ZINC, IMMUNITY, INFECTIONS AND GROWTH Dr. Fernando Sempértegui Universidad Central del Ecuador Corporación Ecuatoriana de Biotecnología
ZINC DEFICIENCY IN ECUADORIAN CHILDREN (PLASMA ZINC <70 ug/dL)
• Country: 40% of children under 60 months. • Andean rural areas: 45% • Quito: 33% Freire W, Dirren H, Mora J, et al. Diagnóstico de la situación alimentaria, nutricional y de salud de la población ecuatoriana menor de 5 años.CONADEMSP. Ecuador:Namur; 1988:202-205.
ZINC DEFICIENCY IN ECUADORIAN CHILDREN • Estimated daily zinc intake in poor urban slums from Quito: 5.9 mg Sempértegui F, Estrella B, Correa E, et al. Effects of short-term zinc supplementation on cellular immunity, respiratory symptoms, and growth of malnourished Equadorian children. Eur J Clin Nutr 1996; 50:42-46.
• Plasma zinc levels (ug/dL) in poor children from Esmeraldas during an acute malaria episode: 49.55 ± 20.24 •
Sempértegui F, Estrella B, Torres D, et al. (ZAP study group). Effect of zinc on the treatment of uncomplicated plasmodium falciparum malaria in African and Latin American children: a randomised controlled trial. Am J Clin Nutr 2002;76:805-12.
ZINC AND RESPIRATORY INFECTIONS
EPIDEMIOLOGY OF RESPIRATORY INFECTION IN CHILDREN • Pneumonia causes around 4 millon deaths every year (Leowski J, 1986; Garenne M, 1992; Sazawal S, 1992). • Case management at community level, including antibiotic treatment to all children with rapid breathing, can reduce pneumonia mortality by 50% (Sazawal S, 1992). • Currently, only a small proportion of all ALRI can be prevented by immunization against measles, pertussis (Fauveau V, 1992; Koening MA, 1990), and H.influenzae.
CHALLENGE: PREVENTION OF PNEUMONIA IN CHILDREN
Prevention of pneumonia is required to complement the case-management and immunizations in developing countries.
COULD ZINC PREVENT PNEUMONIA IN CHILDREN? • Malnutrition increases both incidence and severity of pneumonia (Tupasi TE, 1990; James JW, 1972; Zaman K, 1996)
• Reduction in cellular immunity occurs in malnourished children (Mc Murray DN, 1981; Chandra RK, 1991; Neumann CG, 1975)
• In experimental models, protein/energy malnutrition by itself does not result in impaired cellurar immunity (Good RA, 1979).
COULD ZINC PREVENT PNEUMONIA IN CHILDREN? The reduced immunological competence in malnourished children may be attributable to zinc deficiency, because this is associated with impaired cellular immune status, an effect that is reversed by zinc supplementation (Fraker PJ, 1987; Schoen LA, 1979; Castillo-Duran C, 1987).
Pneumonia: RR 0.55; 95%CI 0.33,0.90
ZINC PREVENTS RESPIRATORY INFECTIONS VIA IMPROVEMENT OF IMMUNITY Our Ecuadorian team reported that prevention of respiratory symptoms is associated with improvement of immunity as indicated by skin test.
ZINC AND DIARRHEAL INFECTIONS
EFFECTS OF ZINC SUPPLEMENTATION ON DIARRHEA INCIDENCE IN ECUADORIAN CHILDREN 2000-2004 VAZPOP STUDY Diarrheal Incidence Placebo Zinc Zinc + Vitamin A Vitamin A
33/1000 CW 28/1000CW 31/1000CW 32/1000CW
RR
(95%CI)
0.86 (0.78-094) 0.95 (0.86-1.04) 0.98 (0.89-1.07)
Sempértegui F, Estrella B, Egas J, Naumova E, Hamer DH, Wanke C, Meydani SN, Griffiths JK, 2008. (manuscript in preparation)
PATTERN OF ZINC SUPLEMENTATION ON THE PREVENTION OF DIARRHEA 2000-2004 VAZPOP STUDY
Zinc Vitamin A + Zinc Vitamin A Mild malnourished Underweight Age Sex female
Weeks 1-20 beta t -0.050 -1.520 0.001 0.090 0.015 1.100 0.050 1.780 -0.006 -0.360 -0.030 -10.700 -0.077 -1.590
Weeks 21-50 beta t -0.0910 -2.50 0.0100 0.83 0.0100 1.36 0.0400 1.34 0.0080 0.50 -0.0490 -14.55 -0.1900 -3.79
SempĂŠrtegui F, Estrella B, Egas J, Naumova E, Hamer DH, Wanke C, Meydani SN, Griffiths JK, 2008. (manuscript in preparation)
Diarrhea: RR 0.82; 95%CI 0.72,0.93 Pneumonia: RR 0.59; 95%CI 0.41,0.83
Dose-response trial of prophylactic zinc supplements, with or without copper, in young Ecuadorian children at risk of zinc deficiency Sara E Wuehler, Fernando SempĂŠrtegui, and Kenneth H Brown Am J Clin Nutr 2008;87:723â&#x20AC;&#x201C;33
Dose-response trial of prophylactic zinc supplements, with or without copper, in young Ecuadorian children at risk of zinc deficiency
Dose-response trial of prophylactic zinc supplements, with or without copper, in young Ecuadorian children at risk of zinc deficiency Table 5. Diarrhea incidence and prevalence, estimated means (95%CI) with group-wise p-value Variable Placebo 3 mg zinc 7 mg zinc 10 mg zinc 10 mg zinc + p-value 0.5 mg copper n=116 n=117 n=116 n=118 n=121 Incidence of diarrhea 1.93 1.29 1.11 1.53 1.40 <0.01 (episodes /100 days) (1.60,2.29) (1.02, 1.59) (0.86, 1.39) (1.24, 1.85) (1.12, 1.70) Prevalence of diarrhea 3.56 2.51 2.16 2.69 2.60 0.03 (% days with diarrhea) (2.91, 4.27) (1.96,3.13) (1.65,2.73) (2.13, 3.31) (2.04, 3.22)
Dose-response trial of prophylactic zinc supplements, with or without copper, in young Ecuadorian children at risk of zinc deficiency
ZINC AND MALARIA
EFFECT OF ZINC ON THE TREATMENT OF Plasmodium falciparum MALARIA IN CHILDREN: A RANDOMIZED CONTROLLED TRIAL The Zinc Against Plasmodium Study Group Ecuador: Fernando SempĂŠrtegui, Bertha Estrella, Franklin R Toapanta, Darwin Torres, Dheyanira E Calahorrano. Am J Clin Nutr 2002;76:805-12 Corresponding Author: DH Hamer, ARCH Project, Boston University, School of Public Health.
BACKGROUND • Zinc supplementation improves cellular immune function (Sempértegui F, 1996). • In The Gambia zinc supplementation given twice weekly (1.25 years) showed the trend toward a reduction in the clinic visits for malaria (Bates CJ, 1993). • In Papua New Guinea daily zinc supplementation (46 weeks) reduced significantly P.falciparum malaria episodes (Shankar AH, 2000).
HYPOTHESIS
Zinc as an adjuvant to standard antimalarial therapy would reduce the duration of fever, and parasitemia at 72 h.
METHODS • • • • • •
Children 6 months to 5 years age. (City of Esmeraldas) ≥ 2,000 asexual froms of P. Falciparum/ul Zinc group: Zinc 20mg or 40 mg/ day (4 days) plus chloroquine. Placebo group: Chloroquine plus placebo (4 days). Fever monitoring every 6 hours Parasitemia monitoring: 0, 24, 36, 48, 72 h; 7,14,and 28 days (Quality control, Dar-Es-Salaam, Tanzania) • Hemoglobin monitoring: 0h, 7, 14 and 28 days. • Plasma zinc: 0 and 72 h (Dr. Hambidge’s Lab, Denver, Colorado)
RESULTS
1
Summary of severe adverse events Zinc Group Adverse event (n=542) Cerebral malaria (n) 1 Severe anemia (n) 17 Febrile convulsion (n) 1 Death (n) 12 Total (n) 21 1
Placebo group (n=545) 1 9 2 2 14
There were not significant differences between groups
RESULTS
RESULTS
Reduction of parasitemia â&#x2030;Ľ 75% compared with values on admission, within 72 h. ___________________________________________________________________________________
Zinc group
398/542 (73.4%).
Placebo group
423/545 (77.6%)
_______________________________________________________________________________________________
X2 = 2.57, P = 0.11
RESULTS 1
Plasma zinc concentrations at baseline and 72 h Plasma zinc concentration Study group Baseline 72h Zinc group
2
(umol/L)
8.54 ±3.93
10.95± 3.63
(ug/dL) Placebo group
55.9 ±25.7 71.60 ±23.70
(umol/L)
8.34 ±3.25
10.16 ± 3.25
(ug/dL)
54.5 ±21.3
66.5 ± 21.30
2
2 2
1
mean±sd. Interaction between group and time, p= 0.038
2
Significantly different from baseline, p <0.001
CONCLUSIONS • Zinc has to improve the immune function to show a benefit on malaria. • It is not know how long it takes zinc supplementation to improve the immune function. • Three days of zinc supplementation may have been insufficient to improve the immune function in children with underlying zinc deficiency.
“BENEFICIO DE SUPLEMENTOS DE ZINC EN LA INMUNIDAD ORAL, LA PREVENCION DE LA CARIES Y EL CRECIMIENTO” PIC.002
Dra. Janeth Parra C1, Dra. Diana Astudillo1, Dr. Fernando Sempértegui2. 1. Universidad de Cuenca, 2. Universidad Central de Quito. Manuscrito en preparación
Hipรณtesis โ ข Suplementos diarios de zinc disminuyen la prevalencia de caries (CPOD, CPOS), modifican la concentraciรณn de IgA salival y mejoran la ganancia de talla.
Diseño • 320 niños de 6-12 años. Escuelas de la ciudad de Cuenca. • Grupo Z: 10 mg /día (Sulfato de Zinc). • Grupo P: Placebo /día. • Tiempo de suplementación: 40 semanas
Resultados Tabla 3. Características basales de los grupos suplementado (GZ) y placebo (GP) Placebo n=137 Media ± DE
Zinc n=123 Media ± DE
p
11,9
15,30
<0.001
104,22 ± 20,55
107,32±20,30
PESO (Kg)
25,17±5,51
25,69±5,20
WAZ (DE)
-0,80±0,77
-0,83±0,74
119,65±8,78
121,98±9,02
HAZ (DE)
-1,92±0,69
-1,73±0,64
BMI
17,37±1,64
17,09±1,67
104,10±15,55
106,82±21,84
IgA
8,65±6,59
7,29±5,54
CPOD (Indice de Caries)
8,95±3,46
9,19±3,90
CPOS (Indice de superfices cariadas)
16,15±8,27
17,60±10,26
CARACTERISTICAS
SEXO FEMENINO (%) EDAD (meses)
TALLA (cm)
ZINC (ug/dL)
Resultados Tabla 5. Características postsuplementación en los grupos suplementado y placebo Placebo n=137 Media ± DE
Zinc n=126 Media ± DE
p*
11,9
15,30
<0.001
116,22 ± 20,55
119,32± 20,30
PESO (Kg)
28,74 ± 6,65
29,80± 10,55
WAZ (DE)
-0,70 ± 0,94
-0,72 ± 0,92
TALLA (cm)
125,60± 8,69
127,12± 8,39
HAZ (DE)
-1,79 ± 0,73
-1,72 ± 0,64
BMI
17,98± 2,13
18,33 ± 6,47
105,57± 15,75
123,03± 24,29
7,83± 6,17
8,49± 5,84
CPOD (Indice de Caries)
10,76 ± 4,09
9,87 ± 3,89
CPOS (Indice de superfices cariadas)
20,03± 10,74
17,30 ± 9,55
CARACTERISTICAS
SEXO FEMENINO (%) EDAD (meses)
ZINC (ug/dL) IgA
<0.001
0.032
Resultados Tabla 6. Regresi贸n Lineal M煤ltiple: CPOS (Indice de superficies cariadas) postsuplementaci贸n, variable dependiente
Variables explicativas
Coefi. Beta
EE
P
WAZ inicial (DE)
-0,130
1,386
0,925
HAZ inicial (DE)
-0,269
1,578
0,865
Zinc inicial (ug/dL)
-0,001
0,040
0,990
IgA inicial(ng/ml)
-0,056
0,137
0,682
Cepillado dientes am
-1,247
1,705
0,466
Cepillado dientes pm
2,303
1,701
0,177
Uso de pasta dental
-7,141
3,323
0,033
Uso de agua potable
-2,953
1,837
0,110
Suplemento Zinc/Placebo
-3,972
1,852
0,033
Sexo femenino/masculino
1,047
1,711
0,541
ZINC AND GROWTH
EFFECT OF ZINC ON CHILDREN’S LINEAR GROWTH Average effect size 0.350 (95%CI: 0.189,0.511)
MODIFYING VARIABLES OF EFFECT SIZE FOR HEIGHT
EFFECT OF ZINC ON HEIGHT ACCORDING TO INITIAL HEIGHT- FOR- AGE Z SCORE IN CHILDREN ≥ 6 MONTHS AGE
EFFECT OF ZINC SUPPLEMENTATION ON CHILDREN’S SERUM ZINC. Average effect size 0.820 (95%CI: 0.499,1.14)
Estimated prevalence of stunting (<2 Z-score) among children under five years of age, by nation; adapted from the WHO Global Data Base on Child Growth and Malnutrition (WHO, 1977)
< 10% 10-25% 25-40% > 40%
Figure 2.1: IZiNCG Technical Document #1, Draft I, 2002
Relationship between two sets of suggestive information concerning national risk of zinc deficiency: the prevalence of stunting (low height for age) in preschool children and the % of population at risk of inadequate zinc intake (based on national food balance sheet data) (r = 0.61, p<0.001)
Prevalence of stunting (%)
70 60 50 40 30 20 10 0
0
10
20
30 40 50 Prevalence of risk of inadequate zinc intakes (%)
Figure 2.2: IZiNCG Technical Document #1, Draft III, 2002
60
70
Risk of zinc deficiency, based on combined information regarding the prevalence of childhood growth stunting and the percent of individuals at risk of inadequate zinc intake
Low
Intermediate
High
Figure 2.3: IZiNCG Technical Document #1, Draft III, 2002
DEDICATED TO The poor Ecuadorian children