1 Cholera outbreak Haiti

2 Diarrheal Diseases in Tropical MedicineMED/GH561 April 10, 2013 Frederick S. Buckner, MD

3 Topics to be discussed Epidemiology of diarrheal diseaseClinical presentations, pathophysiology, etiologic agents Diarrhea in children in developing countries Watery diarrhea Dysentery Persistent diarrhea Rotavirus Cholera

4 Major causes of death among children under five years of age - World 2008 8.8 M deaths worldwide* 68% due to infectious dz 15% due to diarrhea #1 respiratory: M #2 diarrhea: M #3 malaria: 0.732 Proportional mortality However, in spite of this impressive achievement acute diarrhoea remains a leading cause of childhood death in developing countries. Black RE, Lancet, 2010 *7.7 M deaths worldwide, 2010 4

5 Center for Vaccine DevelopmentM. Levine, Univ. Maryland Millenium Declaration adopted by all 189 United Nations Member States, 2000

6 Approaches to understanding diarrheaDiarrheal syndromes Acute diarrhea Watery Bloody (dysentery) Chronic diarrhea (persistent): >14 days Etiologies: viruses, bacteria, parasites Host factors Children (malnourished) HIV infected Travelers

7 How much fluid does your intestine absorb in a day?~10 liters

8 FIC-NIH

9 Case 1 You are working in a clinic in rural Thailand. A mother brings in a 4 month baby with diarrhea and lethargy. How long has the diarrhea been going on? “2 days” Can you describe the diarrhea? “Like water” Is it bloody? “No” Is the baby breastfeeding or drinking water? “She stopped feeding earlier today” Seattle Times

10 Case 1 continued What is this syndrome? Acute watery diarrheaIs it important to determine the etiology? Probably not. (Rotavirus, Enterotoxigenic E. coli, etc.) Exception: suspected cholera What is the urgency of the problem? How to Rx? Possibly fatal unless treated urgently with fluids

11 Diarrhea in children: focus on developing countries2008: 1.3 million deaths/year 1 billion episodes/year in children 6-7 episodes/child/year in developing countries 1-2 episodes/child/year in developed countries Darfur orphanage (Sudan)

12 Worldwide distribution of deaths caused by diarrhea in children under 5 years of age in 2000

13 Contributing factors Malnutrition: ¼ of children in developing countries are malnourished 1.1 billion people do no have access to safe drinking water 2.4 billion are without adequate sanitation Social unrest (war zones, refugee camps) Kenya

14 Death rate from diarrhea is declining1980’s: 4-6 million deaths/year 2000: 2.5 million deaths 2008: 1.3 million deaths An estimated 50 million lives have been saved due to use of oral rehydration therapy (ORT) (WHO 2009) “ORT was probably the greatest medical innovation of the 20th century”* Lancet

15 ORS

16 Composition of various solutionsORS (WHO) Pedialyte Gatorade Sodium 75 mEq/L 45 mEq/L 20 mEq/L Potassium 3.2 mEq/L Sugar 20 g/L 25 g/L 59 g/L

17 Coupled sodium and glucose transport in the intestineJAMA 291: , 2004

18 Standard vs. new ORS solutionsmEq/L Standard (1975) Reduced osmolarity ORS (2002) Glucose 111 75 Sodium 90 Chloride 80 65 Potassium 20 Citrate 10 Osmolarity 311 245

19 Amylase resistant starch - ORSJ. Ped. Gastro. Nutr. 42:362, 2006 NEJM 342:308, 2000 Appears to decrease fecal fluid loss and shorten duration of diarrhea.

20 What is the typical acid-base disturbance resulting from diarrhea?Non-anion gap metabolic acidosis Anion gap metabolic acidosis Metabolic alkalosis No acid-base disturbance Answer: a (which is why ORS has base)

21 Acute diarrhea in children: Etiologic treatment is usually not necessaryAssessment and management of dehydration is essential

22 Decreased skin turgor Center for Vaccine DevelopmentM. Levine, Univ. Maryland

23 Assessment of dehydration in children with diarrheaSevere dehydration: Lethargy or unconsciousness Not able to drink or drinks poorly Sunken eyes Skin pinch goes back very slowly (>2 sec) Some dehydration: Restless/irritability Thirsty and drinks eagerly Skin pinch goes back slowly No dehydration

24 Treatment of watery diarrhea*Severe dehydration: Immediate intravenous fluids If IV treatment unavailable within 30 min, consider ORS by nasogastric tube Some dehydration: ORS in the clinic with monitoring for 4 hours No dehydration: Extra-fluids at home *WHO/UNICEF Guidelines: Integrated Management of Childhood illnesses, 2000

25 Intravenous or intraosseous infusion

26 Center for Vaccine DevelopmentM. Levine, Univ. Maryland

27 Case 2

28 Case 2 You are working in a refugee camp in Chad.A woman brings a 6 month boy with watery diarrhea of 1 day duration. The child is breastfeeding well. On physical exam, the baby appears well nourished and alert. He has no abdominal tenderness. What is your medical advice?

29 Administer ORS

30 Treatment of diarrhea with no dehydrationTreat the child as an outpatient Counsel the mother on 3 rules of home Rx Give extra fluid (  breastfeeding or ORS) Teach mother how to mix and give ORS (mother’s card) Up to 2 years: give ml after each loose stool Older than 2 years: give ml after each loose stool Continue feeding (soup, rice water, yogurt drinks) Return immediately if: Child becomes unable to drink or breastfeed Child develops fever Child develops blood in stool

31 Mother’s card

32 ORS

33 WHO and UNICEF See references

34 IMCI

35 Adjunctive therapy in children?Anti-motility agents? No Anti-emetics? No Zinc supplements? Yes, in malnourished populations. Zinc given during an episode of diarrhea and for days after reduces the severity of the episode and the incidence of diarrhea for the following 4 to 6 months. Administer mg per day x days Syrup (20 mg/5 mL) or Tablets (20 mg)

36 Administration of zinc*Use of zinc was found to be safe, with few side effects reported, and did not affect the use of oral rehydration solution. <6 mo: ½ tablet/day x 10 d >6 mo: 1 tablet per day x 10 d *Zinc sulfate 20 mg

37 AUG. 2009

38 Dysentery Campylobacter jejuni www.unc.edu Salmonella enteritidis15-60 uM Very active Ingested RBCs sometimes visible Salmonella enteritidis

39 Dysentery in children (loose frequent stools containing blood)Most cases are due to Shigella and require antibiotic therapy (5 days) TMP/SMX (issues with resistance) Azithromycin, cefixime, ceftriaxone, cipro (?) Check stool for E. histolytica trophozoites When to hospitalize: Infants < 2 mo old (IM ceftriaxone) Malnourished children Supportive care: Prevent dehydration. Continue feeding Never give narcotic analgesics or antimotility drugs

40 Amebic dysentery Entamoeba histolyticaTrophozoite 15-60 uM Very active Ingested RBCs sometimes visible uM 1-4 nuclei Chromidial bars

41 Persistent diarrhea Nepal P. Buckner

42 Persistent diarrhea in children Diarrhea lasting >14 daysAssess for signs of dehydration and Rx ORS is sufficient for rehydration in most cases Evaluation: Examine the child for non-intestinal infections: Pneumonia, sepsis, UTI, otitis media Examine stool (wet mount): Giardia lamblia trophozoites MTZ 5 mg/kg TID x 5 days Cryptosporidium (GEMS study) Consider HIV infection

43 Giardia lamblia Trophozoite Cyst 14x7 uM 2 nuclei Parabasal bodyMotile with jerky movements 8-12 uM 2-4 nuclei Thick wall Granular cytoplasm

44 Persistent diarrhea Importance of dietGood nutrition is essential for recovery of the gut and for prevention Breast feeding should be continued For children > 4 mo First diet*: Starch based, reduced milk (low lactose) diet Second diet* (if no improvement on first diet): A no-milk (lactose free) diet with reduced cereal (starch) Iraqi child homepages.stmartin.edu/orgs/sac *

45 Rotavirus infection Responsible for ~500,000 child deaths/yr and 2 million hospitalizations worldwide (1400 deaths/day) Almost all morbidity and mortality in age <5

46 Rotarix (GSK) vaccine trial in developing countries

47 Rotavirus vaccine programPATH = Program for Appropriate Technology in Health Rotavirus movie GAVI = Global Alliance for Vaccines and Immunisations

48 Cholera Death comes through the water for the people of 19th century London. Kew Bridge Steam Museum.

49 Cholera Vibrio cholerae: Gram negative, comma shaped rodsSerovar 01 causes cholera “Classical” biotype: caused 1st six cholera pandemics in south Asia during the 19th and 20th centuries El Tor biotype: started spreading in 1960s Now the predominant biotype (e.g. Haiti) Serovar 0139 causes cholera like illness First appeared in India in 1992 Tends to affect adults

50 V. cholerae Killed by heating at 55°C for 15 minKilled by most disinfectants Survives saline conditions for two weeks at ambient temperatures Can survive on/in shellfish for 2 wks if refrigerated

51 Cholera: TransmissionHumans are the only known natural host Infection requires a large infective dose via contaminated food or water Incubation period: hours to 5 days Symptomatic vs. asymptomatic carrier Classical biotype: 1:5 El Tor biotype: 1:40 Refugee camp in Najaf, Iraq dancewater.blogspot.com

52 Cholera in Haiti Oct, 2010– Jan, 2013 >500,000 cases 7900 deathsDec, 2012: 2,300 hospitalizations/week 40 deaths/week Following Hurricane Sandy: spread to Dominican Republic, Cuba, and Venezuela

53 2008-09 cholera outbreak in ZimbabweAugust 2008 – February 2009 88,000 cases Overall, 4% fatality rate Remote areas, fatality 20-30%

54 Cholera: clinical featuresRice-water stools: up to 30 L/day Usually painless diarrhea Fever is usually absent Vomiting in 80% (shortly after diarrhea begins) Hypovolemia and shock within 12 hr Electrolyte disturbances  Cl-, Ca++ Hypoglycemia Renal failure, cardiac arrythmias

55 Cholera cot

56 Cholera: diagnosis In epidemics, the diagnosis is made on clinical grounds Dark-field microscopy of stool shows comma-shaped “darting” bacteria Stool should be submitted to a reference lab for culture. Transportation in alkaline peptone water and kept cool.

57 Cholera: treatment Rehydration:IV lactated Ringer’s (LR) ORS: by mouth or by NG tube Antibiotics: only beneficial in most severe cases Adults: Doxycycline 300 mg PO x 1 Children or pregnant women: TMP-SMX x 3 d

58 Cholera: prevention Public health measures: Vaccines? Health educationImproved food and water hygiene Improved sanitation Vaccines? Not recommended during outbreaks Health education

59 Source: Wagner and Lanois, 1958Diarrheal disease Primary Prevention The F-Diagram Fluids Sanitation Water Quality Fields Food New Host Feces Water Quantity Flies Hand Washing Fingers Source: Wagner and Lanois, 1958

60 Recommended reading Clinical Management of Acute Diarrhoea. WHO/UNICEF Joint Statement. 2004* Handbook IMCI. Integrated Management of Childhood Illness. World Health Organization * Practice guidelines for the management of infectious diarrhea Clin Infect Dis. 32: Enteric infections, diarrhea, and their impact on function and development J Clin Invest. 118: Water, sanitation and hygiene for the health of developing nations Public Health. 117:

61 The end

62 Appendix materials

63 Millenium Development GoalsMillenium Declaration adopted by all 189 United Nations Member States, 2000

64

65 Is the pathology in the small bowel or colon?Symptoms Nausea, bloating, cramping, gas, weight loss Fever, rectal pain, frequent painful stools Physical signs Dehydration, orthostasis, decreased skin tugor Fever, abdominal pain Diarrhea Large volume, watery Small volume, pasty, and/or blood, mucous Microscopic exam of stool Without inflammatory cells or blood, with/without mucous Inflammatory cells, blood, mucous

66 Agents of diarrhea based on localization within the intestineSmall Bowel Colon Bacteria E. coli (ETEC, EPEC), Staphylococcus aureus, Clostridium perfringens, Bacillus cereus, Vibrio cholera, Salmonella sp. Campylobacter sp., Shigella sp., Salmonella sp., Clostridium difficile, Yersinia sp., EHEC (0157:H7), Vibrio parahemolyticus, Plesiomonas shigelloides, Aeromonas hydrophila Viruses Rotavirus Norovirus Astroviruses Caliciviruses Cytomegalovirus Adenovirus Parasites Giardia lamblia, Cyclospora cayatenensis, Cryptosporidium parvum, Microsporidium sp., Dientamoeba fragilis, Isospora belli Entamoeba histolytica, Balantidium coli

67 Case 3 A 55 y/o business man is traveling to Lima, Peru, for a week. He is healthy except for reflux disease for which he takes omeprazole. He wants to be prepared for the possibility of getting traveler’s diarrhea. Causes? Prophylaxis? Treatment of traveler’s diarrhea? picasaweb.google.com

68 Traveler’s diarrhea Causes: ETEC, Salmonella, Shigella, Campylobacter, viruses, Giardia Prevention: Dietary discretion: avoid raw, uncooked foods Water: boiled or carbonated. (Bottled) Treatment of water: boil x1 min, treat with iodine, or filter Pepto-bismol tablets Treatment: Antimotility agents (symptomatic for mild cases) Antibiotics: quinolones, azithromycin, rifaximin Seek medical attention with dysentery

69 Rifaximin (Xifaxan) Non-absorbed rifampin-like antibioticActive against E. coli strains, but not Shigella Expensive Prevention: 200 mg PO once daily Treatment: 200 mg tid x 3 days ($32)

70 The 1854 cholera epidemic in London and the beginning of modern epidemiology and public health

71 Center for Vaccine DevelopmentM. Levine, Univ. Maryland

72 Center for Vaccine DevelopmentM. Levine, Univ. Maryland

73 Center for Vaccine DevelopmentM. Levine, Univ. Maryland ERI = Excess Rate of Isolation

74 Center for Vaccine DevelopmentM. Levine, Univ. Maryland ERI = Excess Rate of Isolation