Description of the condition

Vitamin D is a family of fat‐soluble molecules that are important micronutrients for humans, and two forms (D2 and D3) play a central role in bone growth by increasing the uptake of calcium from the gut (Bentley 2013). Vitamin D is therefore especially important in growing children, and a deficiency in vitamin D can lead to rickets, which is characterized by weak and deformed bones.

Humans can obtain both vitamin D2 and D3 from their diet, with fish liver oils, eggs, and milk being particularly rich in both. However, we obtain most of our vitamin D in the form of vitamin D3 by synthesizing it directly when their skin is exposed to sunlight. This powers a photochemical reaction in which a derivative of cholesterol is converted into pre‐vitamin D3, which is then transformed into vitamin D3 by the heat of the skin (Wagner 2008a).

Vitamin D2 and D3 are water‐insoluble and are transported in the blood to the liver bound to carrier proteins, mainly vitamin D‐binding protein. Here, they are converted to 25‐hydroxyvitamin D (25(OH)D), which is the major circulating form of vitamin D. In the kidneys, 25(OH)D is converted to 1,25‐dihydroxyvitamin D (1,25(OH)D) via the action of the enzyme 1α hydroxylase (Holick 2008; White 2008). This is the active form of vitamin D in the body, and is thus the true hormonal form of vitamin D. It binds to the vitamin D receptor (VDR), which is found on the nuclear membrane of many cells (Walker 2009).

Vitamin D levels in the body are best measured using the concentration of 25(OH)D in blood serum. According to the US Institute of Medicine (IOM 2010), concentrations of 25(OH)D above 50 nmol/L (20 ng/mL) can provide benefit to most in the population and are considered in the normal range. Vitamin D deficiency refers to concentrations below this cut‐off value. It is estimated that around one billion people in the world may have suboptimal vitamin D concentrations (Walker 2009). The major risk factors are lack of sunlight (especially during winter months), vegetarian diets, a dark pigmented skin (as melanin acts as a natural sunscreen), increased pollution, and wearing long‐sleeved garments or clothes completely covering the body (Williams 2008; Nimitphong 2013). Modern recommendations to avoid the sun to prevent skin cancers may also be contributing to a deficiency in vitamin D (Misra 2008).

Fortified foods such as infant formulas, breakfast cereal, cheese, and cows' milk are the major dietary sources of vitamin D in children, but they may not be consumed in sufficient quantities. Furthermore, dairy products may not be fortified in all countries. Diet contributes less than 10% to 20% of an adult’s vitamin D stores, and this proportion may be even smaller in children (Sichert‐Hellert 2006). Since vitamin D is a fat‐soluble vitamin, a diet that is extremely low in fat can also impair its absorption. Breast milk can be a poor source of vitamin D, particularly if the mother has clinical or subclinical vitamin D deficiency.

Over the past 20 years, much attention has been paid to recognition of vitamin D deficiency in children worldwide. Childhood vitamin D deficiency is highly prevalent in many developing countries, even those with abundant sunlight such as Turkey (Ozgür 1996), Iran (Salimpour 1975; Bassil 2013), Saudi Arabia (Elidrissy 1984), Jordan (Bassil 2013), the United Arab Emirates (Bassil 2013), Algeria (Garabedian 1991), India (Ghai 1991; Wayse 2004), China (Zhao 1991; Zhao 1992; Du 2001; Zhang 2013), and Nigeria (Akpede 1999; Akpede 2001). A study on the health status of children in low‐ and middle‐income countries reported that 73.1% of underprivileged children were 25(OH)D‐deficient (Manaseki‐Holland 2008). A high occurrence of vitamin D deficiency in infants and children has also been reported in many other countries, including industrialized ones (Prentice 2008) such as the USA (Mansbach 2009), the UK (Lawson 1999), Greece (Nicolaidou 2006), Finland Lehtonen‐Veromaa 1999), Canada (Ward 2007), and New Zealand (Grant 2009).

Description of the intervention

In the past, clinicians have primarily focused on the role of vitamin D in preventing and treating rickets. However, a few early researchers realized that children with rickets were more likely to have respiratory infections. Initially, clinicians presumed these infections were caused by poor lung function as a result of bone deformities and the overall compromised nutritional status associated with rickets. Since then, several studies, including case‐control and case series studies, have linked rickets with pneumonia and respiratory tract infections (Salimpour 1975; Muhe 1997; Najada 2004), and implicated vitamin D deficiency as a potential risk factor for these infections. Many epidemiological studies have also been conducted in children to assess the link between inadequate vitamin D concentrations and respiratory infections, including tuberculosis (TB) (Wayse 2004; Nnoaham 2008; Williams 2008; Karatekin 2009; McNally 2009; Roth 2009). The findings from these studies have been mixed, with some reporting strong positive associations and others no associations. A retrospective case‐series of 64 paediatric TB patients during a two‐year period in UK showed that 86% of children were either vitamin D‐deficient or vitamin D‐insufficient (Williams 2008). Other case‐control studies in Europe and Australia showed an increased risk of vitamin D deficiency in children with TB compared to healthy controls (Gray 2012; Venturini 2014), while another study from India did not find vitamin D deficiency a risk factor for TB in children (Jubulis 2014). Evidence is also emerging on the role of vitamin D deficiency as a risk factor for gastroenteritis. A prospective cohort study of school‐age children in Colombia reported a significant two‐fold increased risk of diarrhoea with vomiting over a one‐year period in vitamin D‐deficient compared to vitamin D‐sufficient children. This indicated increased susceptibility to norovirus and Salmonella or Shigella bacterial infections (Thornton 2013). Vitamin D insufficiency has also been linked to more severe malarial infections in Ugandan children 18 months to 12 years old (Cusick 2014). In animal models, vitamin D is known to inhibit the development of cerebral malaria during Plasmodium berghei infection (He 2014); and in another study, the death rate in mice from P. berghei infection reduced after addition of cod liver oil or vitamin D and dicalcium phosphate to antimalarial drugs (Sautet 1957; Luong 2015).

The precise molecular mechanisms by which vitamin D helps defend people against infectious disease are now being elucidated. It has become clear that 1,25(OH)D plays a role not only in calcium homeostasis and bone metabolism, but also in the integrity of the innate immune system (Bhutta 2008; Wagner 2008b; Dimitrov 2015). Acting via the VDR, 1,25(OH)D alters the activity of many immune system cells, including macrophages, regulatory T cells, and natural killer cells.

Based on bone health benefits of vitamin D, the US Institute of Medicine (IOM) published new dietary guidelines in 2010, with the adequate intake for infants of 400 International Units (IU) daily of vitamin D, and raised the Recommended Dietary Allowance (RDA) for children older than one year from 400 IU/day in 2008 (Wagner 2008a) to 600 IU/day (IOM 2010). Health Canada also has similar recommendations of 400 IU/day for all exclusively breastfed, healthy infants; this should be continued until the infant's diet provides at least 400 IU/day from other sources (Canadian Paediatric Society 2007). However, the IOM committee did not find sufficient conclusive evidence for effects on non‐skeletal outcomes (Shapses 2011). It is therefore not yet known if these doses are sufficient to deliver all potential non‐skeletal health benefits related to vitamin D, and some experts recommend that at least 1000 IU/day may be required to consistently raise serum 25(OH)D concentrations above 30 ng/mL (Holick 2011). Vitamin D is generally safe and well tolerated when given at appropriate doses; cases of hypercalcaemia have been documented with vitamin D toxicity (only at doses of 50,000 IU/day or more for several weeks), which may eventually lead to vascular and tissue calcification with subsequent renal and cardiovascular damage (IOM 2010).

How the intervention might work

Vitamin D influences the action of more than 200 human genes in a wide range of tissues and displays as many molecular mechanisms (Cannell 2008). In particular, it interacts with the human immune system in a wide variety of ways, and helps to protect against infectious diseases (Gunville 2013). For example, it has been known for 20 years that exposure to 1,25(OH)D stimulates anti‐mycobacterial activity in human monocytes and macrophages. Recent research suggests that this is due to vitamin D helping to generate antimicrobial peptides (AMPs) like cathelicidin and some β defensins (White 2008; Gunville 2013). These AMPs then lead to enhanced killing of intracellular Mycobacterium tuberculosis by direct membrane damage and also by acting as chemoattractants for monocytes.

Recent research also indicates that a sufficient intake of vitamin D is essential for killer T cells to fend off serious infections, by controlling T cell antigen receptor (TCR) signalling and the activation of human T cells. Besides this, 1,25(OH)D also suppresses an overzealous adaptive immune response to pathogens that may be difficult for macrophages to handle efficiently (Walker 2009). The levels of plasma interleukin‐1ß have also been shown to be low in children with vitamin D deficiency which can predispose them to infections (Liang 2010; Bentley 2013).

The relationship between vitamin D and infectious diseases is also supported by genetic studies of polymorphisms in the gene for the VDR. Researchers have found a significant link between single nucleotide polymorphisms of genes related to the innate immune function, including the VDR, and genetic susceptibility to respiratory syncytial virus (RSV) bronchiolitis (Janssen 2007).

While there is much research on the beneficial effects of vitamin D for TB infections, data are emerging from various sources about its role in fighting other bacterial and viral pathogens. Apart from the synthesis of AMPs (cathelicidin and defensins), the binding of activated vitamin D to the VDR can modulate viral lower respiratory tract disease. One of the defensins, retrocyclin‐2, inhibits infection with the influenza virus by blocking its fusion with cell membranes (Leikina 2005). Respiratory tract infections peak during the winter season when there is less sunlight and so vitamin D deficiency during this season may enhance the infectivity of influenza viruses. A randomized controlled trial (RCT) on 334 schoolchildren showed that vitamin D supplements had a beneficial effect on influenza A incidence during the four‐month study period (Urashima 2010).

Vitamin D and its role in malarial infection has also been explored. It inhibits development of cerebral malaria in animal models due to suppression of inducible systemic inflammatory responses with reduced production of cytokines (interferon‐Ƴ and tumour necrosis factor) (He 2014). Vitamin D also inhibits penetration of P. berghei into erythrocyte membranes (Sergacheva 1986) and inhibits growth of Plasmodium falciparum in red blood cells in vitro (Vial 1982). VDR expression was also higher in patients with Plasmodium vivax infection, which indicates a link between VDR polymorphism and severity of malarial infection (Ray 2012).

Cystic fibrosis (CF) is an inherited disorder seen in children, and is characterized by pancreatic insufficiency and recurrent infections. Children with CF have inadequate fat‐soluble vitamins, including vitamin D. Yim 2007 showed that there was enhanced antibacterial activity against airway pathogens, such as Pseudomonas aeruginosa and Bordetella bronchiseptica, in both normal and CF bronchial epithelial cells in participants supplemented with 1,25(OH)D. They also witnessed 1,25(OH)D‐induced production of cathelicidin in this cell type.

Why it is important to do this review

Globally, pneumonia and diarrhoea constitute the leading infectious causes of childhood deaths in children under five years of age, and the burden is concentrated in Southeast Asia and Africa. This also explains the focus of this Cochrane Review on this age range. According to 2010 estimates, there were 120 million episodes of pneumonia and 1.731 billion episodes of diarrhoea worldwide (Walker 2013). Twelve per cent of pneumonia episodes and 2% of diarrhoea episodes progressed to severe disease; the case‐fatality ratio for severe pneumonia was 8.9% (uncertainty range: 3.1 to 12.5%) and for severe diarrhoea 2.0% (1.4 to 4.4%) (Walker 2013).

Rickets is the best‐known medical condition associated with vitamin D deficiency. It has also been linked to various infectious diseases, especially respiratory infections such as pneumonia, TB, and bronchiolitis, which suggests that suboptimal concentrations of vitamin D may be responsible in the aetiology of these infections (see the 'Description of the intervention' section). Due to lack of evidence on the role of vitamin D in preventing infections, the mortality and morbidity burden of infections in children due to vitamin D deficiency has not yet been quantified.

Vitamin D supplementation is a relatively simple intervention that might decrease the incidence of many infections. A study in the UK on a small cohort reported that the cost of preventing vitamin D deficiency in a high‐risk population of Asian children was much lower than the cost of treating the general health issues linked with chronic vitamin D deficiency (Zipitis 2006). Because of its cost effectiveness and ease of administration, it can easily be applied on a large scale to children in communities or in health facilities. Vitamin D could therefore help prevent the enormous burden of morbidity and mortality in children.