Serum 25-hydroxyvitamin D and the incidence of acute viral respiratory tract infections in healthy adults.

Issue 2 - Sept 16, 2010
Study of the Month

Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Landry ML. Published in PLoS One. 2010.14;5(6):e11088

Why was the study done?

As distance from the equator increases, serum levels of 25-hydroxyvitamin (25-(OH)D), the storage form of vitamin D, fall during the winter months. Since fall and winter are peak seasons for colds and flu, it has been speculated that higher circulating levels of 25-(OH)D may increase resistance to infection and conversely, lower levels in the winter would increase vulnerability. The study was done to see if there was a link between circulating blood levels of 25-(OH)D and the incidence of acute viral respiratory tract infections.

How was the study carried out?

During the fall and winter of 2009-2010, blood levels of 25-(OH)D were tested monthly in 198 healthy adults, who were not informed as to what substance was being measured in their blood. Investigators tracking the development of any acute respiratory tract infections were not aware of the participants’ serum 25-hydroxyvitamin D concentrations. At the end of the study the incidence of infection in participants with different blood levels of 25-(OH)D was determined.

What were the results?

In this study, those who supplemented with vitamin D, or had light skin pigmentation, and those with lean body mass generally had higher concentrations of 25-(OH)D. Blood levels of 38 ng/ml (about 98 nmol/L) had a significantly reduced risk (p<0.0001) of developing acute respiratory tract infections, and a marked reduction in the percentages of days ill.

What conclusions did the researchers come to?

By maintaining a blood level of 25-(OH)D of around 100 nmol/L or higher, those living in temperate zones could significantly reduce colds and flu during the fall and winter. The researchers call for future studies examining the efficacy of vitamin D supplementation to reduce the incidence and severity of specific viral infections, including influenza, in the general population. They also suggest that those known to have generally lower circulating levels of 25-(OH)D such as pregnant women, dark skinned individuals, and the obese might be particularly helped by supplementation.


The findings of this study confirm what vitamin D researchers have long suspected: It is not just coincidence that we suffer more from coughs and colds during the winter months. Increased susceptibility is likely to be related to the fact that circulating blood levels of vitamin D plummet as summer memories fade and winter sets in.

This was an observational study done in adults, and the researchers have not yet confirmed their hypothesis in intervention studies, where the effect of supplementing vitamin D over the winter months is compared with placebo to see if vitamin D supplements reduce risk of winter colds and flu in healthy adults. However, other recent studies suggest that boosting wintertime vitamin D with supplements above current recommended daily intakes might indeed be beneficial, and is unlikely to be harmful.

Vitamin D supplements prevent seasonal flu in school-age children

A recently published study gave Japanese schoolchildren either 1200 IU vitamin D3 or placebo from Dec ‘08 – March ’09 and tracked the incidence of seasonal influenza A.1 The diagnosis of flu was correctly made – that is, in the laboratory – by examining nasal swabs for evidence of the virus. This is important, as so often a diagnosis of flu is made based on the presence of symptoms alone. And since the symptoms of flu may be confused with those of colds or allergy, it is critical in this type of research that an accurate laboratory diagnosis is made.

In this study, Influenza A occurred in 18/167 (10.8%) of the children on vitamin D(3) supplements compared with 31/167 (18.6%) on placebo. As a secondary outcome, children included in the study who also suffered from asthma were followed to see if supplementing with vitamin D had any positive effect on the number and severity of asthma attacks over the winter. They found a significant reduction in asthma exacerbations among children taking the vitamin D supplements.

Vitamin D and innate immunity

So how might vitamin D work to protect against colds and flu? In healthy individuals, immune cellspatrol tissues,seeking out pathogens. This is our first line of defence against infection and is known as the innate immune response. Molecules on the surface of immune cells – toll-like receptors – sense the presence of strings of amino acids common to a wide range of potentially infective organisms, but foreign to our own tissues. Innate immunity is particularly important to enable us to fight viruses like Clostridium difficile and other microbes to which we have not previously been exposed.  The presence of toll-like receptors on the surface of our cells depends on adequate vitamin D stores. 2

Clostridium difficile-associated diarrhea is an increasingly common infection often first encountered in a hospital setting. It can be difficult to control.  A recent study among hospitalized patients with confirmed C. difficile infections showed that infected patients were less likely to clear the infection within 30 days when they had low vitamin D levels. Moreover, mortality rates from any cause were also higher – there was a 56% increase in mortality in patients with low vitamin D compared with 33% for those with serum 25(OH)D levels of 21 ng/dL (52 nmol/L) or above.

The study was presented recently as an abstract at a meeting (Digestive Disease Week 2010). So the findings should be considered preliminary until the full paper is published in a peer-reviewed journal. The effect of supplementing patients with low vitamin D and recovery from C. difficile infection also remains to be seen.

Other nutrients are required for a healthy immune response

Following activation of the innate immune response by vitamin D dependent mechanisms, other nutrients such as the antioxidant vitamins A, C and E, and the minerals manganese, selenium and zinc also come into play.

Once a pathogen is identified, the immune system begins the elaborate process of disabling and eliminating it. First the pathogen is engulfed and ingested by immune cells (phagocytes), and then it is killed by rapid bursts of free radicals, also known as reactive oxygen species (ROS). As well as disarming invading pathogens ROS also injure host tissues, and this produces the nasty symptoms of flu – the sore throat and achy joints.3 If left unchecked the ROS response also damages immune cells, prolonging symptoms.4 The antioxidant vitamins and minerals work synergistically to neutralize free radicals,5 and good tissue stores of antioxidants are therefore needed to prevent such tissue injury.6

There are some interesting studies from the late 1980s where the transmission of influenza between family members over the winter months was tracked. What these studies showed was that not everyone who gets a virus ends up sick. Some individuals, although shown to be infected and harbouring the virus managed to remain symptom free.7 One has to wonder if these individuals were lucky enough to have higher tissue stores not only of vitamin D, but also antioxidants.

Are higher than recommended doses of vitamin D safe in pregnancy?  

Pregnant women are vulnerable to infection during pregnancy, and it has been suggested that intakes of vitamin D higher than recommended might be helpful for mother and baby. But the issue is controversial and raises issues of safety. The Canadian Paediatric Society suggests pregnant women take 2000 IU of vitamin D daily, while the American Academy of Pediatrics recommends 200 IU a day, a 10-fold difference. But are higher levels safe? Recent research suggests they are not only safe but prevent many complications of pregnancy.

Carol Wagner, MD, of the Medical University of South Carolina in Charleston and colleagues enrolled 494 pregnant women in a randomized trial of three daily doses of the vitamin – 400, 2,000, and 4,000 IU a day – to see if higher doses reduced complications of pregnancy,8 and also to test the safety of each dose. Not only were all doses shown to be safe, but the highest dose – 4000 IU per day – was associated with reduced rates of pre-term labor, pre-term birth and infection, as well as higher blood levels of vitamin D levels in the newborns. According to Carol Wagner, pregnant women can safely take 4,000 International Units a day and would benefit from so doing.   


1. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Urashima M et al. Am J Clin Nutr. 2010 May;91(5):1255-60

2. 1-alpha-calcidol modulates major human monocyte antigens and toll-like receptors TLR 2 and TLR4 in vitro. Scherberich JE, Kellermeyer M, Ried C, Hartinger A. Eur J Med Res. 2005 Apr 20;10(4):179-82

3.  Herman Award Lecture, 1995: infection-induced malnutrition–from cholera to cytokines. Beisel WR. Am J Clin Nutr.1995 Oct;62(4):813-9.

4. Reactive oxygen species in immune responses. Grisham MB. Free Radic Biol Med. 2004 Jun 15;36(12):1479-80.

5. Increased antioxidant capacity in healthy volunteers taking a mixture of oral antioxidants versus vitamin C or E supplementation. Lara-Padilla E et al. Adv Ther. 2007 Jan-Feb;24(1):50-9

6. Effects of dietary antioxidants on the immune function of middle-aged adults. Hughes DA. Proc Nutr Soc.1999 Feb;58(1):79-84.

7. Influenza B in households: virus shedding without symptoms or antibody response. Foy HM et al. Am J Epidemiol. 1987;126(3):506-15

8. Wagner CL et al. “Vitamin D supplementation during Pregnancy Part I, NICHD/CTSA Randomized Clinical Trial (RCT): Safety Considerations” PAS 2010; Abstract 2630.7

Note: Articles or commentary in this newsletter are not intended as medical advice. Please check with your doctor if you have a concern about your health.
©2011 Aileen Buford-Mason. All rights reserved.


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