathy: Treatment Non-severe disease: – Simple transfusion – Supportive management for sickle cell disease Severe Disease: – Exchange transfusion: only effective therapy – Supportive treatment – ? Role of hydroxyurea, ursodeoxycholic acid

47. Case 2 14 year old boy with blood per rectum for 6 months Frank blood, tablespoon full, not associated with pain No h/o constipation No h/o bleeding disorder Boarding school in Eastern Kenya

48. Case 2 Examination: NAD! Diagnosis? Management? Colonoscopy: 1 pedunculated polyp at 25cm, removed Histology: juvenile retention polyp with multiple eggs of Schistosoma!

49. Case 3 4 yr old Kenyan Asian girl, known “asthmatic” child with recurrent chest infections since birth c/o: loose stools since late infancy (1 st mention!) – X1-2/day, oily, bulky stools, foul smelling, worse with fatty foods, not readily flushable – No abdominal pain, vomiting, jaundice, pruritus – Poor weight gain, normal milestones Strong family h/o atopy, consanguineous parents

50. Case 3: cont’d Fair GC, P°, J°, afebrile, no pedal oedema Malnourished: Wt: 9.5 kg (<3SD), Ht: 90 cm (<3SD) ENT: rhinorrhoea, Chest clear Abdomen: soft, not distended, non tender, no masses/organomegally Stool: fecal fat present, pH/reducing substances not done, occult blood negative Hb: 10.3, MCV: 70, WBC: 8.5, Platelet 195, Albumin: 28

51. Case 3: Diagnosis? FTT (9.5 kg at 4 yrs) Malabsorption Differential diagnosis: – Immune suppression: HIV, Ig deficiency – Allergic enteropathy – Shwachman Diamond Syndrome, ?CF

52. Case 3: Final Diagnosis Self-referred to India: – Upper endoscopy: reportedly normal – Sweat chloride test: suggestive of Cystic Fibrosis – Confirmatory test (DNA): not done Started on pancreatic enzyme supplements – Good response to GI symptoms, stools normal – Weight and height gain still not optimal, respiratory symptoms continue Final Diagnosis: Cystic Fibrosis

53. Thank You! Asante! Enkosi!