Anna Amoako-Mensah1
Frank Ekow Atta Hayford1
Joanna Ainuson-Quampah1
Eunice Nortey1
Rebecca Kissiwa Steele-Dadzie1
Freda D. Intiful1,*
Zinc is an essential micronutrient required for several metabolic activities. It plays a key role in immune system function, growth, protein and DNA synthesis, and is also needed in the metabolism of over 200 enzymes. Its role in child growth and development cannot be overemphasized. Despite zinc's established immunological benefits, a significant knowledge gap exists regarding the prevalence, consequences, and impact of its deficiency on immunological function among children in low- and middle-income countries (LMICs). This review aims to establish the relationship between zinc deficiency and immune system function among children in LMICs. Literature databases were searched with keywords related to zinc deficiency, children, and immune function. The search included studies focused on children from 0 to 18 years in LMICs, assessing zinc status and immune-related outcomes. The studies should have been published between 2010 and 2024 and published in English. Animal studies and editorials were excluded. Scopus, PubMed, Web of Science, Google Scholar, and Cochrane were searched for eligible articles. Data was extracted by 2 independent reviewers. Information obtained included characteristics of participants, assessments, immune parameters, and interventions. Prevalence of zinc deficiency ranged from 9.5 to 99%. Zinc deficiency in children significantly reduced T-cell counts, impaired cytokine regulation, and elevated inflammatory markers such as CRP and IL-6. Intervention studies reported that zinc supplementation significantly increases serum zinc concentrations. Supplementation was also found to reduce the incidence of diarrhea and pneumonia. Fortification showed moderate improvements with smaller effect sizes. Zinc deficiency in children remains a significant public health concern in LMICs and is strongly related to impaired function and heightened susceptibility to infections in children. Current evidence supports zinc supplementation and fortification as effective strategies for improving zinc status and immune outcomes.
Keywords: Zinc, Micronutrients, LMICs, Immune Function, Children
Zinc has long been known and used for medicinal purposes. For example, an Egyptian papyrus dating from the year 2000 BCE mentions its use in cream for the skin (Khan et al., 2022). Some appropriately refer to it as a metal of life due to its significance in the physiology and metabolism of both plants and animals (Khan et al., 2022). However, its significance was not fully recognized until centuries after the acknowledgement of the biological role and importance of iron (Hambidge, 2000). Eventually, studies conducted in Egypt by Prasad et al. in 1963 conclusively established zinc as essential for human health (Prasad, 2009). Zinc can be found in all classes of enzymes, including those which catalyze DNA replication, repair, translation, inter and intracellular signaling and maintenance of membrane integrity (Andreini et al., 2006). Evidence points to the fact that zinc also plays a key role in human immunity, neurotransmission, and proper brain function (Frederickson, Koh, & Bush, 2005). It strengthens the defense against oxidative stress and the synthesis, storage, and release of insulin.
In terms of immune function, zinc is necessary for both humoral and cell-mediated immunity (Chasapis et al., 2020). A zinc deficiency can lead to a decline in innate immunity cellular mediators, including neutrophils, macrophages, and natural killer cell activity, as well as cytokine production and complement activity. Zinc deficiency also affects intracellular killing and phagocytosis and negatively impacts T and B cell development and function (Prasad, 2009). Zinc deficiency further causes a decrease in peripheral and thymic T cells, an impaired proliferative response, and a reduction in the function of T helper and cytotoxic T cells (Overbeck, Rink, & Haase, 2008). Moreover, a zinc deficit suppresses the Th1 response, which is critical for infection defense. These immune response deficiencies result in increased vulnerability to infections (Prasad, 2009). The risk of micronutrient deficiency remains high in low and middle-income countries, including those in Sub-Saharan Africa (SSA) and children remain the most vulnerable. Due to the presence of antinutritive factors that inhibit its absorption, zinc deficiency is especially prevalent in areas where the staple local diet consists of cereals (Prasad, 2017). This of course is the case in many LMICs, besides inadequate dietary intake.
The risk of zinc deficiency during diarrhea increases because zinc is lost through feces and therefore the presence of diarrhea in children exacerbates zinc deficiency. Impaired intestinal integrity affects absorption and increases endogenous zinc loss as well (Sangeetha et al., 2022). In infants and young children, deficiency may also be acquired as a result of low zinc concentration in the mothers' breastmilk.
Micronutrient deficiencies in general are highly costly and include loss of productivity, direct medical cost and cost due to disability-adjusted life-years (DALYs). To put this into context, it is also estimated that addressing micronutrient deficiencies may save 35 trillion dollars for the world economy (Dimkpa & Bindraban, 2016). The effect among children, particularly in low- and middle-income countries, is dire. According to one estimate, globally, approximately 50% of all childhood deaths under the age of 5 years occur because of micronutrient deficiency (Bailey, West Jr, & Black, 2015). Estimates by (Wessells & Brown, 2012) indicated that zinc deficiency may have contributed to as many as 453,207 deaths including 4.4% of paediatric deaths and 1.2% of the disease burden, which includes 3.8% of children aged 0.5 to 5 years and corresponds to 16 million disability-adjusted life years. Despite the documented importance of zinc for immune health, there is a lack of comprehensive current literature of the extent and impact of zinc deficiency on immunological function specifically among children in LMICs. This review aimed to map the existing literature on zinc deficiency and its effects on immune function in children within these regions, identify research gaps and provide a foundation for future studies and interventions.
This review followed the methodological framework outlined by (Arksey & O'Malley, 2005) and (Levac, Colquhoun, & O'brien, 2010). The review was guided by the research question: "What is the current state of knowledge on zinc deficiency and immune function among children in LMICs?"
Thorough literature search was done in the following databases: Cochrane, PubMed, Scopus, Medline, CINAHL, Google Scholar, Embase and Web of Science.
The following keywords and MeSH terms were used: ("zinc deficiency" OR "zinc inadequacy") AND ("immune function" OR "immunological function" OR "immune response") AND ("children" OR "childhood" OR "pediatric" OR "adolescent") AND ("low-income countries" OR "middle-income countries" OR "developing countries" OR "LMICs").
Data extraction was done with Microsoft Word using a standardized data extraction form to capture relevant information. Extracted data were organized and summarized using thematic analysis. References were managed using EndNote X9. Two independent investigators (FI and AAM) extracted and reviewed the data. Discrepancies were checked and resolved by a third investigator (FH). Data obtained were further synthesized and analyzed following the procedures outlined by Arksey & O'Malley (2005) and Levac et al. (2010).
The review did not collect primary data and so institutional review board approval was not obtained. However, it was ensured that all data included in the primary studies had ethical approval.
The review focused on zinc deficiency in children living in LMICs and tackled the following areas: prevalence of deficiency, deficiency causes, dietary patterns and zinc, immune function and zinc, growth and development as well as accurate assessment of zinc. A total of 1606 articles were obtained from different bases. After removal of duplicates and articles with only abstracts and those that did not meet inclusion criteria, 37 full text articles were included in the review.
Figure 1: PRISMA flow diagram showing identification of studies via databases.
Table 1 provides information on prevalence and causes of zinc deficiency in LMIC. The studies showed zinc deficiency as a major public health problem in LMIC among children. Prevalence ranged from 9.5% in semi-urban Nigeria among school children to 40.5% among Ghanaian children aged 2–10 years. Extreme levels of deficiency (99%) were also recorded in Nigeria. Broader reviews showed over 20% of children being zinc deficient in at least 23 countries while an overall prevalence of about 24% was observed among children below five years of age. Poor dietary diversity, high consumption of phytate rich cereals and legumes, low socioeconomic status and metabolic conditions that impair zinc absorption were identified as key contributing factors.
| Title of Study | Study Type | Population | Study Period | Key Findings | Reference |
|---|---|---|---|---|---|
| Zinc in Human Health and Infectious Diseases | Review | General population / children | 2022 | Overview of zinc biology and deficiency prevalence | Maywald & Rink (2022) |
| Risk of Zinc deficiency among children aged 0–59 months in sub-Saharan Africa | Review | Children 0–59 months | 2023 | Estimated 24% prevalence among African children under 5 | Dembedza (2023) |
| Zinc deficiency in low- and middle-income countries: prevalence and approaches for mitigation | Review | Children in LMICs | 2020 | Prevalence and mitigation strategies across LMICs | Gupta et al. (2020) |
| Preventing & Controlling Zinc Deficiency across the life course: A Call to Action | Policy review | All ages/children | 2024 | ≥20% deficiency in 23 LMICs where data exist | Lowe et al. (2024) |
| Prevalence of Zinc Deficiency Among School Children in Rural setting in North-Central Nigeria | Cross-sectional | School children | 2015 | Reported 99% zinc deficiency; lower zinc in poorer children | Abah et al. (2015) |
| Relationship between zinc levels and anthropometric parameters and socio-demographic status among primary school pupils in a semi-urban community in Nigeria | Cross-sectional | Primary school pupils | 2023 | 9.5% zinc deficiency; lower zinc in poorer socioeconomic groups | Oladibu et al. (2023) |
| Prevalence of vitamin A, zinc, iodine deficiency and anaemia among 2–10-year-old Ghanaian children | Cross-sectional | Children 2–10 years | 2012 | 40.5% zinc deficiency reported | Egbi (2012) |
| Dietary phytate reduction improves zinc absorption in Malawian children recovering from tuberculosis but not in well children | Intervention | Children recovering from TB | 2000 | Low-phytate diets improved zinc absorption in recovering children | Manary et al. (2000) |
Table 2 reports on the immune function of zinc. Zinc deficiency is found to be strongly associated with compromised immune function among children. Zinc was found to be primarily vital for T-cell activity, cytokine production, integrity of the epithelial barrier and overall immune competence. Children with zinc deficiency were found to have reduced T-cell proliferation and weakened mucosal barriers, therefore increasing their risk of infections. Inadequate zinc status increased susceptibility to pneumonia, diarrhea, malaria and other gastrointestinal and respiratory infections.
| Title of Study | Study Type | Population | Study Period | Key Findings | Reference |
|---|---|---|---|---|---|
| Zinc and the immune system | Review | General population | 2000 | Zinc's role in inflammation and immunity | Rink (2000) |
| Estimating the global prevalence of zinc deficiency: results based on zinc availability in national food supplies and the prevalence of stunting | Epidemiological analysis | Children / populations | 2012 | Deficiency linked to higher risk of infectious diseases (diarrhea, pneumonia, malaria) | Wessells & Brown (2012) |
| Maternal and child undernutrition and overweight in LMICs | Review | Children | 2013 | Undernutrition (including zinc deficiency) increases infection risk | Black et al. (2013) |
| Zinc supplementation and growth in Tanzanian children | Intervention trial / analysis | Children | 2012 | Discusses zinc, absorption and growth outcomes | Dewey et al. (2012) |
| Preventive zinc supplementation for children, and the effect of additional iron: a systemic review and meta-analysis | Systematic review | Children <5 years | 2011 | Zinc supplementation reduced pneumonia and diarrhea incidence | Mayo-Wilson et al. (2014) |
| Effect of zinc supplementation on T cell immunity | Experimental study | Malnourished children | 2018 | Low zinc associated with reduced T-cell proliferation and altered cytokines | Ali et al. (2018) |
| Zinc deficiency compromises mucosal immunity | Cross-sectional | Children | 2018 | Disruption of tight junctions and compromised mucosal barriers | Hossain et al. (2018) |
| Increased risk of infectious disease associated with zinc deficiency in children | Cross-sectional | Children in developing countries | 2020 | Low serum zinc associated with higher diarrhea and pneumonia rates | Nussenzweig & Sclafani (2020) |
Table 3 reports on some intervention trials and supplementation of zinc. Across the various studies, zinc supplementation was found to result in 20–30% reduction in diarrhea, improved immunity among HIV positive children, decreased severity and duration of diarrhea, 15–20% reduction in incidence of pneumonia and reduction in the risk of sepsis.
| Title of Study | Study Type | Population | Study Period | Key Findings | Reference |
|---|---|---|---|---|---|
| Role of zinc administration in prevention of childhood diarrhea and respiratory illnesses | Meta-analysis | Children | 2007 | 20–30% reduction in diarrhea incidence with zinc | Aggarwal et al. (2007) |
| Oral zinc for treating diarrhea in children | Cochrane review | Children | 2016 | Zinc reduced diarrhea duration and incidence | Lazzerini & Wanzira (2016) |
| Zinc supplementation and immune function in children with HIV | Randomized trial | HIV-positive children | 2005 | Zinc improved some immune parameters | Bobat et al. (2005) |
| Zinc supplementation and inflammation in treated HIV | Trial | Children with HIV | 2019 | Zinc associated with reduced inflammatory markers | Dirajlal-Fargo et al. (2019) |
| Zinc supplementation and prevention and treatment of sepsis in young infants: a systematic review and meta-analysis | Systematic review & meta-analysis | Infants | 2022 | Zinc associated with reduced sepsis outcomes | Irfan et al. (2022) |
| Zinc deficiency and risk of sepsis in children | Systematic review & meta-analysis | Children | 2018 | Low zinc increased sepsis risk | Li et al. (2018) |
| Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years | Randomized controlled trial | Children 6 months–3 years | 2002 | Routine zinc supplementation reduced pneumonia incidence (15–20% in some trials) | Bhandari et al. (2002) |
| Zinc and immune function in children: observational findings | Observational study | Children | 2008 | Zinc deficiency linked to lower immune cell counts and cytokine changes | Bhandari et al. (2008) |
| Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries | Randomized controlled trial | Children with diarrhea | 2019 | Daily zinc reduced duration and severity of diarrhea | Bhutta et al. (2019) |
| Effect of zinc supplementation in Children less than 5 years on Diarrhea attacks | Randomized controlled trial | Children <5 years | 2022 | Zinc supplementation reduced diarrhea attacks | Abd El-Ghaffar et al. (2022) |
| Title of Study | Study Type | Population | Study Period | Key Findings | Reference |
|---|---|---|---|---|---|
| Human zinc deficiency: discovery to translation | Review | Children / general | 2013 | Zinc deficiency linked to cognitive impairment and developmental issues | Sandstead (2013) |
| Preventive zinc supplementation among infants, preschoolers, and older prepubertal children | Review | Infants and children | 2009 | Preventive zinc associated with growth benefits and reduced morbidity | Brown et al. (2009) |
| Discovery of human zinc deficiency: Its Impacts on Human Health and Disease | Review | General | 2013 | Historical impacts of zinc deficiency including growth and immunity | Prasad (2013) |
| Undernutrition as underlying cause of malaria morbidity and mortality in children | Review | Children | 2014 | Stunting and nutritional deficiencies linked to disease burden and DALYs | Caulfield et al. (2014) |
| Conclusions of Joint WHO/UNICEF/IAEA/IZiNCG Meeting on Zinc Status Indicators | Technical report | Populations | 2007 | Recommended biochemical, dietary and functional indicators for zinc status | de Benoist et al. (2007) |
| Zinc supplementation for preventing mortality, morbidity, and growth failure in children ages 6–12 years | Cochrane review | Children 6 months–12 years | 2023 | Evidence synthesis supporting supplementation programs | Imdad et al. (2023) |
| Large-Scale Food Fortification and Biofortification in Low- and Middle-Income Countries | Review / policy analysis | Populations in LMICs | 2018 | Fortification and biofortification shown to improve micronutrient status | Osendarp et al. (2018) |
It is well established that zinc is the second most abundant micronutrient in the human body, second only to iron (Maywald & Rink, 2022). Zinc is also widely available in most foods such as beef, poultry, seafood, grains, legumes, cereals and nuts. The wide range of dietary sources notwithstanding, zinc deficiency is one of the most common forms of micronutrient deficiency globally (Abdulahi et al., 2021; Dembedza, 2023; Gupta, Brazier, & Lowe, 2020; Lowe et al., 2024). Prevalence of zinc deficiency (24%) has been reported among African children under 5 years old (Dembedza, 2023). Although data from most low-and-middle-income-countries (LMIC) is scarce, zinc prevalence of ≥ 20% is reported in about 23 LMIC where data is available (Lowe et al., 2024). Among school children in rural Nigeria, 99% had zinc deficiency. Serum zinc levels were significantly lower among those from lower socioeconomic background compared to middle and upper socioeconomic class (Abah, Okolo, John, & Ochoga, 2015). Among school children in a semi urban population in Nigeria, 9.5% were found to be zinc deficient. A prevalence of 40.5% was reported among 2–10-year-old Ghanaian children (Egbi, 2012).
The primary cause of zinc deficiency has been identified as malnutrition (Maywald & Rink, 2022). The absence of available reserve or store for zinc in the human body, coupled with the involvement of the nutrient in numerous human biological functions, puts a high demand on the nutrient, and mandates its constant adequate provision primarily through dietary intake. This may partly explain the high prevalence of zinc deficiency, especially in low- and middle-income countries where food insecurity and poverty threaten the adequacy of dietary zinc intake. Zinc is a versatile nutrient and plays many roles in human health and development including ensuring normal growth, reproduction, being a part of various enzymatic activities and immune defense (Dembedza, 2023; Maywald & Rink, 2022).
Zinc is involved in the activation of various immune cells, including T-cells, natural killer cells, lymphocytes, neutrophils, and macrophages. These cells collectively coordinate the body's immune response against pathogens and help regulate the production of cytokines, essential proteins such as antibodies that combat infections. A deficiency in zinc can result in a diminished antibody response, thereby increasing susceptibility to infections (Shankar & Prasad, 1998). Additionally, zinc possesses anti-inflammatory properties that are pivotal in mitigating the severity of infections (Rink, 2000).
Inadequate zinc levels may lead to chronic inflammation, elevating the risk of prevalent infectious diseases such as diarrhea, pneumonia, malaria, and respiratory tract infections (Wessells & Brown, 2012), which are major causes of morbidity and mortality in LMICs (Black et al., 2013). In these countries, zinc deficiency is often exacerbated by suboptimal dietary intake, malabsorption issues, and frequent infections.
A systematic review conducted by Mayo-Wilson et al. (2011) delved into the effects of zinc supplementation on childhood infections. The findings revealed a significant reduction in the incidence of pneumonia and diarrhea in children under five years of age following zinc supplementation. A study by Ali et al. (2018) investigated the impact of zinc deficiency on T-cell functionality. The research demonstrated that children with low zinc levels exhibited diminished T-cell proliferation and altered cytokine production. In a study by Hossain et al. (2018), it was shown that zinc deficiency compromises mucosal immunity by disrupting tight junctions in epithelial cells. A cross-sectional study by Nussenzweig et al. (2020) evaluated the zinc status of children in developing nations and identified a robust association between low serum zinc levels and heightened rates of infectious diseases such as diarrhea and pneumonia.
The evidence supporting the use of zinc supplementation in preventing infections in children is robust, with numerous studies consistently demonstrating the efficacy of zinc in reducing both the occurrence and duration of such infections. A systematic review showed a 20–30% reduction in diarrhea incidence with zinc supplementation (Aggarwal, Sentz, & Miller, 2007). A similar review corroborated these findings revealing that zinc supplementation led to a decrease in the rates of diarrhea and pneumonia among children under 5 years of age (Lazzerini & Wanzira, 2016). Notably, zinc supplementation has also been proven to lower the risk of sepsis in children (Irfan, Black, Lassi, & Bhutta, 2022; Li, Wang, & Zhang, 2018). A randomized controlled trial among Indian children further supported these results by demonstrating a 15–20% decrease in pneumonia incidence due to zinc supplementation (Abd El-Ghaffar et al., 2022; Bhandari et al., 2002).
Zinc deficiency continues to be a major public health problem among children in LMICs and strongly linked to adverse growth and development, increased susceptibility to infections and impaired immunity. Current evidence shows that poor dietary diversity, inadequate intakes, recurrent infections and consumption of high phytate source foods contribute significantly to low zinc status. Food fortification and supplementation consistently improve serum levels of zinc, reduce pneumonia infection, diarrhea and other infections. Strengthening assessment methods, improvement of dietary quality and scaling of effective intervention strategies are crucial to decreasing the burden of zinc deficiency and improvement of child health across LMICs.
Further research studies should assess the long-term effects of zinc supplementation and fortification on cognitive outcomes, growth and immunity through randomized controlled trials and thoroughly designed longitudinal studies. Priority should be given to improving bioavailability of zinc by reducing phytates in foods and exploring food processing techniques. Development of more sensitive biomarkers in combination with dietary and biochemical indicators will strengthen the assessment of zinc status on the population level.
Policies to combat zinc deficiency should promote diversification of diet, scaling up of zinc fortification of staple foods, and integration of zinc supplementation into routine child health welfare programs. Scaling up public education on zinc-rich foods and improvement of access to supplements, especially in underserved communities, will help decrease population-level deficiencies.
Community based interventions including training of health workers, improvement of food availability through the markets, and provision of household nutrition education should be adopted for a sustainable impact. Partnerships with local and government agencies as well as international agencies can enhance the delivery of supplements and fortified foods, while strong monitoring systems will safeguard program effectiveness.
The author received no financial support for the conduct of this study.
The authors declare no conflict of interest.