Slide 1 Unit 5 Persistent Diarrhoea Unit 5 should take approximately 40 minutes to implement (total of 28 slides) Step 1: Learning Objectives & Definition (Slides 1-3) – 2 minutes Step 2: Dehydration & Rehydration (Slides 4-11) – 5 minutes Step 3: Clinical Categories of Diarrhoea (Slides 12-20) – 8 minutes Step 4: Treatment (Slides 21-26) – 10 minutes Step 5: Diarrhoea Summary & Key Points (Slides 27-28) – 5 minutes Step 6: Question and Answer (No Slides) – 10 minutes NOTE: These facilitation notes provide information on timing, items to emphasize, and background information to help the facilitator understand and explain the slide content. These notes are not meant to be read aloud by the speaker. It may be necessary to darken the lighting in the training room so that participants can see sufficient detail in the photographs contained in this unit.

Learning Objectives Participants will be able to: Slide 2 Participants will be able to: Provide empirical treatment for persistent diarrhoea Use and interpret stool exams in patients who do not respond to empirical therapy Provide appropriate treatment for identified infections Step 1: Learning Objectives & Definition (Slides 1-3) – 2 minutes ASK participants if they have any questions about the learning objectives before continuing. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Definition: Persistent Diarrhoea Slide 3 Liquid stools 3 or more times per day Continuous or intermittent At least 2 weeks duration HIV positive Defined in the MoHSS Guidelines for the Clinical Management of HIV and AIDS, 2001. Republic of Namibia, Ministry of Health and Social Services (MoHSS), Guidelines for the Clinical Management of HIV and AIDS. (2001?) Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Case History - Nangura Slide 4 Nangura is a 28 year old woman with HIV who presents with diarrhoea and nausea. She has had 4 liquid stools per day most days for about 2 weeks. She otherwise feels well and is urinating normally. She thinks the symptoms may be improving over the past 2 or 3 days. Step 2: Dehydration & Rehydration (Slides 4-11) – 5 minutes Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Case History (2) Slide 5 Nangura was diagnosed with HIV 6 months ago. Her most recent CD4 count 4 months ago was 46. Her opportunistic infection history includes tuberculosis treated last year, and oral candidiasis 6 months ago that resolved with nystatin suspension. She developed hepatitis when she started nevirapine and HAART was discontinued until she recovered. Three weeks ago, she began stavudine (d4T) + lamivudine (3TC) + Lopinavir/ritonavir. She has taken cotrimoxazole daily for 6 months. Aluvia® (lopinavir 200mg / ritonavir 50 mg) tablets have replaced Kaletra® (lopinavir 133.3 mg / ritonavir 33.3 mg) capsules because of Aluvia®’s favourable qualities Does not need to be stored in a refrigerator Can be taken with or without food Reduced pill burden Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Case Exam Slide 6 On exam, Nangura is afebrile. She appears agitated, but she relates this to her long wait to see you. BP 110/60. Pulse 94. RR 16. Weight 50 kg. Her mouth appears mildly dry with some chapping of the lips. Her skin retracts promptly on pinching. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Additional History - Nangura Slide 7 She reports no fevers. She reports no visible blood in the stools. She has no recent sick contacts. She reports no recent antibiotic use besides cotrimoxazole. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

First Assess for Dehydration Slide 8 Clinical Feature Moderate Severe General Irritable Cold, Sweaty Pulse Rapid Rapid, Feeble Respiration Deep Deep, Rapid Skin Elasticity Poor Very Poor Eyes Sunken Deeply Sunken Mucous Membranes Dry Very Dry Urine Flow Reduced None > 6 hours Table 3 of the Republic of Namibia, Ministry of Health and Social Services (MoHSS), Guidelines for the Clinical Management of HIV and AIDS. (2001?) Table 3 - MoHSS, Guidelines for the Clinical Management of HIV and AIDS, 2001. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Rehydration in Primary Care Setting Slide 9 Mild or moderate dehydration – Oral rehydration Oral Rehydration Solution (ORS) packets preferred ‘Home’ recipe ½ tsp salt with 8 tsp sugar in 1 liter boiled water Severe dehydration – initial IV rehydration preferred If unable to correct, refer to level 2 Oral rehydration salts (ORS) are especially important for children. Adults without severe dehydration can use other fluids, including some sodium and potassium intake. Research has shown that home preparation of oral rehydration is not very accurate, and the resulting solution has very variable electrolyte concentrations. Also, glucose based solutions do not provide as rapid GI absorption of liquid as some other carbohydrate sources. Therefore, if available, oral rehydration solution (ORS) is preferred. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Potassium Replacement Slide 10 Oral rehydration solution (ORS) Fruits – like bananas, oranges, etc. Vegetables including potatoes and leafy greens like spinach Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Nutrition Slide 11 Maintain intake of healthy balanced diet during episodes of diarrhoea Remind clinicians that it is important for patients to maintain a healthy diet in settings of diarrhoea; that reducing oral intake over time does not reduce the illness causing diarrhoea but does lead to malnutrition and more disease. The second half of the unit gives more information on nutrition counselling. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Some Clinical Categories of Diarrhoea Slide 12 Bloody with fever Bloody without fever Any CD4 count CD4 < 200 Non-bloody with fever Non-bloody without fever Step 3: Clinical Categories of Diarrhoea (Slides 12-20) – 8 minutes One widely used method for developing a differential diagnosis for diarrhoea starts by characterizing diarrhoea by the presence or absence of blood, and the presence or absence of fever, leading to 4 categories. We further divide these by the presence or absence of severe immunosuppression. In the next few slides, we will examine the common causes of diarrhoea that occur within each category. Causative agent is not found in 15 to 46% of cases in a review study. Ref; The Clinical Practice of HIV Medicine, 2005, Dr. D.C Spencer pg 150 Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Bloody Diarrhoea with Fever Slide 13 Any CD4 count Bacillary dysentery Shigella* Salmonella* Campylobacter* Invasive E. coli* Clostridium difficile colitis* Schistosoma mansoni Ulcerative colitis* CD4 < 200 CMV** The common causes of bloody diarrhoea with fever are the organisms that cause bacillary dysentery, and the toxin of clostridium difficile. Shigella sp: very common. Watery diarrhoea , mucus +/- blood, fever, WBCs in stool, not related to CD4 count. Rx: CTX 960 mg (1 DS) bd x 3 d OR nalidixic acid 1 g qds x 5 days OR ciprofloxacin 500 mg bd x 3 d Non-typhi salmonella: watery diarrhoea, fever, prostration, confusion, may have WBCs in stool, any CD4 count. Rx: CTX 960-1920 mg bd x 14d or longer OR ciprofloxacin 500 mg bd x 14 d or longer Campylobacter: watery diarrhoea sometimes with blood, fever, stool may contain WBCs, any CD4 count. Rx: erythromycin 500 mg qid x 5 days or longer Invasive E. coli: low CD4 counts. Rx: ciprofloxacin 500 mg bd x 7 days C. difficile: watery diarrhoea in context of hospitalisation and prior antibiotic use (penicillins, clindamycin), fever, increased WBC, stool may contain WBCs. Rx: metronidazole 400 mg po tds x 10 days (“Orange” book) Schistosoma mansoni: abdominal pain and blood-streaked stool. Rx: praziquantel 20 mg/kg po bd for one day Ulcerative colitis, non-infectious inflammatory bowel disease, may also cause chronic and recurrent bloody diarrhoea with fever. Diagnosis of exclusion; not specifically related to HIV - may be less frequent in persons with advanced immunosuppression. CMV colitis only occurs with severe immunosuppression, typically the CD4 count is <50. It can be difficult to diagnose. Abdominal pain bloating, flatus, diarrhoea may be bloody. Gancyclovir and foscarnet not available. Restore immunity with HAART. Ref: The Clinical Practice of HIV Medicine, Dr. D. Spencer, 2005, p. 150-156 *Specific treatment available ** May respond to HAART Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Bloody Diarrhoea without Fever Slide 14 Any CD4 count Amebic dysentery* Entameba histolytica Bacillary dysentery* Strongyloides stercoralis* Ulcerative colitis* CD4 < 200 CMV** E histolytica is present in some areas of Namibia. It is not increased with HIV. Bloody diarrhoea with cramps and colitis. Rx: metronidazole 400 mg po tds x 5-10 days Strongyloides stercoralis: pain, diarrhoea, acute steatorrhea described, may get “creeping eruption” skin lesions often on the back produced by migrating larvae. Hyperinfection syndrome can occur following severe immunosuppression, giving diffuse mucosal injury with dysentery, septicaemia, dyspnea and even larval invasion of the brain. Rx: thiabendazole 50 mg/kg/day divided in 2 doses x 2 days, maximum 3 g/d BUT this is not in NEMlist – guidelines for the clinical management of HIV and AIDS, MoHSS “Orange book” p. 18, recommends albendazole 400 mg daily x 3 days, repeat after 3 weeks. *Specific treatment available ** May respond to HAART Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Non-Bloody Diarrhoea with Fever Slide 15 CD4 < 200 CMV** MTB* or MOTT** KS* ** and Lymphoma* HIV enteropathy** Any CD4 count Bacillary dysentery* Crohn’s* Disease C. difficile* KS can involve the bowel so extensively that it can block water re-absorption and can also cause secretions HIV enteropathy described in 15-60% of patients with severe refractory diarrhoea in era prior to HAART. Villous atrophy on small bowel biopsy and evidence of small bowel dysfunction. Diarrhoea and wasting with fat malabsorption. Alternative diagnoses should be excluded. Rx: HAART (subsequent improvement diagnostic) *Specific treatment available ** May respond to HAART Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Non-Bloody Diarrhoea without Fever Slide 16 CD4 < 200 Opportunistic protozoa Isospora* Cryptosporidia** Microsporidia** Opportunistic viruses CMV** Adenovirus** HIV enteropathy** KS** Any CD4 count Protozoa Giardia* Helminths Ascaris* (Hookworm*) Strongyloides * Schistosomiasis (Bilharzia)* Non-invasive bacteria* Intestinal viruses Drug toxicity Other causes Giardia is present in Namibia. It is not increased with HIV disease. Rx: metronidazole Helminths: Ascaris lumbricoides: may be asymotpmatic; large worm loads can cause episodes of recurrent colic. Rx: albendazole 400 mg po stat Hookworm: large infestations can produce severe anaemia as parasite feeds on human blood in GIT. Usually no abdominal symptoms. Rx: albendazole 400 mg po stat Strongyloides stercoralis: pain, diarrhoea, acute steatorrhea described, may get “creeping eruption” skin lesions often on the back produced by migrating larvae. Hyperinfection syndrome can occur following severe immunosuppression, giving diffuse mucosal injury with dysentery, septicaemia, dyspnea and even larval invasion of the brain. Rx: thiabendazole 50 mg/kg/day divided in 2 doses x 2 days, maximum 3 g/d BUT this is not in NEMlist – guidelines for the clinical management of HIV and AIDS, MoHSS “Orange book” p. 18, recommends albendazole 400 mg daily x 3 days, repeat after 3 weeks. Schistosoma mansoni: abdominal pain and blood-streaked stool. Rx: praziquantel 20 mg/kg po Ref: Manual of Tropical Pediatrics, M.D. Seear, Cambridge University Press, 2000, p 149-153. HIV enteropathy described in 15-60% of patients with severe refractory diarrhoea in era prior to HAART. Villous atrophy on small bowel biopsy and evidence of small bowel dysfunction. Diarrhoea and wasting with fat malabsorption. Alternative diagnoses should be excluded. Rx: HAART (subsequent improvement diagnostic) *Specific treatment available ** May respond to HAART Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Non-Bloody Diarrhoea without Fever (2) Slide 17 Lactose intolerance and fat malabsorption Can cause diarrhoea or occur following diarrhoea from another cause Irritable bowel syndrome Colonic malignancy Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Empiric Therapy of Severe or Persistent Diarrhoea Slide 18 Bloody with fever Bloody without fever Nalidixic acid (bacillary dysentery) +/-metronidazole (C. difficile) Metronidazole (Amebic dysentery or C. difficile colitis) Non-bloody with fever Persistent non-bloody without fever Nalidixic acid (bacillary dysentery) Metronidazole +/- albendazole (Giardia +/- helmiths) Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Stool Examinations Slide 19 Can be done at same time as empiric therapy where available Can be done if empiric therapy at primary care level is not successful Can be done for chronic diarrhoea Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Stool Examinations (2) Gram Stain (1 sample) For WBC Slide 20 Gram Stain (1 sample) For WBC Bacterial Culture (1 sample) Salmonella, Shigella, Campylobacter, Clostridium Wet Mount (3 samples) Motile protozoa Helminth eggs Acid Fast Stain (3 samples) MTB, MOTT, Isospora, Cryptosporidium C. difficile toxin (sent to South Africa only) Send 3 samples on 3 separate days Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Parasites and Their Treatment Slide 21 Aetiology Treatment Giardia lamblia Metronidazole 400 mg tds x 5d E. histolytica 400 mg tds x 10d Strongyloides stercoralis Albendazole 400 mg bd X 2-7d Ascaris, hookworm 400 mg once Isospora belli Cotrimoxazole (80/400) 2 tab bd or qds x 7-21 d Cryptosporidium Immune Restoration with ARVs Microsporidium Step 4: Treatment (Slides 21-26) – 10 minutes Doses are from Table 4 of the Republic of Namibia, Ministry of Health and Social Services (MoHSS), Guidelines for the Clinical Management of HIV and AIDS. (2001?) except as noted. Source: Mandell, G.L., J.E. Bennett, R. Dolin. Principles and Practice of Infectious Disease. Sixth Edition, 2004. Elseiver, Inc. www.elseiver.com Strongyloides- although increased with other immunodeficiencies, it is not increased in HIV disease. It is normally treated with albendazole for 2-7 days depending on if there is hyperinfection or not (longer course than in guidelines). Hyperinfection is more common in immunosuppressed patients. Ascaris, hookworm are treated with a single 400 mg dose of albendazole, whipworm (trichuris) requires 3 days of therapy Isospora is diagnosed on a (modified) acid fast stain of stool. It is treated with cotrimoxazole, but often recurs unless chronic suppressive therapy is used. Cryptosporidia is diagnosed on a modified acid fast stain of stool: the test is not generally performed in Namibia. Cyrptosporidia usually improves with HAART. A new drug, nitazoxanide or Alinia, is licensed for cryptosporidiosis in children. The manufacturer is seeking FDA approval for use in adults and HIV patients Microsporidia, a group of related tiny parasites, are found on electron microscopy of intestinal biospies (not available) and by a modified trichrome stain (probably not available in Namibia currently). So a specific diagnosis of microsporidia may not be possible. The microsporidium that most often causes diarrhoea, Enterocytozoon beineusi, is not effectively treated by albendazole but often improves with HAART. Encephalitozoon intestinalis, a rare cause of diarrhea, responds to albendazole 400 mg bd x 3 weeks. Eye disease, kidney disease, disseminated microsporidiosis caused by other related parasites may respond to albendazole but are even less likely to be diagnosed. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Bacteria and Their Treatment Slide 22 Aetiology Treatment Salmonella Chloramphenicol 250-500 mg qid x 7-14 d OR Nalidixic Acid 1g qid x 5d Shigella Nalidixic Acid Campylobacter Erythromycin 500mg qid x 7d Clostridium difficile Stop other antibiotics Metronidazole 400mg tds x 10d E. coli Doses are from Table 4 of the Republic of Namibia, Ministry of Health and Social Services (MoHSS), Guidelines for the Clinical Management of HIV and AIDS. (2001?) Salmonella was 85% susceptible to nalidixic acid and 100% susceptible to chloramphenicol (500 mg qd for 7-14 days) per NIP. Ciprofloxacin, used in other countries, was not tested. Ceftriaxone IV is also effective. (Guideline recommends chloramphenicol; this was been a treatment for typhoid fever prior to quinolones]. Shigella was 90-100% susceptible to nalidixic acid, depending on the species. Campylobacter was not tested by NIP, but is usually susceptible to erythromycin. Susceptibility to flouroquinolones is decreasing worldwide. C difficile colitis may improve when other antibiotics are stopped. If that is not sufficient, the treatment of choice is metronidazole E coli in Namibia are usually susceptible to nalidixic acid. The guidelines recommend cefuroxime, but it is rarely available. MoHSS, Guidelines for the Clinical Management of HIV and AIDS, 2001. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Persistent Diarrhoea: No Organism Identified Slide 23 Consider empiric C. difficile treatment if: Patient is toxic History of recent antibiotic use Stool sent for culture ELISA for C. difficile toxin available in South Africa Consider cotrimoxazole for isospora Consider albendazole 400 mg bd for 2-3 weeks for one type of microsporidia For isospora treatment see slide 21 This dose of albendazole, 400 mg bd for 3 weeks, is the treatment of a rare cause of diarrhea in AIDS patients, the microsporidium parasite Encephalitozoon intestinalis. [Drugs for parasitic infections, Medical Letter on Drugs and Therapeutics, August 2004.] A study in Zambia used 800 mg bd for 3 weeks as empiric therapy in a randomized controlled trial of AIDS patients with chronic diarrhea. There were 29% fewer days with diarrhea in albendazole arm compared with placebo arm. These patients did not receive antiretroviral therapy. [ Kelly P et al, BMJ 1996;312:1187-1191] Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Persistent Diarrhoea: No Organism Identified (2) Slide 24 If not on HAART consider starting: Immune restoration can help improve diarrhoea from Cryptosporidia, Microsporidia, and HIV enteropathy Unexplained chronic diarrhoea for < 1 month is a WHO Clinical Stage 3 condition If on HAART or other medications, consider drug toxicity HAART is likely to be effective, although some persons do develop diarrhea as a drug toxicity, especially on protease inhibitors. Remember that HIV wasting syndrome includes: unexplained involuntary weight loss (<10%) PLUS unexplained chronic diarrhoea >1 month OR fever or night sweats >1 month. It is a WHO Clinical Stage 4 event and therefore qualifies the patient to receive HAART Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Persistent Diarrhoea: No Organism Identified (3) Slide 25 Consider colonoscopy with biopsy if available: Cytomegalovirus (CMV) Kaposi’s Sarcoma (KS) Lymphoma Other malignancy Inflammatory bowel disease Consider anti-motility medication (e.g. loperamide) IF: No organism identified after careful search Diarrhoea is non-bloody Patient not elderly or a child Ref: Guidelines for the clinical management of HIV and AIDS, MoHSS, p. 17 Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Persistent Diarrhoea: Nutrition Slide 26 Continue fluid replacement as needed Emphasize nutrition to overcome maldigestion or malabsorbtion Trial of lactose free diet Trial of reduced fats But use fats to maximize calories if fat restriction does not reduce diarrhoea Maximize calories Every food and drink item should include useful calories Balanced diet and/or vitamin supplements Training on Clinical Care of HIV, AIDS and Opportunistic Infections

HIV Wasting Syndrome Slide 27 Unexplained involuntary weight loss (>10% body weight) with obvious wasting or BMI<18.5 PLUS Unexplained chronic diarrhoea for > 1 month OR Reports of fever or night sweats for > 1 month (T>37.5°C) without known cause and lack of response to antibiotics or antimalarials WHO Clinical Stage 4 Diarrhoea is defined as loose or watery stools three or more times daily Fever should have been investigated at least with blood culture, malaria slide and CXR Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Case Follow-up Slide 28 Nangura was advised to take more liquids and given nutritional counselling to maintain food intake while minimizing dairy products. Stool studies were negative for bacteria and parasites. The diarrhoea was attributed to the recently started lopinavir/ritonavir She has been given anti-diarrhoeal agents as needed. Despite intermittent diarrhoea and gas pains, she has gained weight and strength. Step 5: Diarrhoea Summary & Key Points (Slides 27-28) – 5 minutes Continue with a brief discussion of the follow-up to Nangura’s case of persistent diarrhoea introduced at the beginning of this unit. Sometimes diarrhoea and other GI symptoms are adverse events from antiretroviral therapy. She has few options, is tolerating the side effects with symptomatic treatment and otherwise is improving on HAART. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

Key Points First correct any dehydration Slide 29 First correct any dehydration Consider empiric therapy of persistent diarrhoea If unsuccessful, use stool laboratory studies to identify a cause and guide treatment Key Points serve as a tool for summarizing and reviewing the main ideas that were discussed in the unit. Summarize this presentation and review the Key Points for diarrhoea presented. Step 6: Question and Answer (No Slides) – 10 minutes Spend 10 minutes answering participant questions about diarrhoea Collect the questions first, and then answer the most important, avoid repetition, and postpone questions referring to topics to be covered later in the course. Questions that cannot be answered at the time, or are not immediately relevant, should be written on flip chart paper and answered later (this is often called the ‘parking lot’). If there are more questions than time allows, remind participants that questions can be asked informally of faculty throughout the day, at breaks, or during the daily review sessions. Training on Clinical Care of HIV, AIDS and Opportunistic Infections