Zinc Supplementation Promotes a Th1 Response and Improves Clinical Symptoms in Fewer Hours in Children With Pneumonia Younger Than 5 Years Old. A Randomized Controlled Clinical Trial

Jorge Alberto Acevedo-Murillo, Miguel Leonardo García León, Verónica Firo-Reyes, Jorge Luis Santiago-Cordova, Alejandra Pamela Gonzalez-Rodriguez, Rosa María Wong-Chew, Jorge Alberto Acevedo-Murillo, Miguel Leonardo García León, Verónica Firo-Reyes, Jorge Luis Santiago-Cordova, Alejandra Pamela Gonzalez-Rodriguez, Rosa María Wong-Chew

Abstract

Background: Pneumonia caused 704,000 deaths in children younger than 5 years in 2015. Zinc is an important micronutrient due to its role in immune function. Since 2004, WHO recommends zinc supplementation for children with diarrhea to shorten the duration and decrease severity. Zinc supplementation for children with pneumonia is controversial. Methods: A randomized controlled clinical trial was conducted, and 103 children 1 month to 5 years old with pneumonia were included. Zinc or placebo was given during hospitalization. Clinical symptoms were recorded, and a blood draw was obtained to determine serum zinc levels, lymphoproliferation, and cytokines at hospitalization and at discharge of the patient; a nasal wash was obtained to detect viral or bacterial pathogens by multiplex RT-PCR. Results: Zinc supplementation improved in fewer hours the clinical status (76 ± 7 vs. 105 ± 8, p = 0.01), the respiratory rate (37 ± 6 vs. 57 ± 7, p = 0.04), and the oxygen saturation (53 ± 7 vs. 87 ± 9, p = 0.007) compared to the placebo group. An increase in IFNγ and IL-2 after treatment in the zinc group was observed. Conclusions: Zinc supplementation improved some clinical symptoms in children with pneumonia in fewer hours and induced a cellular immune response. Clinical Trial Registration: The trial was retrospectively registered in ClinicalTrials.gov, identifier NCT03690583, URL https://ichgcp.net/clinical-trials-registry/NCT03690583?term=zinc+children&cond=Pneumonia&draw=2&rank=1.

Keywords: Th1 cytokines; children; immune response; pneumonia; zinc supplementation.

Copyright © 2019 Acevedo-Murillo, García León, Firo-Reyes, Santiago-Cordova, Gonzalez-Rodriguez and Wong-Chew.

Figures

Figure 1
Figure 1
CONSORT flow diagram of the inclusion and analysis of the patients.
Figure 2
Figure 2
Viral and bacterial detection in children with pneumonia who received zinc or placebo. (A) Detection of single agents by group. (B) Number of combined detection of virus–virus, bacteria–bacteria, or virus–bacteria by group.
Figure 3
Figure 3
Cytokine responses of children with pneumonia supplemented with zinc or placebo. (A) TH1 cytokines: IL-2 and INF-γ increased in the zinc group, and TNFα increased in the placebo group, although in the zinc group, it remained high. (B) Th2 cytokines: IL-10 increased in both groups, IL-4 decreased, and IL-6 remained high in both groups.

References

    1. Bryce J, Black RE, Victora CG. Millennium development goals 4 and 5: progress and challenges. BMC Med. (2013) 11:225. 10.1186/1741-7015-11-225
    1. McAllister DA, Liu L, Shi T, Chu Y, Reed C, Burrows J, et al. . Global, regional, and national estimates of pneumonia morbidity and mortality in children younger than 5 years between 2000 and 2015: a systematic analysis. Lancet Glob Health. (2019) 7:e47–57. 10.1016/S2214-109X(18)30408-X
    1. Collaborators GL. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory tract infections in 195 countries: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Infect Dis. (2017) 17:1133–61. 10.1016/S1473-3099(17)30396-1
    1. GBD 2016 Lower Respiratory Infections Collaborators. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect Dis. (2018) 18:1191–210. 10.1016/S1473-3099(18)30310-4
    1. Howie SRC, Murdoch DR. Global childhood pneumonia: the good news, the bad news, and the way ahead. Lancet Glob Health. (2019) 7:e4–5. 10.1016/S2214-109X(18)30446-7
    1. Wessells KR, Brown KH. Estimating the global prevalence of zinc deficiency: results based on zinc availability in national food supplies and the prevalence of stunting. PLoS ONE. (2012) 7:e50568. 10.1371/journal.pone.0050568
    1. Hojyo S, Fukada T. Zinc transporters and signaling in physiology and pathogenesis. Arch Biochem Biophys. (2016) 611:43–50. 10.1016/j.abb.2016.06.020
    1. Gammoh NZ, Rink L. Zinc in infection and inflammation. Nutrients. (2017) 9:624. 10.3390/nu9060624
    1. Shankar AH, Prasad AS. Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr. (1998) 68:447–63S. 10.1093/ajcn/68.2.447S
    1. Black CLFWaRE. Zinc Supplementarion for Diarrrhoea Treatment. e-Library of Evidence for Nutrition Actions (eLENA): World Heath Organization; (2014).
    1. Basnet S, Shrestha PS, Sharma A, Mathisen M, Prasai R, Bhandari N, et al. . A randomized controlled trial of zinc as adjuvant therapy for severe pneumonia in young children. Pediatrics. (2012) 129:701–8. 10.1542/peds.2010-3091
    1. Ganguly A, Chakraborty S, Datta K, Hazra A, Datta S, Chakraborty J. A randomized controlled trial of oral zinc in acute pneumonia in children aged between 2 months to 5 years. Indian J Pediatr. (2011) 78:1085–90. 10.1007/s12098-011-0495-9
    1. Valentiner-Branth P, Shrestha PS, Chandyo RK, Mathisen M, Basnet S, Bhandari N, et al. . A randomized controlled trial of the effect of zinc as adjuvant therapy in children 2-35 mo of age with severe or nonsevere pneumonia in Bhaktapur, Nepal. Am J Clin Nutr. (2010) 91:1667–74. 10.3945/ajcn.2009.28907
    1. Bose A, Coles CL, Gunavathi, John H, Moses P, Raghupathy P, et al. . Efficacy of zinc in the treatment of severe pneumonia in hospitalized children <2 y old. Am J Clin Nutr. (2006) 83:1089–96; quiz 207. 10.1093/ajcn/83.5.1089
    1. Tie HT, Tan Q, Luo MZ, Li Q, Yu JL, Wu QC. Zinc as an adjunct to antibiotics for the treatment of severe pneumonia in children <5 years: a meta-analysis of randomised-controlled trials. Br J Nutr. (2016) 115:807–16. 10.1017/S0007114515005449
    1. Bagri NK, Bagri N, Jana M, Gupta AK, Wadhwa N, Lodha R, et al. . Efficacy of oral zinc supplementation in radiologically confirmed pneumonia: secondary analysis of a randomized controlled trial. J Trop Pediatr. (2018) 64:110–7. 10.1093/tropej/fmx036
    1. Valavi E, Hakimzadeh M, Shamsizadeh A, Aminzadeh M, Alghasi A. The efficacy of zinc supplementation on outcome of children with severe pneumonia. A randomized double-blind placebo-controlled clinical trial. Indian J Pediatr. (2011) 78:1079–84. 10.1007/s12098-011-0458-1
    1. Wahed MA, Islam MA, Khondakar P, Haque MA. Effect of micronutrients on morbidity and duration of hospital stay in childhood pneumonia. Mymensingh Med J. (2008) 17:S77–83.
    1. Yakoob MY, Theodoratou E, Jabeen A, Imdad A, Eisele TP, Ferguson J, et al. . Preventive zinc supplementation in developing countries: impact on mortality and morbidity due to diarrhea, pneumonia and malaria. BMC Public Health. (2011) 11(Suppl. 3):S23. 10.1186/1471-2458-11-S3-S23
    1. Lassi ZS, Haider BA, Bhutta ZA. Zinc supplementation for the prevention of pneumonia in children aged 2 months to 59 months. Cochrane Database Syst Rev. (2010) 12:CD005978. 10.1002/14651858.CD005978.pub2
    1. Fischer Walker C, Black RE. Zinc and the risk for infectious disease. Annu Rev Nutr. (2004) 24:255–75. 10.1146/annurev.nutr.23.011702.073054
    1. Wang L, Song Y. Efficacy of zinc given as an adjunct to the treatment of severe pneumonia: a meta-analysis of randomized, double-blind and placebo-controlled trials. Clin Respir J. (2018) 12:857–64. 10.1111/crj.12646
    1. Lassi ZS, Moin A, Bhutta ZA. Zinc supplementation for the prevention of pneumonia in children aged 2 months to 59 months. Cochrane Database Syst Rev. (2016) 12:CD005978. 10.1002/14651858.CD005978.pub3
    1. Mda S, van Raaij JM, de Villiers FP, MacIntyre UE, Kok FJ. Short-term micronutrient supplementation reduces the duration of pneumonia and diarrheal episodes in HIV-infected children. J Nutr. (2010) 140:969–74. 10.3945/jn.109.110312
    1. Sempertegui F, Estrella B, Rodriguez O, Gómez D, Cabezas M, Salgado G, et al. . Zinc as an adjunct to the treatment of severe pneumonia in Ecuadorian children: a randomized controlled trial. Am J Clin Nutr. (2014) 99:497–505. 10.3945/ajcn.113.067892
    1. Srinivasan MG, Ndeezi G, Mboijana CK, Kiguli S, Bimenya GS, Nankabirwa V, et al. . Zinc adjunct therapy reduces case fatality in severe childhood pneumonia: a randomized double blind placebo-controlled trial. BMC Med. (2012) 10:14. 10.1186/1741-7015-10-14
    1. Assad FA, Brès P, ten Darn HG, Dowling MAC, Hitze KL, Houang L, et al. Clinical management of acute respiratory infections in children: a WHO memorandum. Bull World Health Organ. (1981) 59:707–16.
    1. Bradley JS, Byington CL, Shah SS, Alverson B, Carter ER, Harrison C, et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. (2011) 53:e25–76. 10.1093/cid/cir531
    1. Harris M, Clark J, Coote N, Fletcher P, Harnden A, McKean M, et al. . British Thoracic Society guidelines for the management of community acquired pneumonia in children: update 2011. Thorax. (2011) 66(Suppl. 2):ii1–23. 10.1136/thoraxjnl-2011-200598
    1. Mahalanabis D, Lahiri M, Paul D, Gupta S, Gupta A, Wahed MA, et al. . Randomized, double-blind, placebo-controlled clinical trial of the efficacy of treatment with zinc or vitamin A in infants and young children with severe acute lower respiratory infection. Am J Clin Nutr. (2004) 79:430–6. 10.1093/ajcn/79.3.430
    1. Shehzad N, Anwar MI, Muqaddas T. Zinc supplementation for the treatment of severe pneumonia in hospitalized children: a randomized controlled trial. Sudan J Paediatr. (2015) 15:37–41.
    1. Haider BA, Lassi ZS, Ahmed A, Bhutta ZA. Zinc supplementation as an adjunct to antibiotics in the treatment of pneumonia in children 2 to 59 months of age. Cochrane Database Syst Rev. (2011) CD007368. 10.1002/14651858.CD007368.pub2
    1. Wong-Chew RM, Garcia-Leon ML, Noyola DE, Perez Gonzalezc LF, Mezad JG, Vilaseñor-Sierra A, et al. . Respiratory viruses detected in Mexican children younger than 5 years old with community-acquired pneumonia: a national multicenter study. Int J Infect Dis. (2017) 62:32–8. 10.1016/j.ijid.2017.06.020
    1. Haase H, Rink L. Zinc signals and immune function. Biofactors. (2014) 40:27–40. 10.1002/biof.1114
    1. Ma L, Terwilliger A, Maresso AW. Iron and zinc exploitation during bacterial pathogenesis. Metallomics. (2015) 7:1541–54. 10.1039/C5MT00170F
    1. Rawlings BA, Higgins TS, Han JK. Bacterial pathogens in the nasopharynx, nasal cavity, and osteomeatal complex during wellness and viral infection. Am J Rhinol Allergy. (2013) 27:39–42. 10.2500/ajra.2013.27.3835

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever