INFANTILE DIARRHEA CHCUMS DIVISION OF INFECTIOUS DISEASE AND

INFANTILE DIARRHEA CHCUMS DIVISION OF INFECTIOUS DISEASE AND GASTROENTEROLOGY 1

Background n Diarrhea is a clinical syndrome of diverse etiology associated with many influencing factors. n It is the most frequent childhood disease second only to the respiratory infection. n The major cause of death among world’s children and the number one killer of children under five in many developing countries. 2

Disease Burden n n Worldwide 3 -5 billion episodes/year 4 -5 million deaths/year Children are the predominant populations. 3. 2 billion episodes/year in <5 y children 1. 3 million deaths/year in <5 y children In China n 836 million episodes of diarrhea every year n 1/4 -1/3 of all outdoor patients and a large amount of hospitalizations of children are due to diarrhea 3

Definition In pediatrics, diarrhea is defined as an increase in the Fluidity Volume Number of stools relative to the usual habits of each individual 4

Normal Stool of Children Breastfed babies: pass stools 3 -4 times a day yellow loose (soft to runny) but textured sweet-smelling Bottlefed babies: once a day pale yellow or yellowish-brown bulkier and more formed pretty pungent Babies on solids: thicken and darken slightly have a stronger odor 5

Why diarrhea is more dangerous for children ? Dehydration Malnutrition Mortality 6

Malnutrition and Child Mortality 7

If: Diarrhea + Malnutrition The RISK of DEATH is 4 fold higher than that of well nourished children 8

Why children are highly vulnerable to diarrhea? Immature digestive system More nutrition demand Weakness of defense system The normal intestinal flora have not built up well Bottle feeding 9

Etiology of Diarrhea 10

Etiology of Diarrhea Infective Non infective Allergic Viruses Symptomatic Bacteria Inappropriate feeding Parasites Food intolerance Climate Fungi 11

Viral Enteropathogens Viral enteropathogens cause most illnesses in pediatric population. n n n Rotavirus (morn than 50% acute diarrhea) Astrovirus Norwalk virus Coronavirus Calicivirus Enteric adenovirus (serotypes 40 and 41) 12

Rotavirus 13

Bacterial Enteropathogens The most common cause of childhood diarrhea second only to the viral enteropathogens n n n n Escherichia coli EPEC; ETEC; EITC; EHEC; EAEC Campylobacter jejuni Shigella species Salmonella typhimurium Yersinia enterocolitica Staphylococcus aureus Clostridium difficile Vibrio cholerae 14

Parasites Pathogens Rare etiologic pathogen of diarrhea n Cryptosporidium parvum n Entamoeba histolytic n Giardia lamblia 15

Fungous Pathogens Rare etiologic pathogen of diarrhea n Candida albicans n Aspergillus n Mucor 16

The most important infective causes of acute diarrhea in developing countries in children are: u Rotavirus u Enterotoxigenic escherichia coli u Shigella u Campylobacter jejuni u Salmonella typhimurium 17

Etiology of Diarrhea Infective Non infective Allergic Viruses Symptomatic Bacteria Inappropriate feeding Parasites lactose intolerance Climate Fungi 18

n Dietary Diarrhea Inappropriate feeding: Overfeeding Indigestible diet Sudden change of formula Inappropriate feeding for a milk-fed baby shifting into solid food (too much, too early, too rapid…) u u 19

n Allergic Diarrhea Primary food hypersensitivity: 3 months after birth Second food hypersensitivity: Infection→ injury and hyperpermeability of intestinal mucosa → large molecular protein entering bloodstream → allergic state Cow's milk protein Soy bean protein Egg white peanuts, meat, and fish etc. 20

n Symptomatic Diarrhea is only one of the symptoms of primary disease. Problem is not originally located in intestinal tract. ü Respiratory tract infection ü Otitis media ü Some infectious diseases, etc. Always be mild, and recover with the primary disease getting better The younger the children, the more chance to get a symptomatic diarrhea accompanied by other diseases. 21

n Lack of Disaccharidase Lactose Intolerance Primary Disaccharidase Deficiency is a rare disease (congenital defects of carbohydrate hydrolysis). Second Diaccharidase Deficiency : Rotavirus infection → Injures the enterocytes of villi → Transient disaccharidase deficiency → Malabsorption of lactose in the milk → Typical loose and watery stools 22

n Climate Seasonal variation affects the digestive function of small children : incidence of diarrhea is highest during the early raniny season Cold weather causes increasing of enterokinesia Hot weather causes decreasing of digestive enzyme and malfunction of digestive tract …… 23

Pathophysiological Mechanisms of Diarrhea 24

Pathophysiological Mechanisms of Diarrhea Virus Diarrhea- Rotavirus Enterotoxigenic Enteritis – ETEC, Vibrio Cholerae Entero-Invasive Organisms – Shigella Species, EIEC Dietary Diarrhea 25

Pathogenesis of Virus Diarrhea Rotavirus Virus invades the absorptive enterocytes of villi but spares crypt cells The viruses replicates and infected enterocytes are destroyed 26

Pathogenesis of Virus Diarrhea Osmotic Diarrhea 1 - Infected absorptive enterocytes are killed causing patchy epithelial cell destruction and villous shortening 2 - Destroyed absorptive cells are rapidly replaced by cells that migrate from the crypts. Villi become covered with immature non-absorptive secretory cells having: - no brush border enzymes 27

Pathogenesis of Virus Diarrhea (Osmotic Diarrhea) Rotaviruses attach and replicate in the mature enterocytes at the tips of small intestinal villi Destroy villus tip cells, variable degrees of villus blunting mononuclear inflammatory infiltrate in the lamina propria Impairment of digestive functions discreasing hydrolysis of disaccharides Malabsorption of complex carbohydrates, particularly lactose Other than degested into monosaccharide, lactose be lysis into organic acid, hyperosmosis Impairment of absorptive functions the transport of water and electrolytes via glucose and amino acid co-transporters An imbalance in the ratio of intestinal fluid absorption to secretion Watery stool 28

Pathophysiological Mechanisms of Diarrhea Virus Diarrhea- Rotavirus Enterotoxigenic enteritis – ETEC, Vibrio Cholerae Entero-Invasive Organisms – Shigella Species, EIEC Dietary diarrhea 29

Pathogenesis of Enterotoxigenic Diarrhea Pathogens: ü Vibrio cholerae (cholera) ü ETEC ü Staphylococcus aureus ü Clostridium difficile 30

Pathogenesis of Enterotoxigenic Diarrhea (Secretory Diarrhea) enterotoxigenic organisms Ingestion small bowel mucosa and proliferate Heat-stable enterotoxin Heat-labile enterotoxin binds to receptors of epithelial cells activates cellular guanylatecyclase cellular adenylcyclase increased intracellular concentrations of c. GMP increased intracellular concentrations of c. AMP promote the net secretion of water and chloride decrease absorption of sodium and chloride by villous cells Secretory diarrhea 31

Pathogenesis of Enterotoxigenic Diarrhea (Secretory Diarrhea) 1 Enterotoxigenic 1 Bacteria secrete Enterotoxins 1 2 Toxin stimulates the 2 production of C-AMP Increased C-AMP leads to : --2 3 +++ 4 33 - Inhibition of absorption of Na and Cl from the cells of villi 4 - Stimulation of 4 secretion of Cl from crypt cells 32

Pathogenesis of Enterotoxigenic Diarrhea (Secretory Diarrhea) The mucosa is not destroyed during this process 33

Pathogenesis of Enterotoxigenic Diarrhea (Secretory Diarrhea) An imbalance in the ratio of intestinal fluid absorption to secretion, so watery stool may occur in clinical observation 34

Enterotoxigenic Diarrhea Clinical finding: 1. Watery diarrhea and vomiting develop after an incubation period of 6 hr- 5 days(2 -3 days, average) 2. Low-grade fever occurs in some children 3. Profuse, painless, watery diarrhea, sometimes with flecks of mucus but no blood 4. Fluid and electrolyte losses, tachycardia, tachypnea, a sunken anterior fontanel, progress to circulatory collapse 35

Pathophysiological Mechanisms of Diarrhea Virus Diarrhea- Rotavirus Enterotoxigenic enteritis – ETEC, Vibrio Cholerae Entero-Invasive Organisms – Shigella Species, EIEC Dietary diarrhea 36

Invasive Diarrhea The central event in pathogenesis is invasion of colonic mucosa Entero-Invasive Organisms: ü Shigella species ü EIEC (enteroinvasive E. coli) ü Campylobacter jejuni ü Salmonella typhimurium ü Yersinia enterocolitica 37

Pathogenesis of Invasive Diarrhea Ingestion Invasive enteropathogen Gut lumen Colon and rectum mucous membrane proper Extensive destruction of the epithelial layer Inflammation: Hyperemia, swelling, heavy neutrophil infiltration, inflammatory exudate The desquamation, ulceration, and formation of microabscesses in the colonic mucosa inhibit absorption of water stools that are frequent and scanty and that contain blood inflammatory cells and mucus 38

Pathogenesis of Invasive Diarrhea 39

Invasive Diarrhea Clinical finding: 1. Stools that are frequent and scanty and that contain blood inflammatory cells, and mucus 2. Stool examination: large amount of WBC, pus cell , and RBC 3. Dehydration and electrolyte disturbances are less frequent because of less loss of digestive fluid 40

Pathophysiological Mechanisms of Diarrhea Virus Diarrhea- Rotavirus Enterotoxigenic enteritis – ETEC, Vibrio Cholerae Entero-Invasive Organisms – Shigella Species, EIEC Dietary diarrhea 41

Pathogenesis of Dietary Diarrhea Inappropriate diet Dyspepsia Indigested food accumulate in the upper part of intestine Acidity decreasing Give the chance to the bacteria which lived in lower part of bowel coming up Indigested food ferment and putrescence Decomposed product amineslactic acidacetic acid Hyperosmosis Irritates the bowel Promote the peristalsis Water entering the lumen Endogenous infection Aggravate the intestinal function disturbance Diarrhea 42

Morphology of Intestinal Mucosa 43

Morphology of Intestinal Mucosa Villi covered mainly (90%) by tall columnar absorptive cells (Enterocytes) having a micrevillar brush border Crypts of lieberkuhn Covered mainly by short columnar secretory cells Goblet cells without brush border 44

Defense Barriers of the Enterocytes 1 3 2 1. Physical barrier: mucus 2. Bacteriological (flora) 3. Immunological: Secretory Ig. A 45

Normal Flora Breast-fed: A Gram-positive population: Bifidobacteria and Lactobacilli Bottle-fed: A Gram-negative flora: Enterobacteriaceae 46

Clinical Manifestations 47

Clinical manifestations u Gastrointestinal symptom u Systemic symptom u Dehydration and electrolyte disturbances 48

Assessment of a child with dehydration & electrolyte disturbances 49

Dehydration Excessive loss of water, especially loss of extracellular fluid. 50

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Assessment of a Dehydration Mild Moderate Severe 5% 5 -10% 10 -15% 50 ml/Kg 50 -100 ml/Kg 100 -120 ml/Kg Mental State Fontanel Tear Bucal Mucosa Tissue Turgor Urine Flow Normal Restless, irritable Prostration/Coma Normal Sunken Deeply Sunken Normal Decrease Absence Moist Dry Very Dry Normal Absent Decrease Slightly Decrease Anuria Shock Absent Present Dehydration 54

Type of dehydration Serum sodium Skin color Skin temperature Skin turgor Duration of vomiting and diarrhea Thirsty Mucous membrane NS syndroms Disturbance of peripheral circulation Hypotonic <280 m. Osm/L Isotonic 280~300 m. Osm/L hypertonic >300 m. Osm/L <130 mmol/L 130 -150 mmol/L <150 mmol/L Pale Cold Absent Pale Cold Normal Flush Normal Very long Long Short No No Yes Moist Dry Lethargy Normal Irritable Yes No No 55

Hypopotassaemia serum potassium<3. 5 mmol/L Etiology 1. Excessive of loss 2. Insufficient intake 3. Distributional disturbance of extracelluar and intracelluar potassium 56

(二) 低钾血症 Hypopotassaemia serum potassium<3. 5 mmol/L Manifestations （1）low nervous and muscular excitability nervous excitability ：downcast, lethargy muscular excitability　：weakness、byporesalexia of tendon jerk, paralysis GI smooth muscle excitability ：paralytic ileus （2）cardiovascular system： cardiac dysrhythmia, low heart sound, electrocardiographic abnormality 57

Hypocalcemia serum calcium<1. 88 mmol/L High nervous and muscular excitability 58

Metabolic Acidosis 1 etiology (1) loss of alkaline substance from GI track (2) acid substance accumulation in body H+ 产生↑ H+排除↓ 2 manifestations: hyperpnoea、increased heart rate、serise lip、 conscious disturbance for the severe cases 59

Classification of Diarrhea based on …… Severity Duration Etiology 60

Classification of Diarrhea 1. Mild diarrhea: ü Most of the cases are non-infectious diarrhea ü Frequency of stool often less than 10 times/day ü Yellowish loose stool, sour smell with a few of mucusfat drop in microscopic exam ü General condition is good, self-limited on several days 2. Moderate diarrhea: 3. Severe diarrhea: ü Most of the cases are infectious diarrhea (rotavirus, shigella ) ü Frequency of stool often more than 10 times/day ü Watery stool, plenty of mucus. ü General condition is poor, usually accompany with vomiting and fever, dehydration and electrolyte disturbance 61

Classification of Diarrhea Acute stage: the course of the diseases less than 2 weeks Persisting type: the course of disease more than 2 weeks but less than 2 months Chronic stage: the course of disease more than 2 months 62

Persisting and Chronic Diarrhea Complicate reasons: Persisting infection, Allergic state, Lack of disaccharidase, Immunodeficience, Broad spectrum antibiotic usage, Malnutrition, Malabsorption , etc. Pathogenesis is not clear Great dangerous: Malnutrition and growth retardation Mortality is high Troublesome to be controlled: Adequate calories Reestablish the normal flora 63

Rotaviruses Infection 64

Rotaviruses infection History: First recognized in humans in 1973 by Australian Scientist Bishop, with a hubbed wheel appearance under electronmicroscope, giving their name Virology: Double-stranded RNA virus VP 6: A-G group, group A is the most important group in childhood infection 65

Rotaviruses infection Peak season: Deep fall and winter(October-February） Causing sharply increasing of outdoor patients in autumn and winter, also named autumn diarrhea Peak age: 6 m-2 y, rarely happen in children above 4 y Disease burden: 80% infectious diarrhea in pediatric clinic in autumn and winter About 1/4 to 1/3 (more than 800 cases) hospitalized diarrhea children are caused by rotavirus in our ward every year 66

Rotaviruses infection Clinical manifestations: Onset of sudden fever, respiratory tract symptoms Vomiting, watery or soft stool that lack gross blood or mucus u Severe dehydration than infection by other viral pathogens u Complications and fatalities are related almost exclusively to the adverse effects of dehydration, electrolyte imbalance, and acidosis u Malnutrition is a risk factor for severe consequences u Disaccharides Intolerance u u Laboratory findings: Specific antigens in stool specimen recommended by WHO 67

Diagnosis 68

Diarrhea? Infective Persisting or chronic diarrhea Acute stage Watery, loose stools without or only a minute amount of WBC Epidemic data Stool culture Serous assay Virus Diarrhea ETEC, EPEC Lots of WBC and RBC, mucus in stools Antibiotic associate diarrhea Persisting infection? Stool culture Serous assay Shigella species Entamoeba histolytic EIEC Staphylococcus Giardia lamblia Campylobacter jejuni Clostridium difficile Salmonella typhimurium Cryptosporidium Candida albicans Yersinia enterocolitica Non-infective Allergic state? Symptomatic diarrhea? Inappropriate feeding? food intolerance Lack of disaccharidase? Immunodeficience? Malnutrition? Malabsorption ? etc. 69

Treatment 70

Main lines of management 1. Feeding 2. Fluid therapy 3. Drugs 71

1. Feeding during diarrhea Continue feeding the child Give as much as the child want Give small frequent feeds Encourage anorexic child to eat 72

1. Feeding during diarrhea For breast-fed Continue breast feeding as usual during and after diarrhea and rehydration therapy. 73

1. Feeding during diarrhea For formula-fed Low lactose of lactose-free formula only in case of lactose intolerance children (rotavirus) 74

1. Feeding during diarrhea Children on Mixed Diet Continue normal feeding as usual u Give repeated small frequent feeds u Avoid too sweetened or oily foods u Avoid foods containing a high fiber content u 75

2. Fluid therapy 76

3. Drugs in the management of Diarrhea 77

Commonly used drugs in diarrhea Antimicrobial agents Antiparasitics Probiotics: lactobacilli, Bifidobacteria u Antidiarrheal agents: adsorbants and mucous membrane protectors: SMECTA u u u 78

u Antimicrobial agents 1. Antimicrobial agents are not recommended for viral diarrhea 2. invasive pathogen and toxic pathogen infection should choose effective antimicrobial agents 3. antibiotics should be stopped or changed for the antibiotic associate diarrhea 79

Functions of Normal Flora Digestion Production of vitamins Stimulation of host immune response Inhibition of pathogen attachment Production of pathogen inhibitory substances 80

Fluid Therapy 81

ORS Therapy in mild to moderate dehydration 1. 2. 3. ORS is the preferred treatment for fluid and electrolyte losses caused by diarrhoea in children who have mild to moderate dehydration 50 -100 ml/kg ORS to be given over a 4 -hour period WHO recommended ORS High sodium content 90 mmol/l 82

Intravenous fluid therapy Severely dehydrated or who are in a state of shock must receive immediate and aggressive intravenous fluid therapy Complete correcting of the deficit Replacing ongoing loss of water and electrolytes Supply the physiological maintenance 83

Intravenous fluid therapy Phase I: Treat shock (0 - 30 minutes) 10 -20 ml/kg 0. 9% Na. Cl Reassess Improved No Change Measure plasma electrolytes Calculate fluid deficit and maintenance Phase II: Initial Rehydration (½ - 8 hours) Initial replacement with saline-dextrose solution Half the calculated fluid deficit plus maintenance Review plasma electrolytes and fluid status Phase III: Continued Replacement (8 - 24 hours) Replacement with saline-dextrose solution Half the calculated fluid deficit plus maintenance 84

Intravenous fluid therapy Complete correcting of the deficit Mild: 50 ml/kg Moderate: 50 ml-100 ml/kg Severe: 100 ml-120 ml/kg Hypotonic: 2/3 tonic Isotonic dehydration: ½ tonic；Hypertonic dehydration: 1/3 -1/5 tonic Duration of fluid therapy： 8 -12 hours Shock and severe dehydration: 20 ml/kg/30 min-1 hour at the beginning Hypertonic dehydration: replace total fluid deficit plus maintenance slowly over 48 -72 hours 85

Intravenous fluid therapy Replacing ongoing loss of water and electrolytes 10 ml-40 ml/kg, 1/3 -1/2 tonic ¢ Supply the physiological maintenance 70 ml-90 ml/kg，1/4 -1/5 tonic Complete within 12 -16 hours for the two parts 86

Treatment of metabolic acidosis For full correction of acidosis, Na. HCO 3 required (mmol)= Base deficit x body weight x 0. 3 In most cases, metabolic acidosis is self-corrected once dehydration corrected and hence effective circulation volume restored In rare situation, half of the calculated required Na. HCO 3 may be given: watch out for Na overload and pulmonary oedema 87

Potassium Replacement 钾盐的补充应在排尿后给钾 100 -300 mg/kg. d divided into 4 times a day Concentration: 0. 15 -0. 3% Replacement should be maintained for 4 -6 days 88

Calcium, and Magnesium replacement Calcium: 10% alcium gluconate 10 ml slow iv/gtt Magnesium: 0. 2 ml/kg iv/gtt Bid-Tid 89

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The following are causes of secretory diarrhea: A. Vibrio cholerae B. Enteropathogenic escherichia coli C. Rotavirus D. Lactose intolerance E. Shigella species 91

Case history A 2 -year-old gril presents with a history of passing 10 -15 water stools and has vomited at least four times in the last 24 hours. She appears distressed but otherwise cooperative and drinks thirstily from a glass of fruit juice but then vomits. The nurse informs you that her pulse is 96 beats/minute, temperature 37. 9 and blood pressure 100/60 mm. Hg. Please discuss the management of this child. 92