Effect of Supplementation with Zinc and Other Micronutrients on Malaria in Tanzanian Children: A Randomised Trial
Background:
It is uncertain to what extent oral supplementation with zinc can reduce episodes of malaria in endemic areas. Protection may depend on other nutrients. We measured the effect of supplementation with zinc and other nutrients on malaria rates.
Methods and Findings:
In a 2×2 factorial trial, 612 rural Tanzanian children aged 6–60 months in an area with intense malaria transmission and with height-for-age z-score≤−1.5 SD were randomized to receive daily oral supplementation with either zinc alone (10 mg), multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Intervention group was indicated by colour code, but neither participants, researchers, nor field staff knew who received what intervention. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. The primary outcome, an episode of malaria, was assessed among children reported sick at a primary care clinic, and pre-defined as current Plasmodium infection with an inflammatory response, shown by axillary temperature ≥37.5°C or whole blood C-reactive protein concentration ≥8 mg/L. Nutritional indicators were assessed at baseline and at 251 days (median; 95% reference range: 191–296 days). In the primary intention-to-treat analysis, we adjusted for pre-specified baseline factors, using Cox regression models that accounted for multiple episodes per child. 592 children completed the study. The primary analysis included 1,572 malaria episodes during 526 child-years of observation (median follow-up: 331 days). Malaria incidence in groups receiving zinc, multi-nutrients without zinc, multi-nutrients with zinc and placebo was 2.89/child-year, 2.95/child-year, 3.26/child-year, and 2.87/child-year, respectively. There was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Neither zinc nor multi-nutrients influenced malaria rates (marginal analysis; adjusted HR, 95% CI: 1.04, 0.93–1.18 and 1.10, 0.97–1.24 respectively). The prevalence of zinc deficiency (plasma zinc concentration <9.9 µmol/L) was high at baseline (67% overall; 60% in those without inflammation) and strongly reduced by zinc supplementation.
Conclusions:
We found no evidence from this trial that zinc supplementation protected against malaria.
Trial Registration: ClinicalTrials.gov NCT00623857
: Please see later in the article for the Editors' Summary.
Vyšlo v časopise:
Effect of Supplementation with Zinc and Other Micronutrients on Malaria in Tanzanian Children: A Randomised Trial. PLoS Med 8(11): e32767. doi:10.1371/journal.pmed.1001125
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pmed.1001125
Souhrn
Background:
It is uncertain to what extent oral supplementation with zinc can reduce episodes of malaria in endemic areas. Protection may depend on other nutrients. We measured the effect of supplementation with zinc and other nutrients on malaria rates.
Methods and Findings:
In a 2×2 factorial trial, 612 rural Tanzanian children aged 6–60 months in an area with intense malaria transmission and with height-for-age z-score≤−1.5 SD were randomized to receive daily oral supplementation with either zinc alone (10 mg), multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Intervention group was indicated by colour code, but neither participants, researchers, nor field staff knew who received what intervention. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. The primary outcome, an episode of malaria, was assessed among children reported sick at a primary care clinic, and pre-defined as current Plasmodium infection with an inflammatory response, shown by axillary temperature ≥37.5°C or whole blood C-reactive protein concentration ≥8 mg/L. Nutritional indicators were assessed at baseline and at 251 days (median; 95% reference range: 191–296 days). In the primary intention-to-treat analysis, we adjusted for pre-specified baseline factors, using Cox regression models that accounted for multiple episodes per child. 592 children completed the study. The primary analysis included 1,572 malaria episodes during 526 child-years of observation (median follow-up: 331 days). Malaria incidence in groups receiving zinc, multi-nutrients without zinc, multi-nutrients with zinc and placebo was 2.89/child-year, 2.95/child-year, 3.26/child-year, and 2.87/child-year, respectively. There was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Neither zinc nor multi-nutrients influenced malaria rates (marginal analysis; adjusted HR, 95% CI: 1.04, 0.93–1.18 and 1.10, 0.97–1.24 respectively). The prevalence of zinc deficiency (plasma zinc concentration <9.9 µmol/L) was high at baseline (67% overall; 60% in those without inflammation) and strongly reduced by zinc supplementation.
Conclusions:
We found no evidence from this trial that zinc supplementation protected against malaria.
Trial Registration: ClinicalTrials.gov NCT00623857
: Please see later in the article for the Editors' Summary.
Zdroje
1. IZiNCG 2009 Systematic reviews of zinc intervention strategies. International Zinc Nutrition Consultative Group Technical Document #2. BrownKHHessSY Food Nutr Bull 30 Suppl. S1 S184
2. BatesCJEvansPHDardenneM 1993 A trial of zinc supplementation in young rural Gambian children. Br J Nutr 69 243 255
3. ShankarAHGentonBBaisorM 2000 The influence of zinc supplementation on morbidity due to Plasmodium malaria: a randomized trial in preschool children in Papua New Guinea. Am J Trop Med Hyg 62 663 669
4. MüllerOBecherHvan ZweedenABYeYDialloDA 2001 Effect of zinc supplementation on malaria and other causes of morbidity in West African children: randomised double blind controlled trial. Brit Med J 322 1567 1570
5. RichardSAZavaletaNCaulfieldLEBlackREWitzigRS 2006 Zinc and iron supplementation and malaria, diarrhea, and respiratory infections in children in the Peruvian Amazon. Am J Trop Med Hyg 75 126 132
6. RonaghyHAReinholdJGMahloudjiMGhavamiPFoxMR 1974 Zinc supplementation of malnourished schoolboys in Iran: increased growth and other effects. Am J Clin Nutr 27 112 121
7. RonaghyHSpivey FoxMRGarnSM 1969 Controlled zinc supplementation for malnourished school boys: a pilot experiment. Am J Clin Nutr 22 1279 1289
8. SazawalSBlackRERamsanM 2006 Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet 367 133 143
9. StolzfusRJHeidkampRKenkelDHabichtJP 2007 Iron supplementation of young children: Learning from the new evidence. Food Nutr Bull 28 S572 S584
10. WHO 2007 Conclusions and recommendations of the WHO consultation on prevention and control of iron deficiency in infants and young children in malaria-endemic areas. Food Nutr Bull 28 S621 S627
11. EkvallHPremjiZBjorkmanA 2000 Micronutrient and iron supplementation and effective antimalarial treatment synergistically improve childhood anaemia. Trop Med Intern Health 5 696 705
12. OuédraogoHZDramaix-WilmetMZebaANHennartPDonnenP 2008 Effect of iron or multiple micronutrient supplements on the prevalence of anaemia among anaemic young children of a malaria-endemic area: a randomized double-blind trial. Trop Med Int Health 13 1257 1266
13. FriisHMwanikiDOmondiB 2003 Effects on haemoglobin of multi-micronutrient supplementation and multi-helminth chemotherapy: a randomized, controlled trial in Kenyan school children. Eur J Clin Nutr 57 573 579
14. OjukwuJUOkebeJUYahavDPaulM 2009 Oral iron supplementation for preventing or treating anaemia among children in malaria-endemic areas. Cochrane Database Sys Rev 3 CD006589
15. VerhoefHWestCENzyukoSM 2002 Intermittent administration of iron and sulfadoxine-pyrimethamine to control anaemia in Kenyan children: a randomised controlled trial. Lancet 360 908 914
16. OppenheimerSJGibsonFDMacfarlaneSB 1986 Iron supplementation increases prevalence and effects of malaria: report on clinical studies in Papua New Guinea. Trans R Soc Trop Med Hyg 80 603 612
17. VeenemansJAndang'oPEAMbugiEV 2008 α+-Thalassemia protects against anemia associated with asymptomatic malaria: evidence from community-based surveys in Kenya and Tanzania. J Infect Dis 198 401 408
18. VeenemansJMankTOttenhofM 2011 Protection against diarrhea associated with Giardia intestinalis is lost with multi-nutrient supplementation: a study in Tanzanian children. PLoS Negl Trop Dis 5 6 e1158 doi:10.1371/journal.pntd.0001158
19. EllmanRMaxwellCFinchRShayoD 1998 Malaria and anaemia at different altitudes in the Muheza district of Tanzania: childhood morbidity in relation to level of exposure to infection. Ann Trop Med Parasitol 92 741 753
20. McAllisterFAStraussSESackettDLAltmanDG 2003 Analysis and reporting of factorial trials: a systematic review. JAMA 289 2545 2553
21. LubsenJPocockSJ 1994 Factorial trials in cardiology: pros and cons. Eur Heart J 15 585 588
22. UNICEF/UNU/WHO 2001 Iron deficiency anaemia: assessment, prevention and control. A guide for programme managers. Document reference no. WHO/NHD/01.3 Geneva, Switzerland World Health Organization Available: http://www.who.int/nutrition/publications/en/ida_assessment_prevention_control.pdf. Accessed 2 November 2011
23. GoodmanSNBerlinJA 1994 The use of predicted confidence intervals when planning experiments and the misuse of power when interpreting results. Ann Intern Med 121 200 206
24. VerhoefH 2007 Malnutrition, zinc deficiency and malaria in Africa. Lancet 369 2156
25. PiperRLebrasJWentworthL 1999 Immunocapture diagnostic assays for malaria using Plasmodium lactate dehydrogenase (pLDH). Am J Trop Med Hyg 60 109 118
26. WhiteNJ 2008 How antimalarial drug resistance affects post-treatment prophylaxis. Malaria J 7 9
27. BrownKHPeersonJMRiveraJAllenLH 2002 Effect of supplemental zinc on the growth and serum zinc concentrations of prepubertal children: a meta-analysis of randomized controlled trials. Am J Clin Nutr 75 1062 1071
28. OgbonnaAUnekeCJ 2008 Artemisinin-based combination therapy for uncomplicated malaria in sub-Saharan Africa: the efficacy, safety, resistance and policy implementation since Abuja 2000. Trans R Soc Trop Med Hyg 102 621 627
29. WhiteNJ 2008 Qinghaosu (artemisinin): the price of success. Science 320 330 334
30. AltmanDGMachinDBryantTNGardnerMJ 2000 Statistics with confidence: confidence intervals and statistical guidelines London, UK BMJ Books
31. IZiNCG 2004 Assessment of the risk of zinc deficiency in populations and options for its control (Hotz C, Brown KH, eds.). International Zinc Nutrition Consultative Group Technical Document #1. Food Nutr Bull 25 Suppl. 2 S91 S204
32. MoorthyVReedZSmithPG 2007 Meeting report. Vaccine 25 5115 5123
33. SchellenbergJRMSmithTAlonsoPLHayesRJ 1994 What is clinical malaria? Finding case definitions for field research in highly endemic areas. Parasitol Today 10 439 442
34. SmithTSchellenbergJAHayesR 1994 Attributable fraction estimates and case definitions for malaria in endemic areas. Stat Med 13 2345 2358
35. O'MearaWPHallBFMcKenzieFE 2007 Malaria vaccine efficacy: the difficulty of detecting and diagnosing malaria. Malar J 6 36
36. SmithTA 2007 Measures of clinical malaria in field trials of interventions against Plasmodium falciparum. Malar J 6 53
37. KoramKAMolyneuxME 2007 When is “malaria” malaria? The different burdens of malaria infection, malaria disease, and malaria-like illnesses. Am J Trop Med Hyg 77 Suppl 6 1 5
38. DelleyVBouvierPBreslowN 2000 What does a single determination of malaria parasite density mean? A longitudinal survey in Mali. Trop Med Int Health 5 404 412
39. CheungYBXuYTanSHCuttsFMilliganP 2010 Estimation of intervention effects using first or multiple episodes in clinical trials: the Andersen-Gill model re-examined. Statist Med 29 328 336
40. O'MearaWPLangT 2009 Malaria vaccine trial endpoints – bridging the gaps between trial design, public health and the next generation of vaccines. Parasite Immunol 31 574 581
41. SazawalSBlackRERamsanM 2007 Effect of zinc supplementation on mortality in children aged 1–48 months: a community-based randomised placebo-controlled trial. Lancet 369 927 934
42. PrenticeAMGhattasHCoxSE 2007 Host-pathogen interactions: can micronutrients tip the balance? J Nutr 137 1334 1337
43. KeenCLGershwinME 1990 Zinc deficiency and immune function. Ann Rev Nutr 10 415 431
44. AlamANSarkerSAWahedMAKhatunMRahamanMM 1994 Enteric protein loss and intestinal permeability changes in children during acute shigellosis and after recovery: effect of zinc supplementation. Gut 35 1707 1711
45. Truong-TranAQCarterJRuffinRZalewskiPD 2001 New insights into the role of zinc in the respiratory epithelium. Immunol Cell Biol 79 170 177
46. ZalewskiPDTruong-TranAQGrosserD 2005 Zinc metabolism in airway epithelium and airway inflammation: basic mechanisms and clinical targets. A review. Pharmacol Ther 105 127 149
47. FinamoreAMassimiMConti DevirgiliisLMengheriE 2008 Zinc deficiency induces membrane barrier damage and increases neutrophil transmigration in Caco-2 cells. J Nutr 138 1664 1670
48. MoranJRLewisJC 1985 The effects of zinc deficiency on intestinal permeability: an ultrastructural study. Pediatr Res 19 968 973
49. SunXBrielMWalterSDGuyattGH 2010 Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. BMJ 340 c117
50. RoySKBehrenRHHaiderRAkramuzzamanSMMahalanabisD 1992 Impact of zinc supplementation on intestinal permeability in Bangladeshi children with acute diarrhoea and persistent diarrhoea syndrome. J Peadiatr Gastroenterol Nutr 15 289 296
51. MurrayMJMurrayNJMurrayABMurrayMB 1970 Refeeding malaria and hyperferraemia. Lancet 1 653 654
52. OppenheimerSJ 2001 Iron and its relation to immunity and infectious disease. J Nutr 131 616S 635S
53. GeraTSachdevHPS 2002 Effect of iron supplementation on incidence of infectious illness in children: systematic review. BMJ 325 1142
54. ShankarAH 2000 Nutritional modulation of malaria morbidity and mortality. J Infect Dis 182 Suppl 1 S37 S53
55. HutchinsonCAl-AshgarWLiuDY 2004 Oral ferrous sulphate leads to a marked increase in pro-oxidant nontransferrin-bound iron. Eur J Clin Invest 34 782 784
56. BaronJBen-DavidGHallakM 2008 Changes in non-transferrin-bound iron (NTBI) in pregnant women on iron supplements. Eur J Obstet Gynecol Reprod Biol 140 281 282
57. DresowBPetersenDFischerRNielsenP 2008 Non-transferrin-bound iron in plasma following administration of oral iron drugs. Biometals 21 273 276
58. PrenticeAM 2008 Iron metabolism, malaria and other infections: What is all the fuss about? J Nutr 138 2537 2541
59. WHO 2011 Guideline: use of multiple micronutrient powders for home fortification of foods consumed by infants and children 6–23 months of age Geneva, Switzerland World Health Organization, 2011 Available: http://whqlibdoc.who.int/publications/2011/9789241502047_eng.pdf. Accessed 9 September 2011
60. TroeschBEgliIZederCHurrellRFde PeeS 2009 Optimization of a phytase-containing micronutrient powder with low amounts of highly bioavailable iron for in-home fortification of complementary foods. Am J Clin Nutr 89 539 544
61. VerhoefHVeenemansJ 2009 Safety of iron-fortified foods in malaria-endemic areas. Am J Clin Nutr 89 1949 1950
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