Coronavirus disease 19 (Covid-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has been declared a pandemic in March 2020(Reference Cucinotta and Vanelli1). The disease was considered milder in children, since most children appeared to have an asymptomatic, mild or moderate disease(Reference Forrest, Burrows and Mejias2). However, severe disease may occur, with the prevalence reported to be 2–10 % in children(Reference Forrest, Burrows and Mejias2–Reference Liguoro, Pilotto and Bonanni4). Due to severe cases and associated mortality in the paediatric population, there is a lot of discussion and research to address risk factors and develop protective measures.
Except for Covid-19 severity and associated mortality, concerns regarding children emerged also from a new clinical entity known as a multisystem inflammatory syndrome in children (MIS-C). This was considered a late presentation of Covid-19 infection and shares similar features with incomplete Kawasaki disease or toxic shock syndrome(Reference Licciardi, Pruccoli and Denina5,Reference Verdoni, Mazza and Gervasoni6) . This complication was rare, with unknown incidence, estimated in one report to be 2 per 100 000(Reference Dufort, Koumans and Chow7). The clinical severity of MIS-C varied, since some patients had only mild disease, while others had severe disease leading to death(Reference Kaushik, Gupta and Sood8,Reference Whittaker, Bamford and Kenny9) .
The pathophysiology of Covid-19 involves a complex interaction between the SARS-CoV-2 and the host’s immune system. The virus enters cells, primarily type 2 alveolar epithelial cells, via the receptor angiotensin-converting enzyme 2 (ACE2) which results in a cytokine storm(Reference Mehta, McAuley and Brown10). Vitamin D is a fat-soluble vitamin with many biological extraskeletal effects including both antiviral and anti-inflammatory actions(Reference Panfili, Roversi and D’Argenio11). The vitamin D receptor regulates the expression of more than 900 genes associated with antioxidation, and innate and adaptive immunity(Reference Cantorna12,Reference Sharifi, Vahedi and Nedjat13) .
Therefore, serum vitamin 25(OH)D concentrations have been proposed as a possible predictor of severe disease. There are many observational studies in children that associated serum vitamin 25(OH)D suboptimal concentrations with increased risk for respiratory infections(Reference Zisi, Challa and Makis14). Following this observation, randomised trials showed that vitamin D supplementation reduced the risk of acute respiratory infections(Reference Camargo, Ganmaa and Frazier15–Reference Jolliffe, Camargo and Sluyter17)and led to a more rapid recovery and shorter hospitalisation in children with bronchiolitis(Reference Saad, Abd Aziz and El-Houfey18). Observational studies in adults indicated that vitamin D insufficiency was associated with Covid-19 severity(Reference Maghbooli, Sahraian and Ebrahimi19,Reference Munshi, Hussein and Toraih20) , and that serum vitamin 25(OH)D concentrations were an independent risk factor for Covid-19 infection and need for hospitalisation(Reference Merzon, Tworowski and Gorohovski21).
This review aimed to summarise data regarding the role of serum vitamin 25(OH)D concentrations in Covid-19 severity in childhood and evidence of vitamin D supplementation as a protective measure during the pandemic.
Methods
We searched the current literature for relevant studies on the role of vitamin D in the severity of paediatric Covid-19 and carried out a narrative review. A PubMed and Google Scholar search was conducted using the terms ‘Covid-19’, or ‘SARS-CoV-2’, or ‘MIS-C’, and ‘children’, or ‘pediatric’, and ‘vitamin D’ up to May 2022. In this narrative review, only papers written in English and particularly meta-analysis, systematic reviews, observational studies, and case series were included. In addition, the reference lists of the retrieved articles were carefully reviewed in the search for other relevant articles, which could have been missed during the initial searching procedure. Abstracts were not included in the paper when the full article was not available.
Vitamin D deficiency as a global problem
Vitamin D deficiency remains a global problem with a high worldwide prevalence(Reference Palacios and Gonzalez22). Usually, vitamin D deficiency is defined as serum concentrations of vitamin 25(OH)D below 12 ng/ml, while insufficiency is defined as concentrations below 20 ng/ml(Reference Lee, So and Thackray23). The range of deficiency in Europe in the various teenage study populations was 12–40 %, whereas in childhood was 4–7 %(Reference Cashman, Dowling and Škrabáková24). Prevalence of vitamin D deficiency in children was 16 % in the USA, 7 % in South Africa, 40 % in China and 36 % in Iran(Reference Palacios and Gonzalez22), whereas prevalence of vitamin D insufficiency was reported in the 5·9 % of the population in the USA, 7·4 % in Canada, 13 % in Europe and in > 20 % of the population in India, Tunisia, Pakistan and Afghanistan(Reference Amrein, Scherkl and Hoffmann25).
Pandemic, accompanied by many restrictions, such as home confinement and school closures, led to the deterioration of this problem by having a significant adverse impact on serum vitamin 25(OH)D concentrations. Many studies noted decreased vitamin 25(OH)D concentrations in children during the pandemic compared with the era before, since the main source of vitamin D is skin synthesis after sunlight exposure(Reference Beyazgül, Bağ and Yurtseven26–Reference Yu, Ke and Che30). This was observed in all ages, from infants and toddlers(Reference Wong, Tung and So29)to school-aged children and adolescents(Reference Beyazgül, Bağ and Yurtseven26). In a study of 303 infants and toddlers in Hong Kong, a decreasing trend was observed in the months post-outbreak at a monthly decline rate of –2·53 ng/ml in serum vitamin 25(OH)D concentrations, and this was stronger among younger infants (2–6 months old)(Reference Wong, Tung and So29). During the pandemic, there was also no seasonal variability in serum vitamin 25(OH)D concentrations(Reference Rustecka, Maret and Drab28).
Serum vitamin 25(OH)D concentrations and Covid-19 severity
Studies in adults, mostly observational and population-based, indicated that vitamin D insufficiency was associated with Covid-19 severity(Reference Maghbooli, Sahraian and Ebrahimi19,Reference Munshi, Hussein and Toraih20) , and that serum vitamin 25(OH)D concentrations were an independent risk factor for Covid-19 infection and need for hospitalisation(Reference Merzon, Tworowski and Gorohovski21). A meta-analysis of twenty-one studies found that patients with concentrations of vitamin 25(OH)D below 20 ng/ml had 2·42 times increased risk to have severe Covid-19, but vitamin 25(OH)D concentrations had no effect on mortality(Reference Kaya, Pamukçu and Yakar31). On the other hand, a meta-analysis of thirty-one observational studies concluded that available evidence to date may be showing a weak association between low concentrations of vitamin 25(OH)D and Covid-19 outcomes, yet a statistically significant relationship could not be established(Reference Bassatne, Basbous and Chakhtoura32). So, even if there is evidence of an association between serum vitamin 25(OH)D concentrations and Covid-19 severity, data are still conflicting in adults.
Regarding children, several retrospective studies noted that those with Covid-19 had lower serum vitamin 25(OH)D concentrations compared with healthy children (Table 1)(Reference Alpcan, Tursun and Kandur33–Reference Yılmaz and Şen36). A meta-analysis of Shah et al. showed a pooled prevalence of vitamin D deficiency of 45·91 % in Covid-19 patients(Reference Shah, Varna and Pandya37). This meta-analysis of retrospective studies and case series also showed that children with vitamin D deficiency have a greater risk for Covid-19 infection compared with children with optimal levels(Reference Shah, Varna and Pandya37). Katz et al., in a retrospective study of patients’ registry, quantified this observation and found that the risk of Covid-19 is five times higher in children with vitamin D deficiency, after adjustment for co-morbidities and demographic covariates(Reference Katz, Yue and Xue34).
Table 1. Studies assessing serum vitamin 25(OH)D concentrations in children with Covid-19
However, most of the available retrospective studies did not associate vitamin D insufficiency or deficiency with infection severity, since the severe disease was rare in the population of the studies and no patients required admission to intensive care. Only in two studies, serum vitamin 25(OH)D concentrations were correlated with disease severity. Bayramoglu et al. assessed in their study vitamin 25(OH)D concentrations in 103 children with Covid-19 and found that levels were significantly lower in the moderate-to-severe disease compared with children with mild disease, while vitamin D deficiency was found to be an independent predictor of severe clinical course. In this study, moderate-to-severe disease was defined as pneumonia in hospitalised children. Interestingly, children with severe disease had a mean vitamin 25(OH)D concentration almost 40 % lower than those who had asymptomatic disease. This association was observed when there was a deficiency of vitamin 25(OH)D concentrations (<12 ng/ml) but not an insufficiency (12–20 ng/ml)(Reference Bayramoğlu, Akkoç and Ağbaş38). In this study, children with co-morbidities were excluded and so were infants due to routine vitamin D supplementation in this age group. This was a single-centre study and due to its retrospective design, a cause–effect relationship cannot be fully established. Furthermore, in this study, other confounding factors, such as obesity and anthropometric measures affecting vitamin 25(OH)D concentrations, were not taken into account.
On the other hand, a smaller study of forty children with Covid-19 did not find a statistically significant difference in severity and length of hospitalisation between children with vitamin 25(OH)D concentrations < 20 ng/ml(Reference Yılmaz and Şen36). However, it should be noted that this study had a smaller population, only two children had severe disease, defined as dyspnea and central cyanosis, and there was no subgroup analysis for children with deficient concentrations (< 12 ng/ml).
Shah et al. included these two studies in their analysis and concluded that in infected paediatric patients, low serum vitamin 25(OH)D concentrations increased the risk of severe disease (OR –5·5; 95 % CI 1·560, 19·515; P = 0·008)(Reference Shah, Varna and Pandya37). However, this evidence arises only from two single-centre studies of retrospective design, with a small total number of subjects. Thus, more accurate conclusions should be drawn from larger randomised controlled trials.
In recent studies, there was also an effort to associate vitamin 25(OH)D concentrations with symptoms and laboratory findings of Covid-19. Plasma vitamin 25(OH)D concentrations negatively correlated with levels of inflammatory markers (C-reactive protein and fibrinogen)(Reference Bayramoğlu, Akkoç and Ağbaş38) and lower lymphocyte count(Reference Alpcan, Tursun and Kandur33,Reference Bayramoğlu, Akkoç and Ağbaş38) . The vitamin D-deficient group of children had the lowest lymphocyte levels(Reference Bayramoğlu, Akkoç and Ağbaş38). Lymphopenia is an indicator of severe disease(Reference Kosmeri, Koumpis and Tsabouri39), and it has been shown that the lowest lymphocyte counts are reached when the inflammatory cytokine levels are at the highest levels(Reference Liu, Li and Liu40). The SARS-CoV-2 may directly infect lymphocytes via the ACE2 receptor(Reference Xu, Zhong and Deng41), while in critical disease, a systemic increase in cytokines and inflammatory mediators may result in marked lymphocytic apoptosis(Reference Liao, Liang and Chen42–Reference Terpos, Ntanasis-Stathopoulos and Elalamy44).
Regarding fever, the available data are conflicting. In a retrospective study of seventy-five children from Turkey, there was no correlation between fever and serum vitamin 25(OH)D concentrations in Covid-19(Reference Alpcan, Tursun and Kandur33), while in another study of forty patients with Covid-19 fever was significantly higher when concentrations of vitamin 25(OH)D were lower(Reference Yılmaz and Şen36).
In conclusion, available data are scarce and there is no high-quality evidence that vitamin 25(OH)D concentrations are associated with Covid-19 severity. There are several retrospective studies with a small number of patients, and most of them did not assess vitamin 25(OH)D concentrations as an independent predictor of disease severity(Reference Alpcan, Tursun and Kandur33–Reference Yılmaz and Şen36).
Serum vitamin 25(OH)D concentrations and multisystem inflammatory syndrome in children severity
MIS-C is an uncommon complication of Covid-19, yet with a disease course that can be quite severe, so risk factors and predictors of severe disease should be addressed(Reference Kaushik, Gupta and Sood8). In a retrospective single-centre study of thirty-one patients under 18 years old with MIS-C from the USA, ten patients had severe vitamin D deficiency, and these patients had longer intensive care unit and hospitalisation length, as well as increased risk for cardiac involvement. Ninety percent of patients with severe vitamin D deficiency had severe disease, which was defined as patients requiring inotropic support, mechanical ventilation, veno-arterial extracorporeal membrane oxygenation or disease resulting in death(Reference Torpoco Rivera, Misra and Sanil45). Nevertheless, the study population was small to allow for proper testing of other possible confounding factors of severe disease.
In another study of eighteen children with MIS-C and no notable co-morbidities, 89 % of children had suboptimal vitamin 25(OH)D concentrations (72 % deficient and 17 % insufficient) and most children required intensive care(Reference Darren, Osman and Masilamani46). In this study, children needing intensive care unit support had lower serum vitamin 25(OH)D concentrations than those not requiring intensive care. Nevertheless, the median differences in the two groups of vitamin25(OH)D concentrations were small (18·2 v. 23·5 nmol/l). The authors proposed vitamin D supplementation all year round, especially for children at high risk for vitamin D deficiency. Finally, a safe conclusion regarding the role of vitamin D in MIS-C severity cannot be made, since available data are only from two single-centre, retrospective studies including a small number of patients.
Vitamin D as an immune regulator
Regarding Covid-19, vitamin D reduces the apoptosis of type II pneumonocytes and stimulates surfactant synthesis in these cells, thus preventing the risk of acute respiratory syndrome(Reference Zheng, Yang and Hu47). Furthermore, vitamin D modulates both innate and adaptive immunity(Reference Panfili, Roversi and D’Argenio11,Reference Charoenngam, Shirvani and Holick48) . Regarding innate immunity, vitamin 1,25(OH)2D induces the production of antimicrobial peptides such as cathelicidin LL-37 and defensins by macrophages and respiratory epithelial cells(Reference Charoenngam, Shirvani and Holick48–Reference Charoenngam and Holick51). Vitamin D also modulates adaptive immunity through suppressing T lymphocyte proliferation and altering the activity of different types of T-helper cells. A shift from type 1 T-helper cells and type 17 T-helper cells profile to type 2 T-helper cells profile is promoted leading to a decrease in the production of pro-inflammatory cytokines and thus reduction of the cytokine storm(Reference Charoenngam, Shirvani and Holick48,Reference Charoenngam and Holick51,Reference Cantorna, Snyder and Lin52) .
SARS-CoV-2 enters the cells via the ACE2 resulting in the down-regulation of ACE2 in the lungs and accumulation of angiotensin II. This leads to inflammation and vasoconstriction and thus the complications accompanying Covid-19.Vitamin 1,25(OH)2D regulates the renin-angiotensin-aldosterone system by inhibiting renin and inducing the expression of ACE2 in the lungs(Reference Charoenngam, Shirvani and Holick48,Reference Charoenngam and Holick51) .
On the other hand, severe infections such as Covid-19 can lead to the consumption of vitamin D by the immunomodulatory cells. The utilisation of vitamin D is faster than its production, and this may lead to vitamin D deficiency. Therefore, decreased concentrations of plasma vitamin 25(OH)D have been proposed to be the end result of vitamin use by immunomodulatory cells in severe Covid-19, rather than a separate predisposing factor(Reference Feketea, Vlacha and Bocsan53).
MIS-C is the result of an altered and exaggerated immune response against SARS-CoV-2, in which the level of inflammation outweighs the inflammation observed in Covid-19(Reference Ahmed, Advani and Moreira54). The cytokines that are mostly involved in the acute phase are IL-1β, IL-6, IL-8, IL-10, IL-17, IFN-γ, and differential T and B cell subset lymphopenia(Reference Carter, Fish and Jennings55,Reference Lee, Day-Lewis and Henderson56) . Vitamin D may have an impact on MIS-C severity mainly through its anti-inflammatory actions. As described above, vitamin 1,25(OH)2D alters the activity of different types of T-helper cells. A shift from type 1 T-helper cells and type 17 T-helper cells profile to type 2 T-helper cells profile is promoted leading to a decrease in the production of pro-inflammatory cytokines and reduction of the cytokine storm(Reference Panfili, Roversi and D’Argenio11,Reference Feketea, Vlacha and Bocsan53,Reference Daneshkhah, Agrawal and Eshein57) .
The role of vitamin D supplementation
There are no available studies assessing the effect of vitamin D supplementation in children with Covid-19. Recent systematic reviews and meta-analyses of adult observational studies concluded that current evidence is insufficient to prove a benefit of vitamin D supplementation in Covid-19(Reference Stroehlein, Wallqvist and Iannizzi58). Regarding other infections, previous meta-analyses of randomised controlled trials have shown an effect of vitamin D supplementation in preventing acute respiratory tract infection both in children and adults(Reference Jolliffe, Camargo and Sluyter17,Reference Martineau, Jolliffe and Hooper59) . Daily administration of 400–1000 μg of vitamin D for up to 12 months reduced the risk of acute respiratory infection(Reference Jolliffe, Camargo and Sluyter17). Children and adults that had baseline vitamin 25(OH)D concentrations lower than 10 ng/ml had the most benefit in protection from acute respiratory infections from vitamin D supplementation(Reference Martineau, Jolliffe and Hooper59). Therefore, the role of vitamin D supplementation should be further studied during the pandemic in children, in randomised controlled studies, for not only its efficacy but also the optimal dose and duration of supplementation to be established.
Conclusion
In conclusion, although there is a lot of discussion regarding the role of vitamin D in the pandemic, the evidence that vitamin D is a risk factor for severe disease in children is of poor quality. Furthermore, it is unclear whether vitamin D is a risk factor, or whether it is an epiphenomenon of severe disease, since vitamin D may be consumed during severe disease process. More studies, of prospective design, are needed to assess the role of this marker independently of other risk factors. The efficacy of vitamin D supplementation should also be assessed in randomised controlled trials. Although vitamin D administration is relatively free of side effects, the optimal dose and duration of its administration in order to have a preventive effect should also be clarified.
Acknowledgement
None.
All authors have participated sufficiently in the work and take public responsibility for the content of the paper and approve of the final version of the manuscript. C. K. searched the literature and drafted the manuscript. D. R. had a substantial contribution in interpreting the data and drafting the manuscript. F. B. and M. B. had a substantial contribution in the conception of the idea of the review and revision of the manuscript. V. G. had the overall supervision of designing the review process and critically revised the final work.
There are no conflicts of interest.
