CURRICULUM VITAE

• Name w/ title : S. Yati Soenarto, MD, Ph.D.Professor ofPediatrics, Consultant for Gastroenterology Place

• DOB : Sukamandi, February 5th 1944 • Home Address : Jalan Sendok CT 8/135 Karanggayam,

Jogjakarta, Indonesia• Office Address : Pediatric Research Office, Department of

Child Health, Faculty of Medicine, Jl.Kesehatan no.1 Sekip Jogjakarta 55281,

RSUP. Dr. Sardjito Teaching Hospital• Phone Number : +62-274-563683 (Home/fax);

+62-274 555455 ; +62-811-256011 • Email : yatisoenarto@yahoo.comCurrent PositionChairs• Pediatric Research Office, Department of Child Health,

Faculty of Medicine, Universitas Gadjah Mada (UGM)• Unit of Research Management of Clinical Epidemiology

&Biostatistics, Sardjito Teaching Hospital, Jogjakarta • Health & Medical Researcher Cluster, Universitas Gadjah

Mada (UGM)

UNIVERSITY TRAININGS AND DEGREES HELD

1970 M.D., Faculty of Medicine, Gadjah Mada University, Jogjakarta Indonesia

1975 Pediatrician, Faculty of Medicine, Gadjah Mada University, Jogjakarta, Indonesia

1978 Pediatric Gastroenterology, Wilhelmina Children Hospital, Utrecht, The Netherlands

1985 Pediatric Gastroenterology, Royal Children Hospital-Melbourne University, Australia

1988 Pediatric Consultant for Gastroenterology, Indonesian Pediatric Society, Indonesia

1988 Health Care Evaluation & Management Skills, University of Toronto, Canada

1995 Freeman fellow, Department of Social Medicine, Harvard Medical School, Boston, Massachucets, USA

1997 Ph.D, Faculty of Medicine, Vrije Universitiet, The Netherlands2007 Professor, Gadjah Mada University, Jogjakarta, Indonesia

PRESENT/RECENT APPOINTMENTS• Visiting Professor, Faculty of Medicine,

Melbourne University (2006)• Coordinator, University Research Cluster for

Health and Medicine, UGM Jogjakarta (2007 – present)

• Chair, Clinical Epidemiology & Biostatistics Unit, Faculty of Medicine Gadjah Mada University / Sardjito Teaching Hospital (2007 – 2010)

• Unit of Research Management of Clinical Epidemiology & Biostatistics, SardjitoHospital (2009-present)

AWARDS• 2010 Achmad Bakrie 2010 award for Outstanding Medical field & Highly

respect for the Idea of Freedom. Freedom Institute, Jakarta, Indonesia• 2009 Asia Pacific Pediatrician Assosiation (APPA), Outstanding Asian

Pediatrician Award.• 2008 Indonesian Pediatrics Society, R. Sutedjo Award (Honor for

Exceeding Social Prestige in Health Profession Appliance, Especially in the Field of Child Health).

• 2008 Faculty of Medicine, Gadjah MadaUniversity, Jogjakarta, Prestigious Lecturer.

• 2006 Faculty of Medicine, Gadjah MadaUniversity, Jogjakarta, Dedication for Helping the Sardjito Hospital and Faculty of Medicine Gadjah Mada University Health Reconstruction Project in Nangroe Aceh Darussalam

• 2006 University of Melbourne, Australia, as Visiting Professor at the Faculty of Medicine and Dentistry.

• 2004 Gadjah Mada University, Award for Best Performance in Research and Public Services, Category of International Collaborative Research on Rotavirus Study

PUBLICATION• Siswanto Agus Wilopo, Yati Soenarto, Joseph S. Bresee, Abu Tholib, Sri Aminah, Anton

Cahyono, Jon R. Gentsch, Paul Kilgore, Roger I. Glass. Rotavirus surveillance to determine disease burden and epidemiology in Java, Indonesia, August 2001 through April 2004. Vaccine27S (2009) F61–F66.

• Siswanto Agus Wilopo, Paul Kilgore, Soewarta Kosen, Yati Soenarto, Sri Aminah, Anton Cahyono, Maria Ulfa, Abu Tholib. Economic evaluation of a routine rotavirus vaccination programme in Indonesia. Vaccine 27S (2009) F67–F74.

• Sundari TA, Soetjiningsih, Soenarto Y, Karyana IPG. Efficacy of reduced osmolarity oral rehydration solution, rice-based oral rehydration solution and standard WHO oral rehidration in children with acute diarrhea: a randomized open trial. Paediatrica Indonesiana 2009; 49(3): 169-76

• Soenarto Y, Tholib AT, Bakri A, Waluya H, Firmansyah A, Kadim M, Martiza I, Prasetyo D, Mulyani N, Widowati T, Soetjiningsih, Karyana IPG, Sukadi IW, Widdowson MA. 2008. The Burden of Severe Rotavirus Diarrhea in Indonesia. Journal of Infectious Diaseases 1 November 2009 Volume 200 Supplement 1 hal 188-194

• Putnam SD, Sedyaningsih ER, Listiyaningsih E, Pulungsih SP, Komalarini, Soenarto Y, Salim Och, Subekti D, Riddle MS, Burgess TH, Blair PJ. 2007. Group A Rotavirus – Associated Diarrhea in Children Seeking Treatment in Indonesia. J Clin Virol. 40 (4) : 289-94.

Prof. DR. dr. S. Yati Soenarto, Ph.D., Sp.AK

Pediatric Research Office (PRO),Department of Child Health,

Unifersitas Gadjah Mada /RSUP Dr. Sardjito

Neonatal 38%

Diarrhea18%/28%

Pneumonia14%/20%

Others22%

GLOBAL

CAUSES OF DEATHS IN CHILDREN U5

Bryce J, et.al., 2005

INDONESIAYR 2000 ‐ 2003

WHO,2006/ RISKESDAS

2007

www.who.int.org

ASIA – WHO SEAROYR 2002

“DIARRHEA”

GLOBAL ASIA – WHO SEARYR 2002

Why is diarrhea dangerous?

DIARRHEA DEATH due to LOST (& LACK) of:

WATER & ELECTROLYTE FOOD

Diarrhea

increased loss of water and electrolytes (sodium, potassium

and bicarbonate) in the liquid stool

losses are not adequately replaced and a deficit of water and

electrolytes develops.

Dehydration

decrease in food intake and

nutrient absorption

weight loss and failure to grow

increased nutrient

requirements

Malnutrition

DEATH

SEVERE DEHYDRATION !

1. Signs or symptoms :

Two/more of the follow :• Lethargy/unconsciousness• sunken eyes• unable to drink/drinks

poorly• skin pinch goes back very

slowly ( ≥ 2 seconds )

2. Treatment :

• Give fluid for severedehydration (DiarrheaTreatment Plan C)

SOME DEHYDRATION

1. Signs or symptoms :

Two/more of the follow :

• restlessness, irritability• sunken eyes• drinks eagerly, thirsty• skin pinch goes back

slowly

2. Treatment :

• Give fluid & food for some dehydration (Diarrhea Treatment Plan B)

• After rehydration, advise mother on home treatment & when to return immediately

• Follow up in 5 days ifnot improving

NO DEHYDRATION

1. Signs or symptoms :Not enough signs to

classify as some or severe dehydration

2. Treatment :

• Give fluid & food to treat dehydration diarrhoea at home(Diarrhea Treatment Plan A)

• Advise mother on when to return immediately

• Follow up in 5 days if not improving

WHO Hospital Care for Children, 2006

Classification of the severity of dehydration in children with diarrhea

CLASSIFICATION

DIARRHEA

Based on duration : Based on pathophysiology :

Acute:

Starts suddenly, may continue for several days

Persistent:

starts like acute diarrhea, lasts for >14 days

Osmotic:Caused by luminal substances that induced fluid secretion

Secretoric:endogenous substances (“secretagogues”) induce fluid secretion

I N D O N E S I A

Mortality MorbidityDiarrhea-U5:

Household survey, 2001Basic Health Research (Riskesdas), 2007

ORS

Simpulan: ORS mampu menurunkan angka kematian akibat diare namuntidak pada morbiditasnya

5 LANGKAH TUNTASKAN DIARE

CASE MANAGEMENT

Rehydration: IV oralit 1. NEW ORALIT (REDUCED OSMOLARITY )

2. CONTINUED FEEDING

PHARMACOLOGIC

5. 5. PATIENT-DOCTOR COMMUNICATION

22.ZINC

3. RATIONALANTIMICROBA

1. DEHYDRATION:

2.NUTRITION:

3. ETIOLOGY(commonly infection)

4. SUCCES OF PRACTICE:

5 STEPS OF MANAGEMENT FOR DIARRHEA(PROGRAM)

4. NO ANTIDIARRHEA & ANTIVOMITING

SEVERITY & INCIDENCE

Intravenous“All”

Fasting

AntibioticAntidiarrhea

• ORT: ORS• Limited IV fluid

Feeding: Continue during & increase after diarrhea

Continued feeding

ANTIMICROBES

New formula ORS

ANTIDIARRHEA&ANTIEMETIC&…DRUGS

Patient-Doctor’s Communication!

Incidence,severity &Recurrentdiarrhea

Selective

1970th-1980th

Duration, volume &IV

+ Patient safety

“No” Patient-Doctor’s-

Communication

Zn Suplementation

ANTIMICROBES

ANTIDIARHEA

Development Management of Diarrhea (Program)

-Pre&Probiotics antiemetics -Vaccine ?

ORS Formulas: 1968 - 1977Sodium

mEq/l

Glucose

mmol/l

Osmol

mOsmol/l

ADULTS 101 - 133 40 - 256 274 - 536

CHILDREN 80 - 120 110 - 140 300 - 400

World Health Organization. Implementing the New Recommendations on the Clinical Management of Diarrhoea: Guidelines for Policy Makers and Programme Managers. Geneva: World Health Organization, 2006.

WHO/UNICEF ORS - 1978

• NaCl 3.5 g• NaHCO32.5 g• KCl 1.5 g• Glucose 20 g

• Na+ 90 mEq/l• K+ 20 mEq/l• HCO3 30 mEq/l• Glucose 111 mmol/l• Cl 80 mmol/l• Osmolar.311

mOsmol/l

World Health Organization. Implementing the New Recommendations on the Clinical Management of Diarrhoea: Guidelines for Policy Makers and Programme Managers. Geneva: World Health Organization, 2006.

What is new in ORS?Standard formulation of

ORS• Sodium 90 MEq/L • Osmolarity of 311

mmol/L

New formulation of ORS

• Sodium 75 mEq/L • Osmolarity 245 mmol/L

Reduction of levels of glucose and salt shortens duration of diarrhea

Reduced osmolarity decreases stool output

Improved effectiveness for children with acute, non-cholera diarrhea

Previous Recommendations

• Use of Oral Rehydration Solution and home fluids to correct and prevent dehydration

• Continued feeding including breastfeeding

• Antibiotics for dysentery

• Why Change ? “No effect” on diarrhea duration

New RecommendationsWHO and UNICEF issued a joint policy for the treatment of diarrhea in children in May 2004Treatment should include

Liberal use of low-osmolarity Oral Rehydration Solution and home fluids to correct and prevent dehydrationZinc supplementation for 10-14 days to shorten duration and severity of diarrheaContinued feeding including breastfeedingAntibiotics for dysentery

WHO/UNICEF. Joint statement on the clinical management of acute diarrhea. 2004.

More than A decade of Research Search for

“Super ORS”

Effect of study ORS solutions of different osmolarity on stool output

310 330 360 380

Osmolarity of study ORS solution (mmol/l)

0

40

80

Per

cent

age

diffe

renc

e in

sto

ol

outp

ut c

ompa

red

with

WH

O O

RS

1. New Lo-ORS

AGE AMOUNT OF ORS AFTER EACH LOOSE STOOL

AMOUNT OF ORS TO PROVIDE FOR USE AT

HOME

<12 MONTHS 5O-100 ml 400ml/DAY

1-4 YEARS 100-200 ml 600-800 ml/DAY

> 5 YEARS 200-300 ml 800-1000 ml/DAYADULT 300-400 ml 1200-2800 ML/DAY

200 ml: 1 SACCHETE

Reducing concentration:

-glucose 75 mmol/L

-sodium (NaCl) 75mEq/L

-overall 245 mOsm/Lthe need of IV therapy 33%

stool output 20%

vomiting 30%WHO/UNICEF Joint Statement, 2004

OUTCOME

Multicenter, randomized, double-blind clinical trial to evaluate reduced osmol ORS efficacy & safety in children with acute

watery diarrhea

Therapy with low osmol ORS

A significantly lower proportion of children who required unscheduled intravenous therapy

95% CI:0.4-1.0

Conclusion

Treatment with reduced osmolarity ORS solution was associated with 33% reduction

in the need for unscheduled IV therapyCHOICE Study group, 2001

Systematical review to evaluate reduced osmol ORS for treating dehydration caused by acute diarrhea in children

Therapy with low osmolORS in acute diarrhea

Low osmol ORS was associated with fewer unscheduled intravenous fluid infusions compared with standard WHO ORS (Maentel hanzel OR 0,59, 95% CI 0,45-0,79). Stool output and

vomiting was reduced in reduce osmol ORS.

Conclusion

Reduce osmol ORS is associated with fewer unscheduled IV infusions, lower stool volume

and less vomiting Hahn et al., Cochrane Database of

Systematic Reviews 2002, Issue 1 2009

Systematical review to evaluate reduced osmol ORS for treating Cholera

Therapy with low osmolORS in cholera

There isn’t a significance difference in the need for unscheduled intravenous infusion. The duration for diarrhea is

also shorter in reduced osmol ORS (MD -16,85 hours, CI -21,22 to -12,48; 102 participant, 2 trials). Hyponatremia also occur in reduced osmol ORS but this wasn’t significance in

severe hyponatremia caused by diarrhea.

Conclusion

Treatment with reduced osmolarity ORS solution was effective in treating cholera although

hiponatremia usually occurs.

Murphy et al., Cochrane Database of Systematic Reviews 2004, Issue 4. 2009

2. Continued feeding

Improper beliefs & lack of knowledge

“Resting of bowels”

Malnutrition

Brown, 2003

CONTINUE BREAST FEEDINGIF NO BF, CONTINUE THE PREVIOUS MILK. <6MONTHS: FREQUENT SMALL FEEDING6MONTHS/ >:−PORRIDGE + NUTS, VEGETABLES,MEAT/FISH

+1-2 TEESPOON OIL− FRESH FRUIT/BANANA (POTASIUM)− FRESH FOOD; COOKED AND SOFT FOOD−STIMULATE TO EAT, AT LEAT 6 TIMES−DIARRHEA STOP: CONTINUE FEEDING + EXTRA

MEAL/DAY->2 WEEKS (WHO, 1997)

Breast feeding shortens the duration of acute diarrhea, rotaviral diarrhea, and persistent diarrhea (cit. WHO, 1997)

Early breast feeding (within the first 3 days of life) reduces the risk of diarrhea in the first 6 months of life due to the effects of human colostrum (Clemens et al, 1999)

• Zinc Supplementation WHO/UNICEF recommendations (2004):

Infant – 6 month old : 10 mg/day (10-14 days)

Children older : 20 mg/day (10-14 days)

Micronutrients

3. Micronutrients - Zinc

Establishing Efficacy and Safety of Zinc Supplementation

Before After Zinc Therapy

Impact of Zinc Deficiency

www. www.doctors.ly, 2009

ZINC : Mechanism of Action

Zinc

immune system

intestinal absorptive and/or

secretorytransport process

Antimicrobialeffect

Inhibit growth (3)

S. thyphi, S. parathypiA, V. cholerae, Shigellaflexneri, Shigella sonnei

Humoral and cellular (1)

Anti-diarrheal agent by inhibiting Cl

secretion (2)

1. Cit. Rahman et al. 2005. Am J Clin Nutr2. Hoque et al. 2005. Am J Physiol Gastrointest Liver Physiol3. Surjawidjaja et al. 2004 Medical Principles and Practice

Trials on the Therapeutic Effect of Zinc on Acute Diarrhea

• Countries: Bangladesh (3), Brazil, India (6), Indonesia, Nepal

• Age groups: 3-60 mo

• Dose of zinc: ≈20 mg/d (range 5-45 mg/d)

• Reduces the duration and severity of the episode

Trials in the Pooled Analysis of the Therapeutic Effects of Zinc

Country

No. in Zinc Group

No. in Control Group

Age (mo.)

Zinc Supplement

Indonesia 739 659 3-35 4-5 mg/kg (acetate)

India 456 481 6-35 20 mg (gluconate)

Bangladesh

57 54 3-24 20 mg (acetate)

Am J Clin Nutr. 2000;72:1516-22.

Additional Trials in the Meta-Analysis of the Therapeutic Effects of Zinc in Acute Diarrhea

Trial

No. inZinc Group

No. in Controlgroup

Age (mo)

Zinc Supplement

Bangladesh

341 340 6-23 14.2 or 40.0 mg (acetate)

India 44 36 3-24 40 mg (sulfate)

Brazil 37 37 3-60 22.5 or 45 mg (sulfate)

India 25 25 6-18 40 mg (sulfate)

Additional Trials in the Meta-Analysis of the Therapeutic Effects of Zinc in Acute Diarrhea

Trial

No. in Zinc Group

No. in Control group

Age (mo)

Zinc Supplement

Bangladesh 2001

620 632 3-59 20 mg (acetate)

India 2001a

547 547 3-35 5 or 10 mg (sulfate)

Nepal 442 449 6-35 15 or 30 mg (gluconate)

Additional Trials in the Meta-Analysis of the Therapeutic Effects of Zinc in Acute Diarrhea

Trial

No. in Zinc Group

No. in Control group

Age (mo)

Zinc Supplement

India 2001c

404 401 3-35

15 or 30 mg (gluconate)

India 2001b

132 134 3-36

15 or 30 mg (sulfate)

Effect of Zinc Supplementation on Duration of Acute Diarrhea/Time to Recovery

*Bangladesh, 1999

Pooled

1*Difference in mean and 95% CI

Relative Hazards and 95% CI

*India, 1988

*India, 2000*Brazil, 2000*India, 2001

Indonesia, 1998India, 1995

Bangladesh, 1997India, 2001India, 2001

Nepal, 2001Bangladesh, 2001

Age <12 months Age ≥12 months

Wasted Not Wasted

Male Female

0 0.25 0.5 0.75 1 1.25 1.5 1.75 2Relative Hazard and 95% CI

Relative Hazard of Continuation of Diarrhea inZinc-Supplemented Children With Acute DiarrheaPooled Effect (Stratified Analysis) in Subgroups

Effect of Zinc Supplementation on continuation of Acute Diarrhea for > 7days

Analysis Odds Ratio (95% CI)

Pooled Analysis (n=3)

0.78 (0.56, 1.09)

Meta – Analysis (n=5) 0.73 (0.55, 0.98)

J Pediatr. 1999 ;135:689-97.

Effect of Zinc Supplementation on Duration of persistent Diarrhea Episode

Analysis Effect MeasureEffect Size (95% CI)

Pooled Analysis (n=4)

Lower probability of continuing diarrhea

24% (9%, 38%)

Meta-Analysis (n=5)

Reduction in mean duration

29% (6%, 52%)

J Pediatr. 1999 ;135:689-97.

Lukacik, M, et.al.; 2007

Conclusion

Zinc supplementation

Reported to have a 18.8% reduction in average stool

frequency

(n=4438)

Reported to have a 17.9% reduction of

diarrhea

(n=4438)

zinc supplementation reduces the duration and severity of acute diarrhea

Reported to have a 15.0% shortening of

diarrhea duration

(n=4438)

Conclusion

Zinc supplementation

Reported to have a 12,27% shortening of acute diarrhea duration(13 trials, n=1417)

Reported to have an adverse effect of vomiting

by 1,71 fold(9 trials, n=2390)

zinc supplementation reduces the duration of acute and persistent diarrhea but vomiting is also occurs

Reported to have a 15.84% shortening of

persistent diarrhea duration

(5 trials, n=267)

Lanzerini and Ronfani, Cochrane Database of Systematic Review issue 3, 2008.

Conclusion

Zinc supplementation

Reported to lower average duration of diarrhea (WMD -0,69; 95% CI -0,97 to -0,40)

(13 trials, n=5643)

Reported to have an adverse effect of vomiting

by 1,22 fold(5 trials, n=1384)

zinc supplementation reduces the duration and severity of gastroenteritis but vomiting is also occurs

Significantly reduce the number of episodes of diarrhea lasting longer than 7 days (RR 0,71;

95% CI 0,53-0,96)(8 trials, n=5769)

Patro et al., Aliment Pharmacol Ther 28:713-723, 2008.

Conclusion

Zinc supplementation

Reported to have a 19,70% shortening of acute diarrhea duration

(26 trials)

Reported to have an adverse effect of vomiting

by 2,13 fold(14 trials, n=6779)

zinc supplementation reduces the duration of acute and persistent diarrhea but vomiting is also occurs especially

when given in pre-admission of diarrhea

Reported to have a 15.84% shortening of

persistent diarrhea duration

(5 trials, n=267)

Patel et al., PLoS ONE 5(4): e10386, 2010.

Preventive Effect of Zinc Supplementation on Diarrheal and Pneumonia Incidence with Continuous Supplementation in Subgroups

0 0.25 0.5 0.75 1 1.25 1.5 1.75 2

Odds Ratio and 95% CI

Age < 12 months (4)

Age >= 12 months (3)

Zinc < 60 ug/dl (2)

Zinc >=60 ug/dl (2)

Wasted (4)

Not wasted (2)

Male (4)

Female (3)0 0.25 0.5 0.75 1 1.25 1.5 1.75 2

Odds Ratio and 95% CI

Diarrhea Pneumonia

* Number in parenthesis gives the number of trials contributing to the data

Preventive Effect of Zinc Supplementation on Diarrheal Incidence in Short - Course Supplementation Trials

Bangladesh (I)Bangladesh (II)

Pakistan

Bangladesh (III)

Pooled0 0.25 0.5 0.75 1 1.25 1.5 1.75 2 2.25 2.5

Odds Ratio and 95% CI

•14 days of supplementation (20mg) with surveillance for 2-6 months

Safety of Zinc Supplementation for Diarrhea Treatment

9,100 children <5 y supplemented with zinc or placebo in 18 trials

Vomiting is the only reported adverse effect5/7 trials report no differences between zinc and placebo2 trials report slightly higher vomiting rates in zinc supplemented children

4/4 trials show no adverse effects on copper status after 2 weeks of zinc supplementation

Statement from WHO Meeting, New Delhi, 2001

“There is now enough evidence demonstrating the efficacy of zinc supplementation on the clinical course of acute diarrhea. However, effectiveness studies to address different strategies for delivering zinc supplementation to children with diarrhea should be undertaken. (feasibility, sustainability, cost-effectiveness, consumption of ORS, antibiotic use, non- diarrhea morbidity, overall mortality).”

Zinc Investigators’ Collaborative Group. J Health Pop Nutr, 2001

American Academy of Pediatrics endorsed and accepted as its policy the Centers for Disease Control and Prevention

guideline : “Managing Acute Gastroenteritis Among Children: Oral Rehydration, Maintenance, and Nutritional

Therapy from the Centers for Disease Control and Prevention”, as follows:

Anti-Emetic

Ondansetron, a serotonin antagonist, either by the oral or IV route,

can be effective in decreasing vomiting and limiting hospital admission.

But, antiemetics are usually unnecessary in acute diarrhea management.Because acute diarrhea is a common illness, cost-effective analyses

should be undertaken before routine pharmacologic therapy is recommended

Evaluating Effectiveness

Community-based Trial of Zinc Supplementation During Diarrhea

In rural Bangladesh, 30 health worker areas randomized

8,070 3-59 mo old children, 11,880 child-years

ORT alone vs. ORT and 20 mg/d zinc

Duration of episodes: RH 0.77 (0.69, 0.86)

Diarrhea hospitalization: RR 0.81 (0.65, 1.00)

Mortality: RR 0.49 (0.25, 0.94)

Baqui, Black, Arifeen, et al., BMJ, 2002

Effects of Zinc Supplementation Started During Acute Diarrhea in Bangladesh*

Outcome Zinc (%) Control (%)

Treated with ORS 75 50†

Antibiotic use 13 34†

Other drug use 15 45†

Care from pharmacy 16 33†

Care from village “doctors”

12 27†

Care from homeopaths 6 13†

Baqui, Black, Arifeen et al, J Health Pop Nutr, 2004†All comparisons p<0.01

Multicountry Acceptability Study (INCLEN)

Brazil, Ethiopia, Egypt, India (2 sites), PhilippinesFormative assessment for messagesZinc dispersible tablets along with ORS for outpatient diarrheaPooled results

84% of children consumed >80% of 14 tablets 5 of 6 sites had no decline in ORS use in zinc-supplemented children48% reduction in use of antimicrobial/ anti diarrheal drugs in zinc-supplemented children

INCLEN. J Ped Gastro & Nutr (In Press)

Reasons:-Caretakers felt Zn no longer needed --diarrhea had resolve

- Nausea- Vomiting- Poor palatability- Only given during-

hospitalization72%

28%

Proportion of patients completed Zn 10-day course

Completed Not completed

N= 133

Soenarto et al, unpublished

Cost Benefit Analysis

Introduction of zinc into the standard treatment of diarrhea may cause:

potential reduction in lives lost in Indonesiareduced morbidityimproved nutritional statusPotential financial savings

Assessment for the introduction of zinc in improved maangement of diarrhea in Indonesia. BASICS

4. Pharmacologic

1. Antimicrobial drugsAntimicrobial agents should not be used routinely.

• should be preceded by appropriate stool cultures or pathogen detection tests.

• only few indications for empiric use , e.g. suspected or confirmed shigellosis or cholera, selected cases of inflammatory diarrhea, travelers’ diarrhea and diarrhea due to parasites.

2. Non-antimicrobial drugs• Anti-diarrhoeal drugs and anti-emetics

have no practical benefits for children with acute or persistent diarrhea.

• Antimotility drugs potentially life-threatening adverse effects, including lethargy, ileus, respiratory depression, & coma

4. Pharmacologic

ETIOLOGY of ACUTE DIARRHEA

BACTERIA

VIRUS PARASITES

Generally caused by 3 different agents (individually or as a combination altogether):

• Virus

• Bacteria

• Parasites

Acute gastroenteritis caused by viruses is one of the leading causes of childhood morbidity.

ETIOLOGY OF <5 DIARRHEA IN INDONESIA

80%

5%

1%

5%

3%

1%

1%

1%

2%

1%

5%

RV

Shigella

Aeromonas

Salmonella

Campylobacter

S. Enteritidis

Giardia Lamblia

Mixed (RV+Salmonella)

Mixed (RV+Campylobacter)

Mixed (RV+Ve Inaba)

Study at Sardjito hospital in collaboration with NIH, Ministry of Health, RI & NAMRU2 research, 2005

84% RV; 16% bacterial

<16% need antibiotic

ROTAVIRUS

Global death due to rotaviral diarrhea

ROTAVIRAL DIARRHEA : UNIVERSAL DISEASE

Percentage of rotaviral-diarrhea inpatients in Asia

Breese, 2005

2001-2004

Median = 45%

ROTAVIRAL DIARRHEA IN INDONESIA“Extension for Hospital Based Surveillance & Strain Characterization of Rotavirus Diarrhea in Indonesia”

Bandung 47%Bali 59%

Yogyakarta 35%

N = 2517 (RV: 57%)

2006-2007

Jakarta 67%

Palembang 60%

Mataram 63%

Soenarto et al,2007 

CLINICAL MANIFESTATIONS RV DIARRHEA

Clinical presentations

# RV(+) diarrhea N=1435 (%)

# RV (-) diarrheaN=1089 (%)

OR CI

Vomiting 1219 (85) 718 (66) 2.9 2.4 –3.5*

Dehydration 1297 (90) 863 (80) 2.4 1.9 –3.0*

Mucus stool 399 (28) 347 (32) 0.8 0.7 –0.97*

Bloody stool 24 (2) 62 (6) 0.3 0.2 –0.5*

Fever 527 (37) 414 (38) 0.9 0.8 – 1.1

Soenarto et al,2007* p < 0.05

LEVEL OF DEHYDRATION

0

200

400

600

800

1000

1200

1400

Dehydration No dehydration

No.

of s

peci

men

s te

sted

# RV-positive patients# RV-negative patients

p < 0.05

Soenarto et al,2007

TREATMENT PRIOR VISITING HOSPITALS

# Sample tested N=2517 (%)

# RV(+) diarrheaN=1435 (%)

ORS 1416 (56) 865 (60)Antibiotics 689 (27) 398(28)Antivomiting 378 (15) 242 (17)Antidiarrhea 317 (13) 196 (14)Other drugs 668 (27) 395 (28)

Soenarto et al,2007 unpublished

• Research found that viral, especially rotavirus infection are more common for treating diarrhea

• Improving sanitation, hygiene & the availability of clean water may prevent bacterial & parasitic infection, but in rotaviralinfection it may not be the case

• rotavirus dominant vomiting symptoms, ORS may prove less effective

Do 5 STEPS OF MANAGEMENT FOR DIARRHEA (Lintas Diare) are Enough?

Efficacy of Rotarix against RVGE*

DiseaseSeverity

Number of Cases

% Efficacy 95% CIHRV

(N=9009)Placebo

(N=8858)

Severe 12 77 84.771.7, 92.4

Hospita-lized 9 59 85.0

69.6, 93.5

*Ruiz-Palacios G. et al N. Engl. J. Med. 2006; 354: 11-22

Type ofContact

Number of Cases % RateReduction

95% CIVaccine Placebo

Hospitalizations†

ED visits †

Office visits††

6

15

14

144

232

100

95.8

93.5

85.2

90.5, 98.2

88.6, 96.3

73.1, 91.9

Efficacy of RotaTeq to reduce healthcare utilization for rotavirus gastroenteritis*

*Vesikari et al New Engl J Med, 2006Per protocol population (includes only cases that occurred at least 14 days after Dose 3)

† N=34,035 vaccine and 34,003 placebo recipients†† N = 2,834 vaccine and 2839 placebo recipients

• Current therapies for pediatric diarrhea are limited to supportive and symptomatic care.

• Probiotics are especially useful in diseases mediated by the disruption of the normally protective microflora may offer an attractive supportive therapy for acute pediatric diarrhea.

Probiotics & Acute Diarrhea

Meta-analysis: Probiotics & Acute Diarrhea

1. Meta-analysis of probiotics for the prevention and treatment of acute pediatric diarrhea (McFarland, L.V.; Gary W. Elmer, G.W.; and McFarland, M.; 2005)

2. Efficacy of Probiotic Use in Acute Diarrhea in Children: A Meta-Analysis (Huang, J.S.; Bousvaros, A.; Lee, J.W.; Diaz, A.; and Davidson, E.J.; 2002)

3. Probiotic for Pediatric Antibiotic-Associated Diarrhea: a Meta Analysis of Randomized Placebo-Controlled Trials (Johston, B.C.; Supina, A.L.; Vohra, S.; 2006)

18 RCT: treatment of diarrhea by probiotic with diarrhea duration as outcome

8 RCT: treatment of diarrhea by probiotic with percent diarrhea cured as outcome

15 RCT: prevention of diarrhea by probiotic with percent failed as outcome

1. (McFarland, L.V.; Gary W. Elmer, G.W.; and McFarland, M.; 2006)

18 Studies: duration of diarrhea (treatment –control)

18 Studies: duration of diarrhea in days (treatment vs control)

2. (Huang, J.S.; Bousvaros, A.; Lee, J.W.; Diaz, A.; and Davidson, E.J.; 2002)

3. (Johnston, B.C.; Supina, A.L.; Vohra, S.; 2006)

6 RCT (n=707): treatment of diarrhea by probiotic with diarrhea duration as

outcome Subgroup analysis efficacy dose and strain of

probiotics from 6 RCT for treatment AAD

CONCLUSION

1. Pooled estimates found that probiotics offer a safe and effective method to prevent and treat acute pediatric diarrhea. No serious adverse reactions were reported in the trials. (McFarland, L.V.; Gary W. Elmer, G.W.; and McFarland, M.; 2006)

2. In conclusion, bacterial probiotic therapy shortens the duration of acute diarrheal illness in children by approximately one day. (Huang, J.S.; Bousvaros, A.; Lee, J.W.; Diaz, A.; and Davidson, E.J.; 2002)

3. Strain Lactobacillus GG with doses ≥5 billion CFU shows a strong evidence for treatment antibiotic associated diarrhea with no serious adverse effect (Johnston, B.C.; Supina, A.L.; Vohra, S.; 2006)

Probiotic and Traveler’s Diarrhea

Conclusion

Probioticsupplementation

Reported to lower incidence of travelers diarrhea by

85% (RR 0,85; 95% CI 0,79 to 0,91)

(12 trials, n=5643)

No severe adverse effect (bactericimia or fungemia)

were occurred from the supplementation with

probiotic

Probiotic supplementation reduces the incidence of travelers diarrhea and safe

McFarland, L.V.; 2007

(McFarland, L.V., Travel Med&Infec Dis., (2007) 5:97-105)

Funnel plot from 12 RCT: no heterogenity was found (X2=18,9; Z=-0,96, p= 0,34).

Forest plot from 12 RCT: probiotic reduce the incidence of TD by 85% (RR 0,85; 95% CI 0,79-0,91; p<0,001).

Probiotics & RV Diarrhea

• There is ample evidence that probiotics reduce duration & severity of RV diarrhea.

• Clinical trials demonstrated effectiveness of probiotics in treatment and prevention of acute diarrhea, decreasing the severity and duration of rotavirus infections in children as well as diarrhea in adults.

Effective prophylaxis against rotavirus diarrhea using a combination of Lactobacillus rhamnosus GG and antibodies

Lactobacillus rhamnosus strain GG showed a strong anti-rotavirus capacity and reduced the diarrhea prevalence to 41% compared to 93% in infected but untreated mice

(Pant, Marcotte, et.al., 2007)

Application of Probiotics• Future studies on the therapeutic potential of

probiotics are necessary

• Efforts should be made to standardize doses, duration of treatment

• Direct comparisons of probiotics versus placebo are indicated

• Adverse reaction data and cost-effectiveness analyses would be helpful

(McFarland, L.V.; et.al.; 2006)

A New Perspective For Treating Diarrhea

Lintas Diare

Rotavirus Vaccine

Probiotic

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References 

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• Pan, Neha; Marcote, H.; Brussow, H.; Svensson, L.; Hammarstrom, L. 2007. Effective prophylaxis against rotavirus diarrhea using a combination of Lactobacillus rhamnosus GG and antibodies. BMC Microbiology; 7:86.

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