JAMA. Effect of Vitamin D3 Supplementation on Upper Respiratory Tract Infections in Healthy Adults: The VIDARIS Randomized Controlled Trial

[Giuseppe]

[Source: The Journal of the American Medical Association, full text: (LINK). Abstract, edited.]

Original Contribution| October 3, 2012

Effect of Vitamin D<SUB>3</SUB> Supplementation on Upper Respiratory Tract Infections in Healthy Adults: The VIDARIS Randomized Controlled Trial

FREE


David R. Murdoch, MD; Sandy Slow, PhD; Stephen T. Chambers, MD; Lance C. Jennings, PhD; Alistair W. Stewart, BSc; Patricia C. Priest, DPhil; Christopher M. Florkowski, MD; John H. Livesey, PhD; Carlos A. Camargo, MD; Robert Scragg, PhD

Author Affiliations: Department of Pathology, University of Otago, Christchurch (Drs Murdoch, Slow, Chambers, Jennings, and Florkowski), Canterbury Health Laboratories (Drs Murdoch, Jennings, Florkowski, and Livesey), and Department of Infectious Diseases, Christchurch Hospital (Dr Chambers), Christchurch, New Zealand; School of Population Health, University of Auckland, Auckland, New Zealand (Mr Stewart and Dr Scragg); Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand (Dr Priest); and Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Camargo).

JAMA. 2012;308(13):1333-1339. doi:10.1001/jama.2012.12505. Published online


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ABSTRACT

Context

Observational studies have reported an inverse association between serum 25-hydroxyvitamin D (25-OHD) levels and incidence of upper respiratory tract infections (URTIs). However, results of clinical trials of vitamin D supplementation have been inconclusive.


Objective

To determine the effect of vitamin D supplementation on incidence and severity of URTIs in healthy adults.


Design, Setting, and Participants

Randomized, double-blind, placebo-controlled trial conducted among 322 healthy adults between February 2010 and November 2011 in Christchurch, New Zealand.


Intervention

Participants were randomly assigned to receive an initial dose of 200 000 IU oral vitamin D<SUB>3</SUB>, then 200 000 IU 1 month later, then 100 000 IU monthly (n = 161), or placebo administered in an identical dosing regimen (n = 161), for a total of 18 months.


Main Outcome Measures

The primary end point was number of URTI episodes. Secondary end points were duration of URTI episodes, severity of URTI episodes, and number of days of missed work due to URTI episodes.


Results

The mean baseline 25-OHD level of participants was 29 (SD, 9) ng/mL. Vitamin D supplementation resulted in an increase in serum 25-OHD levels that was maintained at greater than 48 ng/mL throughout the study. There were 593 URTI episodes in the vitamin D group and 611 in the placebo group, with no statistically significant differences in the number of URTIs per participant (mean, 3.7 per person in the vitamin D group and 3.8 per person in the placebo group; risk ratio, 0.97; 95% CI, 0.85-1.11), number of days of missed work as a result of URTIs (mean, 0.76 days in each group; risk ratio, 1.03; 95% CI, 0.81-1.30), duration of symptoms per episode (mean, 12 days in each group; risk ratio, 0.96; 95% CI, 0.73-1.25), or severity of URTI episodes. These findings remained unchanged when the analysis was repeated by season and by baseline 25-OHD levels.


Conclusion

In this trial, monthly administration of 100 000 IU of vitamin D did not reduce the incidence or severity of URTIs in healthy adults.


Trial Registration anzctr.org.au Identifier: ACTRN12609000486224
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[Vibrant62]

Re: JAMA. Effect of Vitamin D3 Supplementation on Upper Respiratory Tract Infections in Healthy Adults: The VIDARIS Randomized Controlled Trial

It is extremely odd that a monthly dose was used. Supplementation is generally daily - the half life of vitamin D is too short for this to be effective.

 

[Gert van der Hoek]

Re: JAMA. Effect of Vitamin D3 Supplementation on Upper Respiratory Tract Infections in Healthy Adults: The VIDARIS Randomized Controlled Trial

Recommended intake for vitamin D?

The mean baseline 25-OHD level of participants in the study mentioned in post #1 was 29 (SD, 9) ng/mL (= 72,5 nmol/l).

Vitamin D supplementation resulted in an increase in serum 25-OHD levels that was maintained at greater than 48 ng/mL (= 120 nmol/l) throughout the study.

In the US the national 25(OH)D mean was 55.6 nmol/l, according to a CDC-report in april 2012.

The IOM set the sufficiency bar at 20 ng/ml (50 nmol/l), this is what many countries advice.

In Sweden levels between 75-250 nmol/L are regarded as normal, and below 75 is considered a deficiency.

Question remains: what is normal?

This study says:

From these recent studies, it is obvious that we no longer have to guess what a deficient level of circulating 25(OH)D should be in a human subject. Clearly, there is no known harmful effect of maintaining a circulating 25(OH)D level of at least 80 nmol/L, but there are serious risks encountered at levels less than this.

This studie may give us another clue:

Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l.

So maybe your vitamin D level should be at least 80 nmol/l, or even 100 nmol/l or more?

What could this mean for recommended intake for vitamin D?

Current recommendation in the US:

For deficiency, at least 1,000 IU (25 micrograms) of vitamin D has been taken by mouth daily (or 8,400 IU of vitamin D3 weekly).

May be it should be at least 2000 IU/d for adults, some say 4000 or 5000 IU/d from september to april in western countries.


This is not a medical advice, ask your doctor.

 

[Emily]

Re: JAMA. Effect of Vitamin D3 Supplementation on Upper Respiratory Tract Infections in Healthy Adults: The VIDARIS Randomized Controlled Trial

I think they might have gone with a monthly megadose so they could be sure people took the vitamin, (assuming the participant came to a clinic for their pills and a blood draw once a month.) But it didn't seem to raise serum levels all that much. The conclusions seem valid as far as showing that supplementing in this way to these rather low blood levels didn't prevent URTI's.

 

[Vibrant62]

Re: JAMA. Effect of Vitamin D3 Supplementation on Upper Respiratory Tract Infections in Healthy Adults: The VIDARIS Randomized Controlled Trial

Whilst Vitamin D has a half life @2m, Hydroxy vitamin D3 (used in this study) has a half life of only 15 days ... and on reading the full paper, the authors acknowledge that they may get different results with a daily regimen. Agreed that the target serum levels were also rather low.
http://www.ncbi.nlm.nih.gov/pubmed/18689406

I think that this study's findings need validation via a similar trial with a daily supplemental regimen to produce a higher serum level (more akin to optimal Vitamin D levels, or potentially across a range of dosages) to contrast and compare results and findings.

IMHO the study design is perhaps questionable. It would also be beneficial to have a study arm of non-healthy adults, possibly individuals with chronic disease (and whose immune systems are under continual 'stress') for whom this intervention could make a positive difference.

 

[Emily]

Re: JAMA. Effect of Vitamin D3 Supplementation on Upper Respiratory Tract Infections in Healthy Adults: The VIDARIS Randomized Controlled Trial

Here's another study of a different health issue that indicates infrequent dosing, (this time once a year), can be worse than ineffective.

The reason for studying this is valid since the targeted group are women who aren't good candidates for taking vitamin D on a daily basis. The problem is when media outlets take research like this and misinterpret the conclusions and tell people to throw away their vitamin D supplements.

http://jama.jamanetwork.com/article.aspx?articleid=185854

Original Contribution | May 12, 2010
Annual High-Dose Oral Vitamin D and Falls and Fractures in Older WomenA Randomized Controlled Trial FREE
Kerrie M. Sanders, PhD; Amanda L. Stuart, BappSc; Elizabeth J. Williamson, MA, PhD; Julie A. Simpson, PhD; Mark A. Kotowicz, MBBS, FRACP; Doris Young, MD, MBBS, FRACGP; Geoffrey C. Nicholson, PhD, FRACP
[+] Author Affiliations
JAMA. 2010;303(18):1815-1822. doi:10.1001/jama.2010.594.
Text Size: A A A

Context Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.

Objective To determine whether a single annual dose of 500 000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.

Design, Setting, and Participants A double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.

Intervention 500 000 IU of cholecalciferol or placebo.

Main Outcome Measures Falls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.

Results Women in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.

Conclusion Among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.

 

[Vibrant62]

Re: JAMA. Effect of Vitamin D3 Supplementation on Upper Respiratory Tract Infections in Healthy Adults: The VIDARIS Randomized Controlled Trial

It is a common problem with vitamin studies, and I have to admit that I question the purpose of the dosage rationale in study design in this case, especially given the half life of the D3 variation being studied. That said there are no conflicts of interest reported for this study.

Another prime example of poor study design is Vitamin E studies, especially meta-analyses which compile results from different tocopherols (these are chemically different versions) at different dosage regimens. It would not be acceptable for a drug study so I fail to understand why it is apparently acceptable for studies of the effects, benefits and risks of Vitamins.

As you rightly point out, the anti 'natural health' lobby and media seize on all such results. Sadly even the BBC had a report that it ran that was used in exactly this way that was also inaccurate (suggested that the study looked at daily supplementation rather than monthly). I did submit an error report to them but their article remains unchanged. http://www.bbc.co.uk/news/health-19790545

 

[Gert van der Hoek]

Re: JAMA. Effect of Vitamin D3 Supplementation on Upper Respiratory Tract Infections in Healthy Adults: The VIDARIS Randomized Controlled Trial

No "cytokine storm", if your vitamine D level is high enough? Have a lot of vitamine D if you have flu? How much? VitD level should be 100 nmol/l+ ?

See also this thread: Cytokine Storm & Vitamin D relationship?


Eur J Nutr. 2012 Sep 27.

Calcitriol [1, 25[OH]2 D3] pre- and post-treatment suppresses inflammatory response to influenza A (H1N1) infection in human lung A549 epithelial cells.

PURPOSE:
Influenza viruses infect airway epithelial cells, causing respiratory distress. Immune defense is maintained by chemokine/cytokine secretions from airway epithelial cells. While moderate inflammatory response protects from ill effects, hyper-inflammatory response promotes the pathogenesis. High circulating levels of vitamin D are known to mitigate effects of infectious diseases, including respiratory infectious diseases. The question whether and how vitamin D treatment pre-/post-viral exposure modulates inflammatory response is not clear. The present study was undertaken to understand autophagy/apoptosis balance and chemokine/cytokine response to influenza A (H1N1) infection by pre- and post-1, 25-dihydroxyvitamin D3 (1,25[OH]2 D3)[calcitriol] treatment of human lung A549 epithelial cells.

METHODS:
Influenza A (H1N1) virus was propagated in A549 cell line, titrated using hemagglutination assay, and was used to assess effect of calcitriol. After confirming that 100 nM of calcitriol fails to clear virus, A549 cells were either pre-treated (16 h) with 100 nM or post-treated with 30 nM of 1,25[OH]2 D3 of virus inoculation (1 h). Cells after incubation at 37 ?C under 5 % CO2 for 48 h were collected and subjected to RNA and protein extraction. Measurements of viability, influenza M protein, and molecular parameters of cell death and inflammatory response were performed.

RESULTS:
We report that treatment of these cells with 100/30 nM of 1,25[OH]2 D3 prior to/or post-H1N1 exposure does not affect viral clearance but significantly reduces autophagy and restores increased apoptosis seen on H1N1 infection back to its constitutive level. However, it significantly decreases the levels of H1N1-induced TNF-α (tumor necrosis factor-alpha), IFN-β (interferon-beta), and IFN-stimulated gene-15 (ISG15). 1,25[OH]2 D3 treatment prior to/or post-H1N1 infection significantly down-regulates IL-8 as well as IL-6 RNA levels. These results demonstrate that calcitriol treatment suppresses the H1N1-induced transcription of the chemokines RANTES and IL-8 in epithelial cells.

CONCLUSION:
The findings provide support for the initiation of vitamin D supplementation program to VDD populations in reducing the severity of influenza.

 

[Gert van der Hoek]

Re: JAMA. Effect of Vitamin D3 Supplementation on Upper Respiratory Tract Infections in Healthy Adults: The VIDARIS Randomized Controlled Trial

J Aging Res. 2012; 2012: 806198.

Published online 2011 November 15.

Aging Adults and Seasonal Influenza: Does the Vitamin D Status (H)Arm the Body?


Conclusion

Influenza infection remains a major public health concern across the world. The overall body of evidence suggests that older adults are more prone to be infected by influenza virus.

While influenza prevention strategies are mainly based on immunization, current influenza vaccines do not offer optimal protection in this population due, in part, to waning immunity.

Even if VitD has profound effects on immunity and clinical and epidemiological data suggest that VitD insufficiency increases susceptibility to influenza infection, there is not yet sufficient information to clarify the true relationship between VitD status and host resistance or influenza vaccine immunogenicity.

It is, therefore, premature at this time to recommend ?booster? VitD supplementations at the beginning of annual influenza seasons in order to prevent infection in the elderly population.

However, assessing VitD status and maintaining optimal serum levels should be considered in all ageing and old adults in order to prevent bone and promote healthy ageing.

 

[Emily]

Re: JAMA. Effect of Vitamin D3 Supplementation on Upper Respiratory Tract Infections in Healthy Adults: The VIDARIS Randomized Controlled Trial

I think the rationale behind the hope that annual or monthly megadosing of vitamin D would be beneficial might be based on the belief that vitamin D can be stored by the body.

http://medschool.creighton.edu/fileadmin/user/medicine/Departments/Medicine/Endocrinology/ORC/Vitamin_20D_20for_20website_MOD_2.pdf

How long is vitamin D stored in the body?
Vitamin D is a fat soluble chemical compound and when present in large quantities, it is stored in body fat. It can reside there for months, gradually being released into the blood stream. But at prevailing intakes there probably is little or no storage of vitamin D per se. It appears to be converted almost immediately to 25(OH)D, which circulates in the blood and is relatively rapidly used. If I take in more vitamin D today than my body needs today, then I will store the excess. Chances are, there will be days when I will not be getting as much as I need. So some storage seems a good idea. For example, outdoor summer workers get more than they need every day from the sun, but by the end of winter, they have used up all their reserves and are typically in a state of mild deficiency

I wonder if this could be the case only for vit D produced from sunlight exposure?

Here's what Harvard School of Public Health suggests based on the disappointing annual megadose study results:

http://www.hsph.harvard.edu/nutritionsource/what-should-you-eat/super-high-dose-vitamin-d/index.html

So what is the significance of this study for people who want to take vitamin D supplements? A reasonable conclusion would be to continue taking moderate doses of vitamin D regularly, since these have a strong safety record, but to avoid extremely high single doses. This recent finding does present a challenge to scientists who will work to understand why the extreme single dose appears to have adverse effects.