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State of the art review
Vitamin D for secondary prevention of acute wheeze attacks in preschool and school-age children
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  1. Christos Stefanidis1,2,
  2. Adrian R Martineau1,2,
  3. Chinedu Nwokoro1,
  4. Christopher J Griffiths1,2,
  5. Andrew Bush1,3
  1. 1 Asthma UK Centre for Applied Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  2. 2 Centre for Primary Care and Public Health, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  3. 3 Royal Brompton Hospital, Biomedical Research Unit at the Royal Brompton & Harefield NHS Foundation Trust, Imperial College London, London, UK
  1. Correspondence to Christos Stefanidis; c.stefanidis{at}qmul.ac.uk

Abstract

Introduction Vitamin D is best known for its role in bone health; however, the discovery of the vitamin D receptor and the expression of the gene encoding the vitamin D 1α-hydroxylase (CYP27B1) enzyme in a wide variety of tissues including immune cells and respiratory epithelium has led to the discovery of potential roles for vitamin D in the prevention of acute wheeze.

Methods We review here the literature concerning the relationships between circulating 25-hydroxyvitamin D (25(OH)D) concentration and secondary prevention of acute wheeze attacks in preschool and school-age children.

Results Epidemiological data suggest that vitamin D insufficiency (25(OH)D <75 nmol/L) is highly prevalent in preschool and school-age children with wheeze. Preschool age children with a history of wheeze attacks and circulating 25(OH)D <75 nmol/L are at increased risk and frequency of future acute wheeze. However, no consistent association between low vitamin D status and risk of acute wheeze is reported in school-age children. Seven randomised controlled trials (RCTs) with relatively small sample sizes (30–430) and variable quality showed inconsistent results regarding the effect of oral vitamin D supplementation during childhood on the risk of asthma attacks, asthma symptom control, inhaled corticosteroid requirements, spirometry and unscheduled healthcare attendances for wheeze. A RCT showed that vitamin D supplementation had no effect on the frequency of unplanned healthcare attendances due to acute wheeze in 22 preschool children.

Discussion An evidence-based recommendation for the use of vitamin D as a preventive therapy for wheeze attacks cannot be made until results of further trials are available. The assessment of circulating 25(OH)D concentration and the optimisation of vitamin D status to prevent acute respiratory tract infections, and to maintain skeletal and general health in preschool and school-age children with acute wheeze is worthwhile in its own right, but whether this will reduce the risk of acute wheeze attacks is unclear.

  • vitamin D
  • children
  • acute wheeze secondary prevention
  • 25-hydroxyvitamin D

https://doi.org/10.1136/thoraxjnl-2019-213278

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    Introduction

    Asthma affects 339 million people worldwide and is the most common chronic disease of school-age children.1 Globally, asthma is among the top 10 chronic conditions for ranking of disability-adjusted life years in children aged 5–12 years. Mortality for asthma and hospital admission rates in children varies across countries.2 UK asthma outcomes are among the worst in Europe. In London, the mortality rate for all causes of death has been falling except the deaths from respiratory illnesses in preschool and school-age children.3 The majority of children who died had infrequent asthma attacks which were managed within primary care.4 Severe acute attacks of wheeze can have serious consequences, including death and impaired quality of life, and are associated with reduced lung growth trajectories.5 Furthermore, the mean healthcare costs per patient per year are huge, varying from US$ 1900 in Europe to US$ 3100 in USA.6 Viral respiratory infections are important triggers of acute wheeze,7 and the efficacy of specific antiviral therapies in the prevention of acute wheeze is under investigation, but currently influenza immunisation is our only effective intervention to reduce incidence of viral respiratory illness.8

    An increasing number of immunomodulatory effects of vitamin D have been proposed, including antiviral, and the coordinated modulation of inflammatory and anti-inflammatory responses.9 Cord blood 25-hydroxyvitamin D (25(OH)D) has been inversely associated with early life recurrent wheeze.10 There is some evidence for a U-shaped association between circulating 25(OH)D concentration and primary prevention of wheeze in children,11 12 but this is not consistent across studies.13 There is no evidence for a dose effect relationship on circulating 25(OH)D concentration and the secondary prevention of acute wheeze in children. Vitamin D is an inactive preprohormone, the generic term for ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) which is metabolised to the active form in two steps. In the liver, cholecalciferol undergoes hydroxylation at the C25 position by the cytochrome p450 enzymes CYP27A1, CYP2R1 and CYP3A4 resulting in the formation of 25(OH)D.14 25(OH)D is the main circulating vitamin D metabolite in humans, and is the universally accepted measure of vitamin D status. A second hydroxylation step, at the 1α position is catalysed by vitamin D 1α-hydroxylase (CYP27B1), synthesising 1,25-dihydroxyvitamin D or 1,25(OH)2D.15 The optimal 25(OH)D concentration for skeletal health is controversial, and there is no consistent classification for vitamin D deficiency across national guidelines. European experts favours a threshold of 25(OH)D concentration <50 nmol/L for vitamin D deficiency with the exception of the UK experts, who suggest a 25 nmol/L threshold.16 17 Some experts advocate a 25(OH)D concentration ≥75 nmol/L for bone health but it is still unclear if this level is optimal for antiviral immunity.17 Furthermore, for any immune effects, tissue levels of 25(OH)D are important; these are challenging to measure, and are likely at best loosely related to circulating levels. It may also be that tissue 25(OH)D levels respond only slowly to an increased oral intake of vitamin D. Circulating 25(OH)D concentration varies across countries and studies, and in a meta-analysis of 11 case-control and five cohort studies, 28.5% and 26.7% of children with asthma aged up to 18 years were vitamin D deficient (25(OH)D <50 nmol/L) and insufficient (25(OH)D between 50 and 75 nmol/L) globally.18 There is seasonal variation in 25(OH)D concentration and biseasonal measurements are vital to determine vitamin D status.19 This review explores the relationship between 25(OH)D concentration and secondary prevention of acute attacks of wheeze in preschool and school-age children.

    Acute attacks of preschool wheeze

    Acute wheezing illness in preschool children (<5 years) is heterogeneous with at least two phenotypes (viral-induced and multitrigger wheeze) which are not necessarily stable over time and with treatment.20 Viral-induced wheeze accounts for two-thirds of all preschool wheezing whereas multitrigger wheezing is less prevalent in early life.21 Viral-induced wheeze is defined as wheeze in discrete episodes, with the child being well in between,20 and is triggered by (a usually clinically diagnosed) viral infection. In preschool children, viral-induced wheeze may be difficult to distinguish from bronchitis, bronchiolitis or pneumonia because of the lack of consistent definitions internationally. The factors underlying the frequency and severity of the acute episodes are not fully understood; however, atopy (especially in multitrigger wheeze), prematurity and exposure to tobacco smoke have been implicated.22 23 Viral-induced wheeze not consistently associated with allergic sensitisation, total serum IgE levels24 or evidence of airway eosinophilia,25 but is associated with impaired lung function (spirometry). A study including bronchoalveolar lavage has shown that infants with non-atopic, viral-induced wheeze have predominantly neutrophilic inflammation, especially at the time of acute infection.26

    By contrast, multitrigger wheeze more resembles school-age asthma and is strongly associated with fixed and variable airway obstruction.27 Multitrigger wheeze is associated with atopy, a higher risk of persistent wheezing into school-age,28 and airway eosinophilia.29 Children with multitrigger wheeze also wheeze between respiratory infections in response to other factors, including allergens, laughing, crying, strong smells or certain foods or drinks.20 Multitrigger wheeze is often considered as early-onset allergic asthma30; however, not all preschool children with multitrigger wheeze have chronic allergic (type 2) airway inflammation.20 Multitrigger wheeze occurs more commonly at school-age.31

    Acute attacks of wheeze in school-age children

    Wheeze attacks in school-age children (≥5 years) are usually precipitated by respiratory viruses, but bacterial infections are also implicated, as are relative humidity, extreme temperatures, aeroallergens and air pollution.32 At least 85% of childhood asthma attacks are associated with a viral upper respiratory tract infection, with rhinovirus accounting for 61% of the viruses detected.33 Importantly, and unlike preschool children, most school-age children who have an asthma attack are also sensitised to indoor allergens and have background type 2 airway inflammation.34 Rarely, a large allergen load alone (pollen/thunderstorm, soya bean) can cause an attack even in the absence of viral infection.34 School-age children with a history of previous wheeze attacks and persistent asthma symptoms, are at increased risk of future wheeze attack, especially if they have 25(OH)D concentration <75 nmol/L.35

    The differences between preschool wheeze attacks (no background type 2 inflammation, not abrogated by regular inhaled corticosteroids36) and school-age acute wheeze (uncontrolled type 2 inflammation important, attack risk reduced by inhaled corticosteroids35) means that effects of vitamin D should be considered separately in the two age-groups. For example, if any beneficial effects of vitamin D were mediated via abrogation of type 2 inflammation, but the antiviral effects of the vitamin were clinically irrelevant, then benefits at school-age only would be anticipated; if on the other hand, antiviral effects were most significant, then benefit across the developmental spectrum would be expected.

    Effect of vitamin D on host responses to pathogens

    A subgroup analysis conducted within a meta-analysis of individual participant data from 25 randomised controlled trials (RCTs) concluded that vitamin D supplementation significantly reduces the risk of acute respiratory tract infection in a mixed population of 513 children aged 1.1–15.9 years participating in eight studies (adjusted OR: 0.60; 95% CI 0.46 to 0.77, p<0.001).37 Vitamin D coordinates the immune system both by turning on and off inflammation and modulates inflammatory and anti-inflammatory effects of immune cells. The cellular and molecular mechanisms by which vitamin D may exert in vivo antiviral, antimicrobial and immunomodulatory effects on the host innate and adaptive immune responses are summarised in tables 1 and table 2 and are illustrated in figure 1

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    Table 1

    In vitro data on the influence of vitamin D on host innate immune responses to pathogens

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    Table 2

    In vitro data on the influence of vitamin D on host adaptive immune responses to pathogens

    Figure 1
    Figure 1

    Effect of 1,25(OH)2D on components of host immune response in relation to the pathogenesis of acute wheeze attacks. 1,25D, 1,25-dihydroxyvitamin D or 1,25(OH)2D; PAFR, platelet-activating factor receptor; ICAM-1, intracellular adhesion molecule 1; AMP, Antimicrobial peptides; IκBa, I-Kappa-B-Alpha; NFkB, nuclear factor kappa beta; B cell, B lymphocyte; T cell, T lymphocyte; IL, interleukin; Th, T helper cell; Ig, Immunoglobulin; CD, cluster of differentiation; Treg, T regulatory cell; IRF-7, Interferon regulatory factor 7; CXCL5, C-X-C Motif chemokine ligand 5; CCL5, C-C motif chemokine ligand 5; FGF-2, fibroblast growth factor 2; VEGF, vascular endothelial growth factor;--> stimulation and --|: inhibition. Effects that are reported in just one paper (thin arrows) vs effects that have been reported in more papers (thick arrows).

    Effects of vitamin D on type 2 airway inflammation

    The effect of vitamin D on type 2 airway inflammation is complex and controversial.38 39 In vitro, 1,25(OH)2D induced interleukin 4 (IL-4) and IL-13 synthesis by primary murine T cells in one study38 and inhibited IL-4 when added from the onset of differentiation in another.39 Both studies used naïve T cells. In a murine model, early treatment with vitamin D before allergen challenge augmented allergen-induced T-cell proliferation along with IL-4, IL-13 and IgE production.40 However, the local inflammatory response in bronchoalveolar lavage fluid and lung tissue was ameliorated with impaired eosinophil recruitment and inferior levels of IL-5 when vitamin D treatment was given after the establishment of an early immune response. Administration of 1,25(OH)2D was found to decrease IL-4 in bronchoalveolar lavage fluid and T-cell migration in a study of murine allergic airways disease.41 This apparent paradox may be resolved by a study showing that vitamin D enhanced the release of the soluble form of the receptor for IL-33, ST2, which by binding IL-33 may reduce alarmin-driven Th2 inflammation.42

    Search strategy

    One investigator (CS) searched Medline, PubMed, the Cochrane Central Registry of Controlled Trials (CENTRAL), Web of Science and ClinicalTrials.gov using electronic search strategies. Searches were regularly updated. No language restrictions were imposed. Collaborators were asked if they knew of any additional studies.

    Vitamin D deficiency and acute wheeze attacks in preschool children with wheeze and school-age children with asthma: epidemiological studies

    Cross-sectional and longitudinal epidemiological studies investigating associations between circulating 25(OH)D concentration and the risk of acute wheeze attacks in preschool children with wheeze and school-age children with asthma are summarised in table 3, table 4, and online supplementary file 1

    Supplemental material

    View this table:
    Table 3

    Cross-sectional and case-controls studies: vitamin D and acute wheeze in preschool children with wheeze

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    Table 4

    Cross sectional and case-control studies: vitamin D and acute wheeze in a mixed population of preschool children with wheeze and school-age children with asthma

    Ten cross-sectional studies in school-age children reported inconsistent results on the association between higher circulating 25(OH)D concentration and the risk of wheeze attacks managed in primary care, childhood asthma control test (c-ACT) score and spirometry. Specifically, in school-age children higher vitamin D status was associated with better controlled asthma,43 reduced risk of attacks requiring hospitalisation,44 reduced severity and number of asthma attacks,45–47 reduced prescription of inhaled corticosteroids,45 and improved c-ACT scores.45 48 Better vitamin D status was also associated with higher forced expiratory volume in one second (FEV1) and forced vital capacity (FVC),45 48–50 reduced airway reactivity to exercise,49 and reduced total IgE and IgE antibodies against inhalant allergens.51 Five studies reported no association between circulating 25(OH)D levels and risk of asthma attack, prescribed dose of inhaled corticosteroids, frequency of unscheduled healthcare attendances due to asthma,52 total peripheral blood eosinophil count,48 total IgE46 50 or spirometry (FEV1, FEV1/FVC ratio).46 48 51 52 In both preschool and school-age children, better vitamin D status was associated with reduced prescribed dose of inhaled corticosteroids and higher FEV1 and FEV1/FVC ratio53 and also with reduced frequency of acute wheeze requiring oral corticosteroids54 or admission to hospital55 in preschool children.

    Two case-control studies56 57 reported an association between higher 25(OH)D concentration with reduced frequency of acute wheeze attacks and reduced risk for wheeze episodes in preschool children. Out of two case-control studies in a mixed population of preschool and school-age children with asthma,58 59 one showed that higher circulating 25(OH)D concentration was associated with reduced frequency and duration of wheeze attacks59 and the other showed no association between circulating 25(OH)D concentration and asthma control.58 Their observational nature makes it impossible to ascertain causality and the temporal order of vitamin D deficiency and risk of wheeze attack; reverse causality cannot therefore be excluded as a potential cause of the reported associations. Furthermore, these studies only measure circulating concentration of 25(OH)D at enrolment. In a study of 1024 children aged 7–10 years with mild to moderate asthma, after adjustment for age, sex, body mass index, treatment group and season of vitamin D sampling, 25(OH)D concentration was associated with reduced odds of a wheeze attack precipitating a visit to the emergency department unit or hospitalisation.60 However, this study is limited by having only one measure of circulating 25(OH)D concentration.

    In general, observational studies report associations between low vitamin D status and worse respiratory outcomes in preschool children with wheeze and school-age children with asthma. However, these reported associations are inconsistent, and may remain subject to confounders, bias and reverse causality.

    Effect of vitamin D supplementation on the secondary prevention of acute wheeze attacks/asthma control in preschool and school-age children

    RCTs investigating effects of vitamin D supplementation on the secondary prevention of acute wheeze attacks in preschool and school-age children are presented in table 5 and online supplementary file 2, respectively.

    Supplemental material

    View this table:
    Table 5

    A randomised controlled trial: vitamin D and secondary prevention of acute wheeze in preschool age children

    RCTs in school-age children showed mixed results on the effect of oral vitamin D supplementation on asthma control and the risk of an asthma attack. Specifically, in some studies in school-age children vitamin D supplementation reduced the risk of an asthma attack managed in primary care,61–63 improved c-ACT scores,64 65 reduced frequency of asthma attacks precipitating a visit to the emergency department unit,63 reduced school absences due to asthma66 and improved asthma symptoms.67 Supplementation also improved FEV1 67 and FEV1/FVC ratio.66 However, three trials failed to show an effect of vitamin D supplementation on asthma control, unscheduled healthcare visits due to asthma, number of prescribed oral steroid courses,66 FEV1 64, FVC%, IgE66 and fractional exhaled nitric oxide.67 In preschool children, vitamin D supplementation had no effect on the risk of acute episodes of wheezing illness leading to a healthcare visit.68 However, these are small trials (22–430 participants)62–67; in addition some have important limitations including high dropout rates,61 63 64 no assessment of circulating 25(OH)D concentration,61 63 and a vitamin D dosing regimen that failed to elevate circulating 25(OH)D concentration above 75 nmol/L.62 64–66 Furthermore, two trials were underpowered to test the primary outcome.66 68 In a single study lack of power meant that interactions within subgroups could not be evaluated.65 Four trials in school-age children reported no adverse effects of the studied vitamin D supplementation regimen,61 65–67 whereas three trials provided no safety data.62–64 No toxic circulating 25(OH)D concentration was reported in the trial in preschool-age children.68 Three systematic reviews and meta-analyses concluded that vitamin D supplementation led to a reduction in the risk of wheeze attacks managed in primary care69–71 in children aged 5–18 years. However, all three reviews based their conclusions on the same RCTs. Two RCTs were included in the pooled estimate effect for a meta-analysis (relative risk (RR), 95% CI 0.26, 0.11 to 0.59).70 These two RCTs and a further trial were included in meta-analyses of the pooled estimate effect meta-analyses (RR, 95% CI 0.41, 0.27 to 0.63).69 71 None of these analyses presented subgroup analyses and it is unclear if the conclusions were valid for preschool children. A meta-analysis of individual participant data of five RCTs concluded that there was no statistically significant effect of vitamin D supplementation on wheeze attacks requiring treatment with systemic corticosteroids in a mixed population of 290 preschool and school-age children (adjusted incidence rate ratio, 95% CI 0.64, 0.34 to 1.20, p=0.16, note the wide CIs).72 Individual participants’ data from an eligible study that showed a strong positive effect of vitamin D supplementation on the risk of asthma attacks were not available for inclusion in this meta-analysis. In addition, limited power was reported for some of the subgroup analyses.

    In summary, only one small (n=22) RCT (the DIVA pilot) tested the effect of vitamin D supplementation on attacks of wheeze in preschool children as an exploratory outcome (RR, 95% CI 0.88, 0.32 to 2.41, note the wide CIs), from which little can be concluded.68 There are more RCTs of vitamin D supplementation in children with asthma, but there is diversity in study design, treatment protocols and outcome definitions. Furthermore, they are too small-sized, and of variable quality; some show a signal for protection while others do not. This phenomenon may relate to variation in the prevalence of vitamin D deficiency among participants at baseline. Meta-analysis of individual participant data from RCTs of vitamin D for the prevention of acute respiratory infections and severe exacerbations of chronic obstructive pulmonary disease (COPD) reveals stronger protective effects of vitamin D supplementation in those with baseline 25(OH)D levels <25 nmol/L.37 73 In patients with asthma, a similar trend of greater vitamin D-induced protection against exacerbation among participants with baseline 25(OH)D <25 nmol/L was seen, although the p value for interaction was >0.05.72 Therefore, a firm recommendation for vitamin D supplementation as a preventive therapy for wheeze attacks in preschool and school-age children cannot be made until further well-designed and conducted clinical trials become available. Two trials in Canada and the USA are testing the efficacy of oral vitamin D3 on the secondary prevention of acute wheeze in preschool74 and school-age children.75 However, the Celedon75 trial has been stopped. A summary of the trials is shown in table 6.

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    Table 6

    Ongoing randomised controlled trials on the effect of vitamin D supplement on the secondary prevention of acute wheeze in preschool and school-age children

    Should vitamin D status be measured in all children who experience an acute wheeze attack?

    There is clearly no point in measuring anything if useful action does not result. The evidence of benefit from vitamin D supplementation to prevent acute wheeze is weak at best, but there are in vitro studies (effects on innate immunity and type two inflammation) and adult data which are suggestive that there may be a true effect.72 Also, the risks of supplementing vitamin D to achieve normal 25(OH)D levels are practically zero.

    Vitamin D supplements at daily doses up to 2500 IU for preschool and up to 3000 IU daily for school-age children are safe. Doses of up to 4000 IU vitamin D per day are well tolerated in children over the age of 9 years without signs of intoxication.76 Vitamin D intoxication has not been reported where 25(OH)D concentrations are <220 nmol/L.77 Since there is unequivocal evidence that vitamin D deficiency is common in children with acute wheeze, whatever the reason may be, and good reason to optimise levels for non-respiratory reasons, we recommend measuring levels and supplementing those who are deficient. Whether this as an added bonus will reduce future risk of wheezing attacks awaits further trials.

    Summary and conclusions

    There is conflicting evidence for the use of vitamin D supplementation as adjuvant therapy for the secondary prevention of acute wheeze in school-age children with asthma, and limited evidence for the use of vitamin D to reduce risk of wheezing attacks in preschool children. However, there is evidence that vitamin D reduces the risk of asthma exacerbations in adults, and also reduces the risk of acute respiratory tract infections in preschool and school-age children. There are good in vitro studies which lend biological plausibility for a beneficial effect on acute wheeze. Screening circulating 25(OH)D concentration and maintaining optimal vitamin D status may reduce wheeze risk in preschool and school-age children with a history of acute wheeze. Further studies are needed to ascertain the daily oral dose of vitamin D that is necessary to reach optimal 25(OH)D for the prevention of acute wheeze in children, to examine the efficacy of vitamin D supplementation on incidence and severity of acute wheeze in preschool children and school-age children, and to evaluate the mechanisms of any effect of vitamin D supplementation on the pathogenesis of acute wheeze in both preschoolers and school-age children. One approach to synthesising information from diverse studies would be for a clinical trials group such as the Inner-City Asthma Consortium use existing mechanistic and population-based evidence to construct definitive designs to answer the open questions of greatest interest.78

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    Footnotes

    • Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.