Vitamin D and influenza
Encyclopedia
Numerous studies link vitamin D
and influenza
, as well as vitamin D and respiratory infections more generally. This vitamin up-regulates genetic expression of various endogenous antimicrobial peptides
(AMP), which exhibit broad-spectrum microbicidal activity against bacteria, fungi, and viruses. Reports discussed below indicate that susceptibility to influenza is reduced with higher levels of sun exposure or vitamin D supplementation. Seasonal variation of vitamin D levels in humans can help explain the seasonality of flu epidemics.
and colleagues have suggested that vitamin D deficiency
is a major risk factor
for influenza and that vitamin D may be effective in reducing influenza incidence and severity.
In both publications, the authors concluded that physiological doses of vitamin D (5,000 International Units (IU)
/day for adults and 1,000 IU/day for every 25 pounds of body weight
in children) might reduce the incidence of influenza, and proposed that pharmacological doses (2,000 IU/kg/day for 3–4 days) may have a treatment effect in influenza. The authors present epidemiological evidence suggesting that the seasonality of vitamin D deficiency may explain the seasonality of influenza epidemics and that the epidemiology of vitamin D deficiency may help explain the confusing epidemiology of influenza.
However, the seasonality of influenza may also be explicable by other factors. For example, it has been shown that low absolute humidity favours the survival of the influenza virus.
A study published in the February 2009 Archives of Internal Medicine
involving 1900 adults and children done by the University of Colorado Denver School of Medicine, Massachusetts General Hospital, and Children's Hospital Boston, found that people with the lowest blood vitamin D levels reported having significantly more recent colds or cases of the flu. The risks were even higher for those with chronic respiratory disorders, such as asthma and emphysema. They reported that asthma patients with the lowest vitamin D levels were five times more likely to have had a recent respiratory infection; while among COPD patients, respiratory infections were twice as common among those with vitamin D deficiency. However, the authors stress that the study's results need to be confirmed in clinical trials before vitamin D can be recommended to prevent colds and flu.
A randomized, double-blind, placebo-controlled study published in the March 2010 issue of the American Journal of Clinical Nutrition
reported that those in the group of 167 children taking 1,200 international units of vitamin D3 supplements daily in winter were 42% less likely to get infected with seasonal flu than those who were given a placebo.
lamps, the sun, or from supplements, reduces the incidence of respiratory infections. In 1926, Smiley, who first discovered the strong inverse association between sun exposure
and upper respiratory tract
infections, also first theorized that such seasonality was caused by “disordered vitamine metabolism
in the human. . . directly due to a lack of solar radiation during the dark months of winter.” Dutch children with the least sun exposure were twice as likely to develop a cough, and three times as likely to have a runny nose
, as the children with the most sun exposure.
Furthermore, vitamin D–producing ultraviolet radiation administered twice a week for three years to 410 teenage Russian athletes, compared to 446 non-irradiated athletes, resulted in 50% fewer respiratory viral infections
and 300% fewer days of absences.
(25(OH)D) levels are inversely related to respiratory infections.
Wayse et al compared 80 non-rachitic children with lower respiratory tract
infections to healthy controls and found that the children with the lowest 25(OH)D levels were 11 times more likely to become infected.
Sixty thousand IU of vitamin D per week administered for six weeks to 27 children with frequent respiratory infections resulted in a complete disappearance of such infections for the following six months.
Aloia and Li-Ng, in a post hoc analysis of their original 3-year randomized controlled interventional trial, discovered that 104 African American
women given vitamin D were three times less likely to report cold and flu symptoms than were 104 placebo control subjects (p < 0.002). A very low dose (800 IU/d) for two years abolished the seasonality of reported colds and flu, and even a sub-physiological dose of 2,000 IU/d (40% of treated women still had serum 25(OH)D levels of less than 32 ng/mL after 1 year) for an additional year virtually eradicated all reports of upper respiratory tract infections. However, when the same authors gave 2,000 IU/day for four months in the winter, they found no preventative effect, hypothesizing that the dose and length of study was inadequate to show an effect.
This implies that starting sub-physiological doses of vitamin D, such as 2,000 IU/day, in the late fall and winter will be too little and too late and very recent evidence from Creighton University
indicates 25(OH)D levels of even 30 ng/ml, the levels usually obtained by 2,000 IU/day, often signify chronic substrate starvation, thus the full antimicrobial properties of vitamin D require high physiological serum 25(OH)D levels (44-70 ng/ml) levels, that are reached by about 10% of US
citizens.
More recently, Ginde et al found, using NHANES data, that lower 25(OH)D levels were strongly associated with frequent respiratory tract infection
s and that, in patients with asthma and COPD, the odds ratio was OR, 5.67 and 2.26, respectively. Finnish military
recruits with serum 25(OH)D concentrations < 40 nmol/L had significantly (P = 0.004) more days of absence from duty due to respiratory infection. The same is true of newborns.
and immunoglobulins. In addition, AMPs — such as the potent antimicrobial cathelicidin — trigger tissue repair through activation of epithelial growth and angiogenesis.
Antimicrobial peptides protect mucosal epithelial surfaces by creating a hostile antimicrobial barricade. The epithelia secrete them constitutively into the thin layer of fluid that lies above the apical surface of the epithelium but below the viscous mucous layer. To effectively access the epithelium, a microbe must first infiltrate the mucous barrier and then survive assault by the AMPs present in this fluid. Should microbes breach this constitutive cordon, their binding to the epithelium rapidly mobilizes the expression of high concentrations of specific inducible AMPs such as human β-defensin 2 and cathelicidin, which provide a “backup” antimicrobial shield.
Vitamin D’s pivotal role in innate immunity became known around 2004–2008 First White’s group at McGill University
, then 2 independent groups at the University of California–Los Angeles, showed that activated vitamin D [1,25(OH)2D] dramatically up-regulates genetic expression of AMPs in immune cells
. (For details of the mechanism of action
, see White’s review.) Both epithelial cells
and macrophages increase expression of the antimicrobial cathelicidin upon exposure to microbes — an expression that is dependent upon the presence of vitamin D. Pathogenic microbes, much like the commensals that inhabit the upper airway, stimulate the production of a hydroxylase that converts 25(OH)D to 1,25(OH)2D, a seco-steroid hormone. In turn, this rapidly activates a suite of genes involved in pulmonary defense.
In the macrophage, the presence of vitamin D also suppresses the pro-inflammatory cytokines interferon γ, tumor necrosis factor
α, and interleukin-12
and down-regulates the cellular expression of several pathogen associated molecular pattern (PAMP) receptors. In the epidermis, vitamin D induces additional PAMP receptors, enabling keratinocytes to recognize and respond to microbes. Thus, vitamin D both enhances the local capacity of the epithelium to rapidly produce endogenous antibiotics and, at the same time, dampens certain arms of adaptive immunity, especially those responsible for the signs and symptoms of acute inflammation.
The work of Liu et al is of particular interest. Plasma levels of vitamin 25(OH)D in African Americans, known to be about one half those of light-skinned individuals, are inadequate to fully stimulate the vitamin D—25(OH)D restores the dependent circuits and the expression of cathelicidin. High concentrations of melanin in dark-skinned individuals shield the keratinocytes from the ultraviolet radiation required to generate vitamin D in skin.
Therefore, relative — but easily correctable — deficiencies in innate immunity probably exist in many children during the dark days of winter, with dark-skinned children at highest risk. Black children continue to have twice the rate of mortality from pneumonia of white children, despite modern antibiotics. Furthermore, during any season, for any skin type, and at any latitude, a percentage of the population is vitamin D–deficient, although the percentage is highest in the winter and in dark-skinned individuals, and increases the further poleward the population.
For example, seasonal variation of vitamin D levels even occurs in equatorial Hong Kong
, and widespread vitamin D deficiency occurs at such latitudes, probably because of sun avoidance, rainy seasons, and air pollution
. A study of Hong Kong infants showed that about half had 25(OH)D levels of less than 20 ng/mL in the winter. None of the infants had levels higher than 40 ng/ mL, even in the summer. Thus, a substantial percentage of all children will have impaired innate immunity at any given time, although the impairment is greatest during the dark days of the cold and flu season
.
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
and influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
, as well as vitamin D and respiratory infections more generally. This vitamin up-regulates genetic expression of various endogenous antimicrobial peptides
Antimicrobial peptides
Antimicrobial peptides are an evolutionarily conserved component of the innate immune response and are found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides...
(AMP), which exhibit broad-spectrum microbicidal activity against bacteria, fungi, and viruses. Reports discussed below indicate that susceptibility to influenza is reduced with higher levels of sun exposure or vitamin D supplementation. Seasonal variation of vitamin D levels in humans can help explain the seasonality of flu epidemics.
Recent studies
Recently (2006 and 2008), John CannellJohn Cannell
John Jacob Cannell, M.D. is an American activist, most notably taking a stand on the Vitamin D deficiency epidemic. In the past, he contributed to such areas of public debate as Black Lung legislation, and the problems with educational testing. In recent years, Dr...
and colleagues have suggested that vitamin D deficiency
Hypovitaminosis D
Hypovitaminosis D is a deficiency of Vitamin D. It can result from: inadequate nutritional intake of vitamin D coupled with inadequate sunlight exposure , disorders that limit vitamin D absorption, and conditions that impair the conversion of vitamin D into active metabolites including certain...
is a major risk factor
Risk factor
In epidemiology, a risk factor is a variable associated with an increased risk of disease or infection. Sometimes, determinant is also used, being a variable associated with either increased or decreased risk.-Correlation vs causation:...
for influenza and that vitamin D may be effective in reducing influenza incidence and severity.
In both publications, the authors concluded that physiological doses of vitamin D (5,000 International Units (IU)
International unit
In pharmacology, the International Unit is a unit of measurement for the amount of a substance, based on biological activity or effect. It is abbreviated as IU, as UI , or as IE...
/day for adults and 1,000 IU/day for every 25 pounds of body weight
Body weight
The term body weight is used in daily English speech as well as in the contexts of biological and medical sciences to describe the mass of an organism's body. Body weight is measured in kilograms throughout the world, although in some countries it is still measured in pounds or stones and pounds...
in children) might reduce the incidence of influenza, and proposed that pharmacological doses (2,000 IU/kg/day for 3–4 days) may have a treatment effect in influenza. The authors present epidemiological evidence suggesting that the seasonality of vitamin D deficiency may explain the seasonality of influenza epidemics and that the epidemiology of vitamin D deficiency may help explain the confusing epidemiology of influenza.
However, the seasonality of influenza may also be explicable by other factors. For example, it has been shown that low absolute humidity favours the survival of the influenza virus.
A study published in the February 2009 Archives of Internal Medicine
Archives of Internal Medicine
The Archives of Internal Medicine is a peer-reviewed medical journal published twice a month by the American Medical Association. The Archives of Internal Medicine was established in 1908 and covers all aspects of internal medicine, including cardiovascular disease, geriatrics, infectious disease,...
involving 1900 adults and children done by the University of Colorado Denver School of Medicine, Massachusetts General Hospital, and Children's Hospital Boston, found that people with the lowest blood vitamin D levels reported having significantly more recent colds or cases of the flu. The risks were even higher for those with chronic respiratory disorders, such as asthma and emphysema. They reported that asthma patients with the lowest vitamin D levels were five times more likely to have had a recent respiratory infection; while among COPD patients, respiratory infections were twice as common among those with vitamin D deficiency. However, the authors stress that the study's results need to be confirmed in clinical trials before vitamin D can be recommended to prevent colds and flu.
A randomized, double-blind, placebo-controlled study published in the March 2010 issue of the American Journal of Clinical Nutrition
American Journal of Clinical Nutrition
The American Journal of Clinical Nutrition is a monthly peer-reviewed medical journal in the field of clinical nutrition.According to the Journal Citation Reports, it has a 2009 impact factor of 6.307, ranking it third among 66 journals in the category "Nutrition & Dietetics".The journal was...
reported that those in the group of 167 children taking 1,200 international units of vitamin D3 supplements daily in winter were 42% less likely to get infected with seasonal flu than those who were given a placebo.
Links with ultraviolet radiation
In fact, significant evidence exists that suggests vitamin D, whether from ultraviolet BUltraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
lamps, the sun, or from supplements, reduces the incidence of respiratory infections. In 1926, Smiley, who first discovered the strong inverse association between sun exposure
Sunburn
A sunburn is a burn to living tissue, such as skin, which is produced by overexposure to ultraviolet radiation, commonly from the sun's rays. Usual mild symptoms in humans and other animals include red or reddish skin that is hot to the touch, general fatigue, and mild dizziness. An excess of UV...
and upper respiratory tract
Upper respiratory tract
The upper respiratory tract or upper airway primarily refers to the parts of the respiratory system lying outside of the thorax or above the sternal angle. Another definition commomly used in medicine is the airway above the glottis or vocal cords...
infections, also first theorized that such seasonality was caused by “disordered vitamine metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
in the human. . . directly due to a lack of solar radiation during the dark months of winter.” Dutch children with the least sun exposure were twice as likely to develop a cough, and three times as likely to have a runny nose
Rhinitis
Rhinitis , commonly known as a stuffy nose, is the medical term describing irritation and inflammation of some internal areas of the nose. The primary symptom of rhinitis is nasal dripping. It is caused by chronic or acute inflammation of the mucous membrane of the nose due to viruses, bacteria or...
, as the children with the most sun exposure.
Furthermore, vitamin D–producing ultraviolet radiation administered twice a week for three years to 410 teenage Russian athletes, compared to 446 non-irradiated athletes, resulted in 50% fewer respiratory viral infections
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
and 300% fewer days of absences.
Blood calcidiol levels and respiratory infections
Blood calcidiolCalcidiol
Calcifediol , also known as calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D , is a prehormone that is produced in the liver by hydroxylation of vitamin D3 by the enzyme cholecalciferol 25-hydroxylase...
(25(OH)D) levels are inversely related to respiratory infections.
Wayse et al compared 80 non-rachitic children with lower respiratory tract
Respiratory system
The respiratory system is the anatomical system of an organism that introduces respiratory gases to the interior and performs gas exchange. In humans and other mammals, the anatomical features of the respiratory system include airways, lungs, and the respiratory muscles...
infections to healthy controls and found that the children with the lowest 25(OH)D levels were 11 times more likely to become infected.
Sixty thousand IU of vitamin D per week administered for six weeks to 27 children with frequent respiratory infections resulted in a complete disappearance of such infections for the following six months.
Aloia and Li-Ng, in a post hoc analysis of their original 3-year randomized controlled interventional trial, discovered that 104 African American
African American
African Americans are citizens or residents of the United States who have at least partial ancestry from any of the native populations of Sub-Saharan Africa and are the direct descendants of enslaved Africans within the boundaries of the present United States...
women given vitamin D were three times less likely to report cold and flu symptoms than were 104 placebo control subjects (p < 0.002). A very low dose (800 IU/d) for two years abolished the seasonality of reported colds and flu, and even a sub-physiological dose of 2,000 IU/d (40% of treated women still had serum 25(OH)D levels of less than 32 ng/mL after 1 year) for an additional year virtually eradicated all reports of upper respiratory tract infections. However, when the same authors gave 2,000 IU/day for four months in the winter, they found no preventative effect, hypothesizing that the dose and length of study was inadequate to show an effect.
This implies that starting sub-physiological doses of vitamin D, such as 2,000 IU/day, in the late fall and winter will be too little and too late and very recent evidence from Creighton University
Creighton University
Creighton University is a private, coeducational, Jesuit, Roman Catholic university located in Omaha, Nebraska, United States. Founded by the Society of Jesus in 1878, the school is one of 28 member institutions of the Association of Jesuit Colleges and Universities. The university is accredited by...
indicates 25(OH)D levels of even 30 ng/ml, the levels usually obtained by 2,000 IU/day, often signify chronic substrate starvation, thus the full antimicrobial properties of vitamin D require high physiological serum 25(OH)D levels (44-70 ng/ml) levels, that are reached by about 10% of US
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
citizens.
More recently, Ginde et al found, using NHANES data, that lower 25(OH)D levels were strongly associated with frequent respiratory tract infection
Respiratory tract infection
Respiratory tract infection refers to any of a number of infectious diseases involving the respiratory tract. An infection of this type is normally further classified as an upper respiratory tract infection or a lower respiratory tract infection...
s and that, in patients with asthma and COPD, the odds ratio was OR, 5.67 and 2.26, respectively. Finnish military
Finnish Defence Forces
The Finnish Defence Forces are responsible for the defence of Finland. It is a cadre army of 15,000, of which 8,900 are professional soldiers , extended with conscripts and reservists such that the standard readiness strength is 34,700 people in uniform...
recruits with serum 25(OH)D concentrations < 40 nmol/L had significantly (P = 0.004) more days of absence from duty due to respiratory infection. The same is true of newborns.
Mechanism of action
As far as mechanism, several groups have recently reported that vitamin D dramatically up-regulates genetic expression of various endogenous antimicrobial proteins (AMP), which exhibit broad-spectrum microbicidal activity against bacteria, fungi, and viruses. In general, AMP rapidly damage the lipoprotein membranes of microbial targets, including enveloped viruses such as influenza. Both the epithelium, in which they form a protective shield in mucus, and professional phagocytes, in which they provide microbicidal activity within the phagolysosome, produce AMPs. The innate immune system not only provides direct antimicrobial defense for these “front lines,” but it also signals and primes the adaptive immune system to produce antigen-specific T lymphocytesT cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
and immunoglobulins. In addition, AMPs — such as the potent antimicrobial cathelicidin — trigger tissue repair through activation of epithelial growth and angiogenesis.
Antimicrobial peptides protect mucosal epithelial surfaces by creating a hostile antimicrobial barricade. The epithelia secrete them constitutively into the thin layer of fluid that lies above the apical surface of the epithelium but below the viscous mucous layer. To effectively access the epithelium, a microbe must first infiltrate the mucous barrier and then survive assault by the AMPs present in this fluid. Should microbes breach this constitutive cordon, their binding to the epithelium rapidly mobilizes the expression of high concentrations of specific inducible AMPs such as human β-defensin 2 and cathelicidin, which provide a “backup” antimicrobial shield.
Role in innate immunity
Various forms of vitamin D are secosteroids; i.e., steroids in which one of the bonds in the steroid rings is broken.Vitamin D’s pivotal role in innate immunity became known around 2004–2008 First White’s group at McGill University
McGill University
Mohammed Fathy is a public research university located in Montreal, Quebec, Canada. The university bears the name of James McGill, a prominent Montreal merchant from Glasgow, Scotland, whose bequest formed the beginning of the university...
, then 2 independent groups at the University of California–Los Angeles, showed that activated vitamin D [1,25(OH)2D] dramatically up-regulates genetic expression of AMPs in immune cells
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
. (For details of the mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
, see White’s review.) Both epithelial cells
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
and macrophages increase expression of the antimicrobial cathelicidin upon exposure to microbes — an expression that is dependent upon the presence of vitamin D. Pathogenic microbes, much like the commensals that inhabit the upper airway, stimulate the production of a hydroxylase that converts 25(OH)D to 1,25(OH)2D, a seco-steroid hormone. In turn, this rapidly activates a suite of genes involved in pulmonary defense.
In the macrophage, the presence of vitamin D also suppresses the pro-inflammatory cytokines interferon γ, tumor necrosis factor
Tumor necrosis factor
Tumor necrosis factor is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction...
α, and interleukin-12
Interleukin 12
Interleukin 12 is an interleukin that is naturally produced by dendritic cells, macrophages and human B-lymphoblastoid cells in response to antigenic stimulation.-Gene and structure:...
and down-regulates the cellular expression of several pathogen associated molecular pattern (PAMP) receptors. In the epidermis, vitamin D induces additional PAMP receptors, enabling keratinocytes to recognize and respond to microbes. Thus, vitamin D both enhances the local capacity of the epithelium to rapidly produce endogenous antibiotics and, at the same time, dampens certain arms of adaptive immunity, especially those responsible for the signs and symptoms of acute inflammation.
The work of Liu et al is of particular interest. Plasma levels of vitamin 25(OH)D in African Americans, known to be about one half those of light-skinned individuals, are inadequate to fully stimulate the vitamin D—25(OH)D restores the dependent circuits and the expression of cathelicidin. High concentrations of melanin in dark-skinned individuals shield the keratinocytes from the ultraviolet radiation required to generate vitamin D in skin.
Therefore, relative — but easily correctable — deficiencies in innate immunity probably exist in many children during the dark days of winter, with dark-skinned children at highest risk. Black children continue to have twice the rate of mortality from pneumonia of white children, despite modern antibiotics. Furthermore, during any season, for any skin type, and at any latitude, a percentage of the population is vitamin D–deficient, although the percentage is highest in the winter and in dark-skinned individuals, and increases the further poleward the population.
For example, seasonal variation of vitamin D levels even occurs in equatorial Hong Kong
Hong Kong
Hong Kong is one of two Special Administrative Regions of the People's Republic of China , the other being Macau. A city-state situated on China's south coast and enclosed by the Pearl River Delta and South China Sea, it is renowned for its expansive skyline and deep natural harbour...
, and widespread vitamin D deficiency occurs at such latitudes, probably because of sun avoidance, rainy seasons, and air pollution
Air pollution
Air pollution is the introduction of chemicals, particulate matter, or biological materials that cause harm or discomfort to humans or other living organisms, or cause damage to the natural environment or built environment, into the atmosphere....
. A study of Hong Kong infants showed that about half had 25(OH)D levels of less than 20 ng/mL in the winter. None of the infants had levels higher than 40 ng/ mL, even in the summer. Thus, a substantial percentage of all children will have impaired innate immunity at any given time, although the impairment is greatest during the dark days of the cold and flu season
Flu season
Flu season is a annually-recurring time period characterized by the prevalence of outbreaks of influenza . The season occurs during the cold half of the year in each hemisphere. Influenza activity can sometimes be predicted and even tracked geographically...
.