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Vitamin D and asthma: a case to answer
PDPI Sulawesi Selatan & Utara, 12 Okt 2017 15:15:22
Vitamin D and asthma: a case to answer

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The role of vitamin D in human health is an enigma. Associations have been reported between low serum concentrations of 25-hydroxyvitamin D (25[OH]D) and a wide range of disorders and diseases, including (but not limited to) cancer, cardiovascular disease, metabolic disorders, infectious diseases, autoimmune diseases, pregnancy-related outcomes, skeletal disorders, respiratory disease, multiple sclerosis, mental health disorders, and inflammation, as well as mortality.1, 2 If causal, these associations would suggest that vitamin D deficiency can cause a substantive burden of disease and mortality, particularly in populations in which vitamin D deficiency is prevalent, and that supplementation with vitamin D could have widespread therapeutic benefits. However, the highly promising results identified from observational studies have either not been tested or not replicated in most of the randomised controlled trials.1, 2 The discrepancy between observational and intervention studies suggests that low 25(OH)D might be a marker of poor health, possibly related to the inflammatory processes involved in disease occurrence and clinical course, which would reduce 25(OH)D levels.

It was against this background that a Cochrane systematic review and meta-analysis3 of double-blind randomised placebo-controlled trials of the effect of vitamin D supplementation on asthma outcomes was published in 2016. The review3 reported that administration of vitamin D reduced the rate of exacerbations requiring treatment with systemic corticosteroids by 37% (rate ratio [RR] 064, 95% CI 046090; 680 participants across three studies). Because the analysis3 was not based on individual participant data, it was not possible to determine whether a difference in efficacy existed with respect to specific patient characteristics such as baseline vitamin D levels, which might enable targeted treatment. This question has now been investigated by the same research group in a systematic review and metaanalysis4 based on individual participant data published in The Lancet Respiratory Medicine, with particular interest as to whether the protective effect with vitamin D supplementation is strongest in participants with low blood 25(OH)D concentrations. The 25 nmol/L cutoff for baseline 25(OH)D concentrations was selected because it is the threshold for vitamin D deficiency and the level below which vitamin D supplementation protected most strongly against acute respiratory infection in another meta-analysis of individual participant data.5 In this new review in people with asthma, David Jolliffe and colleagues4 reported a similar reduction in the rate of exacerbations requiring treatment with systemic corticosteroids (adjusted-incidence RR 069, 052092; p=001) among 719 participants in the four studies included in the two-step individual participant data meta-analysis. The analyses4 had insufficient power to confidently determine whether the reductions in risk were significantly different between participants with low vitamin D status (67% reduction in risk) versus participants with normal vitamin D status (23% reduction in risk; pinteraction=025), or for that matter, the effect of other characteristics such as age, sex, ethnic group, dosing regimen, body-mass index (BMI), or concomitant use of inhaled corticosteroids on risk. Modelling of the associations between rate of exacerbations requiring treatment with systemic corticosteroids and 25(OH)D concentrations as a continuous covariate to determine if there were step functions might be informative in this regard.

Other methodological issues also need to be considered in the interpretation of these findings.4 None of the four studies in the two-step meta-analysis for the primary outcome of rate of exacerbations requiring treatment with systemic corticosteroids used standardised primary exacerbation variables, with all using different criteria from that used in the meta-analysis. This variation could affect the overall results of the primary outcome of exacerbations depending on which measure is used for the assessment. The study by Martineau and colleagues,6 for example, contributed 48% of the weight of the meta-analysis,4 but their study reported an adjusted hazard ratio of 102 (95% CI 069153) for the co-primary outcome variable of time to first severe asthma exacerbation6 (defined as deterioration in asthma resulting in treatment with oral corticosteroids; hospital admission or emergency department treatment; or decrease in the morning peak expiratory flow rate to more than 25% below the mean run-in value on 2 or more consecutive days), whereas the meta-analysis of the present study4 reported an adjusted-incidence RR of 085 (95% CI 056128) for the primary outcome variable of asthma exacerbation requiring treatment with systemic corticosteroids. The effect of the imputation method used (in which participants who were lost to follow-up before they had an exacerbation were classified as not having an exacerbation) is uncertain, but might lead to both overly precise estimates of differences and potential bias due to differential drop-out.

Certainly there is a case to answer and definitive well powered randomised placebo controlled trials need to be done as a priority because the magnitude of the reduction in risk of severe exacerbations with vitamin D reported in this meta-analysis is substantial. Considering that vitamin D deficiency is prevalent in many countries in which the burden of asthma is high and that vitamin D is a low cost intervention, its supplementation represents a potentially effective, low-cost medication with a favourable safety profile. In addition to determining the efficacy of vitamin D supplementation in asthma, future randomised controlled trials must also be sufficiently powered and designed to identify whether characteristics such as 25(OH)D level, age, sex, BMI, ethnicity, or asthma severity can predict which patients might preferentially respond to treatment, as suggested might be the case in this meta-analysis.4 If true then the specific characteristic of the patient would represent a treatable trait and allow a precision medicine approach to be implemented.7, 8

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RB reports grants from Health Research Council of New Zealand, Roche, and Genentech; and grants and personal fees from AstraZeneca and GlaxoSmithKline, outside of the submitted work. MW declares no competing interests

Articel By : Prof. dr. Tjandra Yoga Aditama, SpP(K), MARS, DTM&H, DTCE

Source : http://www.thelancet.com/journals/lanres/...
Image : http://img4.thelist.com/img/...
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