key: cord-276130-wjnwpn8f
authors: Bradley, Ryan; Schloss, Janet; Brown, Danielle; Celis, Deisy; Finnell, John; Hedo, Rita; Honcharov, Vladyslav; Pantuso, Traci; Pena, Hilda; Lauche, Romy; Steel, Amie
title: The effects of Vitamin D on acute viral respiratory infections: a rapid review
date: 2020-08-03
journal: Adv Integr Med
DOI: 10.1016/j.aimed.2020.07.011
sha: 
doc_id: 276130
cord_uid: wjnwpn8f

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from a variety of dosing strategies. Future clinical trials on vitamin D should consider the sources of heterogeneity in the existing experimental research and design trials that account for baseline status, evaluate the potential for prevention and treatment in at risk populations, standardize dosing strategies, assess product quality, assess outcomes according to gold standard definitions/diagnostic methods, and delineate viral ARTI from other causes when possible. The available mechanistic evidence related to immunological requirements for adequate vitamin D, the availability of observational and experimental evidence suggestive of clinically meaningful benefits (especially in deficient/insufficient participants), and the high margin of safety, should make vitamin D a high priority for additional clinical research during the current COVID-19 pandemic.

Vitamin D, is a fat-soluble, secosteroidal hormone available to humans in the diet, nutritional supplements, and via direct production in the skin upon exposure to adequate ultraviolet light. Vitamin D has numerous fundamental functions in the innate and acquired immune response. Activation of both T-and B-cells leads to upregulation of the vitamin D receptor (VDR), allowing for changes in expression of over 500 vitamin D related genes.[1-3] Select mechanistic effects of Vitamin D on immune function include: enhancement of chemotaxis and phagocytosis [4] , regulation of antibody production in B cells [5] , inhibition of interleukin (IL)-2, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha IL-9, and IL-22 [6] [7] [8] [9] [10] , and increased IL-3, IL-4, IL-5, and IL-10. [11] Observational research in the British Birth cohort has demonstrated significant linear relationships between serum vitamin D concentration (i.e., 25hydroxycholecalciferol or 25-OHD) and lower risk of acute respiratory tract infection (ARTI), with each 10 nmol/L increase associated with a 7% lower risk. [12] Further observational research in the United States (US)-based National Health and Nutrition Examination Survey (NHANES) 2001-20016 suggested those with insufficient serum status (25-OHD<30 nmol/L [<20 ng/ml]) had 58% higher odds of ARTI. [13] Based on the numerous roles of vitamin D in the regulation of immune function, and notable observational research suggesting potential effects on ARTI, numerous randomized controlled trials in adults and children have aimed to learn the direct effects of vitamin D on risk of ARTI and their potential complications. The purpose of this rapid review is to summarize available systematic reviews of randomized, controlled clinical trials of vitamin D on ARTI and related outcomes.

What are the effects of Vitamin D on acute respiratory tract infections (ARTI) and associated complications? Inclusion/exclusion criteria Reviews were included if they were described as "systematic" and exhibited methods consistent with systematic reviews (i.e., defined clinical question, detailed search protocol, etc.) and reported on human prospective intervention trials sampling adults and/or children with reported ARTI. Reviews were excluded if they were designed as narrative J o u r n a l P r e -p r o o f reviews, non-review manuscripts, included only observational studies, and/or the study sample was not reported as diagnosed with ARTI.

Medline (OVID), Embase (OVID), AMED (OVID), and CINAHL Search terms (example) Five search strategies were pursued and compiled as follows: Coronavirus/ or respiratory tract infections/ or bronchitis/ or common cold/ or Pneumonia, Viral/ or (Coronavir* or nCov or Influenza or H1N1 or MERS-COV or flu or Bronchit* or cough or rhinosinusit* or rhinit* or common cold or (respiratory adj2 (infect* or illness or symptom* or acute or virus* or disease))).ti,ab,kw.

#2: exp Vitamin D/ or exp Calcitriol/ or exp Cholecalciferol/ or exp Ergocalciferol/ or exp 25-hydroxyvitamin d 2/ or ("Vitamin d$" or "Vit d" or Calcitriol$ or Cholecalciferol or Ergocalciferol or "25-Hydroxyvitamin D 2").ti,ab,kw #3: Systematic Review/ or Meta-analysis/ or Systematic Review as Topic/ or Meta-Analysis as Topic/ or Review Literature as Topic/ or (Systematic review or meta analy$ or metaanaly$).ti,ab,kw #4: comment/ or letter/ or editorial/ #5: (#1 AND #2 AND #3) NOT #4 Screening Titles and abstract screening and full text screening were completed by one reviewer and checked for accuracy by a second reviewer. Similarly, data extraction was completed by a single reviewer and checked for accuracy by a second reviewer. Any discrepancies were resolved by consensus.

The critical appraisal tool for this rapid review was performed using the BMJ Best practice criteria for appraising systematic reviews (https://bestpractice.bmj.com/info/toolkit/learn-ebm/appraising-systematic-reviews/).

The initial search resulted in 270 citations [Medline (n=57), Embase (n=154), AMED (n=1), and CINAHL (n=58)], after duplicates (n=68) were removed, 202 remained for title and abstract screening. Based on title and abstract review, an additional 138 manuscripts were excluded as irrelevant due methodology (i.e., editorials, commentaries, and/or nonsystematic reviews), or broad outcome measures (i.e., not focused on ARTI outcomes). Following abstract review, 36 manuscripts were excluded by full text screening due to methodological limitations not apparent in the abstracts (i.e., narrative reviews), leaving 28 manuscripts for detailed extraction. During detailed data extraction, 5 additional manuscripts were excluded due to inclusion of only observational studies, plus 3 additional exclusions included: an editorial (n=1), a poster citation (n=1), and a duplicate republished as a report (n-=1), leaving 20 for the final detailed J o u r n a l P r e -p r o o f extraction; see Figure 1 . All citations were imported into Covidence software (Melbourne, Australia) for title and abstract reviews. Full texts were also imported into Covidence for review and data extraction upon finalization of the manuscripts meeting inclusion criteria.

From the appraisal, seven of the 20 reviews met all the requirements. The majority of the studies met most of the criteria in the appraisal tool, however, three reviews were determined to be very poor quality because they met four or fewer of the requirements. The quality of data from these reviews [14] [15] [16] in our conclusions and summaries.

See Table 1 for a summary of all included studies in the final, detailed review. Of the 20 studies, 13 were systematic reviews and/or of meta-analysis [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] , 3 were systematic reviews of randomised controlled trials (RCTs)[28-30], 2 were systematic reviews of various studies [14, 31] and 1 was a detailed narrative review of RCTs (and therefore was included), despite low formal quality of design [15] . The 2 systematic reviews with various studies included RCTs, cohort studies, case-control series, retrospective case studies and cross-sectional studies [14, 31] . The majority of reviews searched 3 or more databases with Pubmed, Embase, Cochrane, Cinahl and Medline being the main ones [15, [17] [18] [19] [20] [21] [22] [23] [25] [26] [27] [28] [29] [30] [31] [32] . Two studies only used one database, Pubmed [14, 33] and 1 didn't specify the databases searched [16] .

The study population and size, type of respiratory condition, form and dose, and administration route or screening of vitamin D varied across the studies reviewed. Fourteen studies included all populations including children, adults and elderly [14-18, 20, 22, 23, 26-30, 32 ] and 5 reviews were conducted on children only [19, 21, 24 , 31], 1 was for pregnant women and children [25] and 1 for children and young men [33] . The number of studies included for the reviews on children included 26 in total, encompassing 12 RCTs, 3 cohort, 2 cross-sectional and 9 case-control studies [19, 21, 24, 31] . The pregnancy and children review contained 22 studies including 4 RCTs and 18 observational [25] while the children and young men review contained 10 RCTs [33] . For the studies that included all populations, 222 studies were identified in the reviews. These included 171 RCTs, 24 cohort studies, 8 case-control studies and 4 crosssectional [14-18, 20, 22, 23, 26-30, 32 ] .

The 7 reviews which mainly focused on children comprised a total sample of 33,503 participants; of those reviews that reported allocation, there were 6,474 participants in intervention arms and 6,464 participants in placebo arms [19, 21, 

The reviews exclusive to children all used oral administration of vitamin D with 4 reviews reporting on administration of a dose ranging from 300 IU -2000 IU per day [19, 21, 24, 31] . In the 2 reviews exclusive to pregnant women plus children and young men plus children, the dose ranged from 800 IU-2000 IU daily [25, 33] . The oral doses for vitamin D in the reviews of all ages varied dramatically from 100 IU to 100,000 IU. See Table 2 for dosage range included in each review.

The measurement outcomes from the reviews varied; however, the primary outcome measure evaluated for this review was the incidence of ARTIs (n=13) [14, 15, 17, 18, 20-23, 25, 27-29, 31 ]. The other main outcome measures included were: the association between vitamin D levels and ARTI risk (5 reviews) [16, 26, 32 , 33], pneumonia incidence (3 reviews) [14, 19, 24] , and frequency of hospitalization rates (2 reviews) [14, 24] . Several individual reviews reported additional, less specific, outcomes including: frequency of doctor visits, [25], asthma exacerbations

[25], incidence of influenza [14] , tuberculosis [15] and extra-skeletal disease [30] .

Of the 21 reviews, 15 concluded vitamin D was safe and has the potential reduce the risk of ARTI [15-18, 22, 23, 25, 27, 29-33] . The other 6 reviews each concluded that there was insufficient evidence to support the protective effect of vitamin D for ARTIs [14, 19-21, 24, 28 ] .

Reviews Supporting a Protective Effect of Vitamin D and ARTI. Clinical significance:

Despite several positive systematic reviews and meta-analyses, the available experimental evidence related to the effects of vitamin D on acute respiratory tract infection (ARTI) is plagued with heterogeneity and mixed quality, and therefore is insufficient to recommend vitamin D supplementation to the general population as a protective agent against ARTI. However, based on the evidence identified in this rapid review (including a high margin of clinical safety), combined with strong mechanistic rationale, the following recommendations can be made for those at risk of ARTI: 1.

vitamin D status should be tested for those at risk of ARTI; 2. patients identified with deficiency or insufficiency should be supplemented with vitamin D until their status is normalized; and 3. daily dosing of vitamin D3 is preferred to 

1 alpha,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells

Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation

The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells

Vitamin D: modulator of the immune system

An update on vitamin D and human immunity

Mechanisms underlying the effect of vitamin D on the immune system

The vitamin D analog, TX527, promotes a human CD4+CD25highCD127low regulatory T cell profile and induces a migratory signature specific for homing to sites of inflammation

Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions

Vitamin D in autoimmune, infectious and allergic diseases: a vital player?

Lineage-specific effects of 1,25-dihydroxyvitamin D(3) on the development of effector CD4 T cells

25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells

Vitamin D status has a linear association with seasonal infections and lung function in British adults

Vitamin D status and acute respiratory infection: cross sectional results from the United States National Health and Nutrition Examination Survey

Vitamin D in the prevention of acute respiratory infection: A systematic review of clinical studies

Vitamin D and Susceptibility to Infection

Vitamin D supplementation beyond the second year of life: Joint statement of the Nutrition Committee of the German Society for Pediatric and Adolescent Medicine (DGKJ) and the German Society for Pediatric Endocrinology and Diabetology (DGKED)

Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

Non-skeletal health effects of vitamin D supplementation: A systematic review on findings from meta-analyses summarizing trial data

Vitamin D and lower respiratory tract infection in children: A systematic review and meta-analysis of randomized controlled trials

Effect of Vitamin D3 Supplementation on Respiratory Tract Infections in Healthy Individuals: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Vitamin D supplementation for the prevention of childhood acute respiratory infections: a systematic review of randomised controlled trials. The British journal of nutrition

SR=systematic review, MA=meta-analysis, RCT=randomized clinical trial, ARTI=acute respiratory tract infection, URTI= upper respiratory tract infection, LRTI=lower respiratory tract infection


