Clinical perspective on pediatric use of zinc for diarrhea and other infectious diseases

Shinjini Bhatnagar Centre for Diarrheal Diseases & Nutrition Research Department of Pediatrics All India Institute of Medical Sciences, New Delhi, India

Initial interest in zinc in acute diarrhea started in India

MAMC, New Delhi AIIMS, New Delhi & Collaborators
Prof MK Bhan, Dr Nita Bhandari, Dr Shinjini Bhatnagar, Dr Sunil Sazawal, Dr Rajiv Bahl Dr RE Black, Dr Halvor Sommerfelt, Dr Tor Strand

Oral zinc supplementation in infants admitted with acute dehydrating diarrhea in a tertiary hospital in India; RCT
50 infants, 40 mg/d zinc
Infants with rectal zinc < 15th percentile had significantly lower stool frequency (P < 0.01) and diarrheal duration (p< 0.05)

Sachdev HPS et al, JPGN 1988

Effect of zinc supplementation in acute diarrhea in an urban community in India

937 children, 6-35 mo, diarrhea < 7 d 20 mg zinc daily

% reduction (95%CI)
Risk of continued diarrhea % episodes > 7d Mean no of watery stools/d No of days with watery diarrhea 23 (12 to 32)* 39 (7 to 61)* 39 (6 to 70)* 21 (10 to 31)*

Sazawal et al, N Eng J Med 1995

Why Zinc?
Zinc deficiency is common Excessive fecal loss of zinc during diarrhea Zinc critical for immune and non immune functions that resist or clear infection & its consequences

Prevalence of zinc deficiency based on plasma or serum zinc in field trials

Site
India India India Mexico Lima PNG

Age
6-35 mo 6-30 mo 12-59 mo 18-36 mo 24 mo

Prevalence (%)
36 44 32 68 80 37

2-10 yrs

Ontario
Dev. countries

5-7
<5

yrs
yrs

21
38

Why is zinc deficiency so prevalent?

Breast milk not a sufficient source > 4-5 mo

Low intake of complementary foods

Low consumption of animal foods

High fecal losses during diarrheal illness

Limited bioavailability; phytates from cereals Low content of soil, of foods

Plasma zinc as a predictor of diarrheal morbidity

Children with low initial plasma zinc (< 8.4 mmol/L) had 47% (3% to 149%) higher risk of diarrhea & 70% (6% to 172%) higher risk of severe diarrhea

The mean prevalence rate of diarrhea associated with fever was 4 times higher in the zinc-deficient

group (P = 0.01)

Bahl et al, Am J Clin Nutr 1998

Pooled analysis of zinc supplementation trials on diarrhea prevention in children <5 years
Zinc 1-2 RDA daily for 4-12 mo India, Mexico, PNG, Peru, Vietnam, Guatemala, Jamaica

%(95% CI) Reduction

Diarrhea incidence
Diarrhea prevalence

18 ( 7 to 28 )*
25 ( 12 to 37 )*

Zinc Investigators Collaborative Group, J Pediatrics 1999

Zinc supplementation reduced the incidence of severe & prolonged diarrhea in young North Indian children
Zinc 1-2 RDA daily for 4 mo

%(95% CI) Reduction

Diarrhea 1-6 d 7-13 d > 14 d 3-5 6-9 > 10 (>6) 8 (0 to 15)* 21 (5 to 35)* 31 (2 to 52)* 10 (2 to 17)* 13 (2 to 23)* 23 (6 to 37)* 49 (27 to 64)*

Stool frequency

Rec episodes

Bhandari et al, Pediatr 2002

Zinc in acute diarrhea

Recovery from diarrhea
No. of subjects
931 1368

Study
Sazawal, 1995 Hidayat, 1998

Relative Hazards (95% CI)

0.79 (0.69, 0.90)* 0.92 (0.83, 1.02)

Roy, 1997
Strand, 2002 Bahl, 2002 Baqui, 2002 Bhatnagar, 2004

101
891 805 1252 266

0.85 (0.57, 1.28)

0.79 (0.68, 0.93)* 0.89 (0.80, 0.99)* 0.75 (0.65, 0.90)* 0.76 (0.59, 0.97)* 0.84 (0.78 to 0.89)*

Combined estimate (Meta-analysis)

Zinc in acute diarrhea Effect on continuation for >7 days

Study
Sazawal, 1995 Hidayat, 1998 Roy, 1997 Strand, 2002 Bahl, 2002 Bhatnagar, 2004

No. of subjects
931 1368 101 891 805 266

Odds ratio (95% CI)

0.85 (0.60, 1.19) 0.72 (0.48, 1.07) 0.77 (0.33, 1.79) 0.57 (0.38, 0.86)* 0.61 (0.33, 1.12) 0.09 (0.01, 0.73)* 0.66 (0.52 to 0.83)*

Combined estimate (Meta-analysis)

Zinc in acute diarrhea Effect on stool volume

Study
Total stool output

Subjects

Difference in means/ ratio of GM (95%CI)

Roy, 1997 Dutta, 2000 Bhatnagar, 2004

Stool output per day of diarrhea

111 80 266

-91 g -900 (-1200, -590)* 0.69 (0.48, 0.99)*

Ratio of GM (95% CI) of geometric means

Bhatnagar,2004

266

0.76 (0.59, 0.98)*

24% reduction

Therapeutic effect of zinc given in persistent diarrhea

Effect size (95% CI)
Time to recovery 24% reduction

Treatment failure/death

39% reduction

Summary estimates from a pooled analysis of 4 trials: Zinc Investigators Collaborative Group, Am J Clin Nutr 2000

Zinc given for 14d beginning during acute or persistent diarrhea

Effect on diarrhea morbidity during the subsequent 2-3 mo without further supplementation

Odds ratio (95% CI)

Diarrhea incidence Diarrhea prevalence 11% reduction 44% reduction

Summary estimates from a pooled analysis of three small trials: Black et al, 1999

Effect of zinc on vomiting

No vomiting

Bhatnagar (JPGN)

132/134

zinc 29% vs. placebo 32%

Bahl (J Pediatr)
Strand (Pediatrics)

404/401
442/449

zinc 38% vs. placebo 26%

zinc 5% vs. placebo 1%

WHO/UNICEF Joint statement on clinical management of acute diarrhea (2001)

Recommendations:
20 mg per day of zinc supplementation for 10-14 days starting as early as possible after onset of diarrhea 10 mg per day for infants <6 mo (more evidence required)
Administration: Once or twice daily

How does zinc work ???

Centre for Diarrhea & Nutrition Research, AIIMS

20

Possible mechanisms for benefits seen with zinc supplementation in infectious diseases
Correction of zinc deficiency &

immunoreconstitution
Direct effects on the epithelial barrier Direct immunostimulatory effect Anti secretory effect
21 Centre for Diarrhea & Nutrition Research, AIIMS

Zinc critical for immune & non immune functions that resist or clear infection & its consequences
The percentage of anergic children decreased from 67% to 47% (p=0.05) in the zinc supplemented group as compared to the controls Zinc supplemented group had: 25% CD3+ 64% CD4+ (p=0.02) (p=0.001)

73% CD4/CD8 (p=0.004)

Sazawal et al, Ind Pediatr 1997
22 Centre for Diarrhea & Nutrition Research, AIIMS

Possible sites of Zn action

On cAMP-stimulated Cl secretion
NKCC

2Cl Na K

?
?

cAMP

3Na Na-K-ATPase

Cl

2K

Zn major intracellular regulator of apoptosis by

inhibiting of Ca/Mg DNA endonuclease

23 Centre for Diarrhea & Nutrition Research, AIIMS

What are the implications of introducing zinc in the programme/clinical practice?

Does it affect hospitalization? Does it have an impact on mortality? Does it reduce antibiotic use? Does it increase use of ORS?

Will it be consumed for 14 days?

24 Centre for Diarrhea & Nutrition Research, AIIMS

Effect on mortality & hospitalizations after giving zinc (with ORS) for 14d started during acute diarrhea
20 mg Zn/d for 14 d, Matlab, Bangladesh

Intervention Child-years of f. up 5866

Control 6015

Decreased non-injury deaths by

50% (6-75%)

Decreased hospitalizations by

24% (2-41%)

Baqui et al, BMJ 2002

Centre for Diarrhea & Nutrition Research, AIIMS

25

Introduction of treatment of acute diarrhea with Zinc & ORS vs ORS alone in Indian rural community through Primary Healthcare Workers Benefits in intervention villages compared to control villages

Reduction in:
Diarrhea prevalence in last 2 weeks Pneumonia prevalence in last 2 weeks 44% 45%

All cause hospitalization in last 3 months

Use of unwarranted drugs in last 1 mo Use of unwarranted injections Average cost of treatment for one diarrheal episode to family Bhandari N et al, Pediatrics, 2008

59%
78% 58% nil vs Rs. 40
26

Introduction of zinc in the treatment of diarrhea

Endorsed by IAP: 2003, 2007
Introduced in NHRM II by Govt. of India: 2007

Centre for Diarrhea & Nutrition Research, AIIMS

27

Key Issues in treatment with zinc

Forms of zinc used:

Zinc sulphate
Zinc acetate

Zinc gluconate
Dose used: 2 RDA

Administration: Once or twice daily Duration: 14 days

Can we mix zinc with ORS ?

ORS fortified with 40 mg zinc/ litre does not
decrease stool output or diarrhea duration in 500 hospitalized children (1-35 mo) with severe acute diarrhea
Bhatnagar et al, in press
29

Centre for Diarrhea & Nutrition Research, AIIMS

Is zinc efficacious in infants 1 to 2 months with acute diarrhea ?

More evidence required

Brooks et al, Am J Clin Nutr 2005; Fischer et al, JPGN 2006

Centre for Diarrhea & Nutrition Research, AIIMS

30

How safe is zinc?

Safe in efficacy & effectiveness trials in almost 100,000 > 2 y from Asia, Lat America & Africa Zinc doses 545 mg/d during diarrhoea

All salts: sulfate, acetate & gluconate safe

Smallest fatal dose of ZnSO4 is 15 gm

Zinc toxicity in adults after 150 mg/d over a long

period or from ingestion of > 1g
31 Centre for Diarrhea & Nutrition Research, AIIMS

Cost Effectiveness of ORS and Zinc Supplementation

Decreased duration & severity of episode
Decreased need for expensive hospitalization

Decreased use of unnecessary antibiotics & other drugs

Further cost-benefit analysis underway
Robberstad et al. Bull WHO 2004 and Baqui et al. J Health Pop Nutr. 2004.
32 Centre for Diarrhea & Nutrition Research, AIIMS

Possible role of zinc in prevention and treatment of other infectious diseases

Summary of evidence from randomized controlled trials

Dysentery
Study
No. of sub in comparison groups 32 16, 16 Age Dose & Duration

Outcome

Bangladesh, Alam, 1994

1 - 12 y

zinc acetate 15 mg/kg /d X 1 mo

Intestinal permeability (p=0.005) & N2 absorption (p=0.03) increased in Zn

India, Sazawal 1996 Bangladesh, Rahman 2001

569 284, 285 800 children Zn = 170 Vit A =159 Zn + Vit A = 175 Placebo= 161

6-35 mo

Zn (10 mg)

Reduction among boys; 38% (95 % CI 8% to 59%, p<0.05)

12-35 mo

G1: 20 mg zinc for 14 d+ placebo on D14 G2: Pl +2 l Vit A (D14) G3: 20 mg zn for 14 d + 2l IU vitamin A, on d 14; G4: placebo 14 days

Zn & Vit. A reduced dysentery Rate ratio of 0.80 ( 95% CI 0.67 to 0.95)

Peru , Penny 2004

246
Zn = 81 Zn+VM= 82 placebo = 83

6-35 mo

Zn (10 mg), Zn (10 mg) + MV at 1-2 RDA or placebo for 6 mo

Greater morbidity in chidren in

Zn+MV (58%) vs Zn (39%). 97% reduction (p=0.05)

Bangladesh, Raqib 2004 Bangladesh, Rahman 2005

56 28,28

12-59 mo

zinc (20 mg) X 14 days

Ipa specific IgG (P 0.001) & lymphocyte proliferation (P 0.002) responses enhanced with zinc

56 28, 28

12-59 mo

zinc (20 mg) X 14 d,

Shigellacidal antibody response 73% (zinc) vs 36% (controls); (P 0.01). % CD20+ (P <001) & CD20+ CD38+ (P 0.007) higher in zinc

Zinc supplemented children have a 41% (95% CI 17 to 59%) lower incidence of pneumonia
Pooled analysis of 5 trials; Am J Clin Nutr, 2000 Routine supplementation of 2RDA zinc to children 6mo-3 y; Bhandari et al, BMJ, 2002 No. per group Pneumonia incidence % (95%CI ) reduction 1241/1241 26 (1 to 44)

Zinc supplementation and outcome of pneumonia

Age-adjusted hazard ratios by group and outcome Median duration (h, 95% CI) Zinc (n=132) Outcomes Chest indrawing 40 (39-48) 48 (40-56) 080 (061-105) Placebo(n=131) Outcome relative hazard (95% CI)

Resp Rate >50/min

Hypoxia Sev pneu resolution Resp Rate >40/min Hospital (days)

48 (40-56)
80 (72-96) 72 (72-96) 104 (88-112) 112 (104-112)

56 (40-64)
88 (80-104) 96 (72-96) 112 (104-128) 112 (111-129)

074 (057-098)
079 (061-104) 070 (051-098) 075 (057-098) 075 (057-099)

Overall 20-25% reduction *Zinc for severe pneumonia in very young children: double-blind placebo-controlled trial W Abdullah Brooks et al

Efficacy of zinc supplementation in prevention and treatment of malaria; RCT

Burkina Faso N=1394 12.5mg Zn /d X 6d/wk X6mo PNG N= 274 10mg Zn /d X 6d/wk X46 wk Africa & Latin America N=1087, (fever & > 2000 asexual Pl falc) 20-40mg Zn/d for 4d

% Reduction in visits to Health Centres

38% (95% CI 360, P 0.037)

RR 0.98 (95%CI 0.86, 1.11) Zn: 74 P: 78 (P=0.11)

% Reduction in incidence of symptomatic P.falc > 75% Reduction in parasitemia

Median time to reduction of fever

Zn: 24h P: 24h (P=0.37)

68% reduction in mortality in low birth weight Indian infants who were supplemented with zinc from 1 to 9 months of age

Sazawal et al, Pediatrics, 2001

LBW infants may require zinc supplements at earlier ages than term AGA infants
Inadequate stores Low breast milk volume in undernourished mothers Extra demands for catch up growth Several fold higher diarrheal morbidity Effects of maternal zinc deficiency on neonatal immune function - may be reversible by postnatal supplement

Introduction of zinc in prophylactic and therapeutic public health programmes could

prevent 9% of all under 5 deaths globally

Bellagio Child Survival Group, Lancet 2003

Implications today
What can be done to improve zinc intakes ?

intake of food with Zn content & bioavailability Zn abs. by soaking, germination, fermentation

Improve complementary feeding

Implications for the future

What can be done to improve zinc intakes ?

Non-enzymatic methods to reduce phytic acid content of plant staples Fortification Soil supplementation Zinc dense or low phytate plants

Future
Understand better how zinc mechanisms
function & translate into clinical application Effectiveness trials to understand introduction of zinc in health programmes Optimal delivery systems Policy decisions for use in young infants Justification of therapeutic dose

Possible role in other infections