Health care–associated and hospital-acquired infections are two entities associated with increased morbidity and mortality. Dermato Endrocinology Volume 4, Issue 2 April/May/June 2012

Dima A. Youssef estecina at hotmail.com, Tamra Ranasinghe, William B. Grant and Alan N. Peiris
They are highly costly and constitute a great burden to the health care system.
Vitamin D deficiency (< 20 ng/ml) is prevalent and may be a key contributor to both acute and chronic ill health.
Vitamin D deficiency is associated with decreased innate immunity and increased risk for infections.
Vitamin D can positively influence a wide variety of microbial infections.
 Download the PDF from VitaminDWiki
Herein we discuss hospital-acquired infections, such as pneumonia, bacteremias, urinary tract and surgical site infections, and the potential role vitamin D may play in ameliorating them.
We also discuss how vitamin D might positively influence these infections and help contain health care costs.
Pending further studies, we think it is prudent to check vitamin D status at hospital admission and to take immediate steps to address existing insufficient 25-hydroxyvitamin D levels.

---

Another publication - 2009

Let the sun shine in: effects of ultraviolet radiation on invasive pneumococcal disease risk in Philadelphia, Pennsylvania
 Download the PDF from VitaminDWiki

---

See also VitaminDWiki

• All items in category After surgery/trauma and vitamin D 351 items
• All items in category Cost Savings with Vitamin D 158 items
• All items in category Immunity and vitamin D 273 items
• 2X more likely to get hospital infection if low vitamin D (10 ng) when enter – Oct 2013
• 5 days longer in ICU if low on vitamin D - April 2012
• How to reduce hospital infections with vitamin D – April 2012 David McCarthy
• ICU surgical patients with low vitamin D stayed longer and had more sepsis – Dec 2011
• Vitamin D might reduce sepsis
• Staph infection reduced 50 percent when have more than 30 ng of vitamin D – Aug 2011
• VA found less testing for vitamin D resulted in increased health costs – Jan 2012
• Vitamin D might reduce military costs for UC and CD – June 2011
• HMOs will save millions of dollars with vitamin D
• Virtually all veterans in ICU had vitamin D less than 32 ng – Jan 2011
• Hospital stay 6 days longer for nursing home residents with low vitamin D – Oct 2011
• MRSA inpatient cost 2X higher if less than 20 ng vitamin D – June 2011
• Hypothesis: A hospital diarrhea epidemic caused vitamin D deficiency – Oct 2012
• ICU Acinetobacter baumannii infection (Iraqibacter) is 2.5X more likely if low vitamin D – Oct 2013
• Superbug (Clostridium difficile) Infections strongly associated with low vitamin D - many studies
• Hospital Acquired Infection, Mortality, Critically Ill and Vitamin D - 2017
• Search Google Scholar for "Hospital Acquired Infection" "vitamin d" 340 items as of Feb 2020
  • Vitamin D Status and the Risk for Hospital-Acquired Infections in Critically Ill Adults: A Prospective Cohort Study - 2015 FREE PDF
  • Vitamin D status and its association with season, hospital and sepsis mortality in critical illness - 2014 FREE PDF

---

Introduction

There is increasing evidence that vitamin D deficiency plays an important role in worsening outcomes and increasing the susceptibility to infections. Vitamin D has potential benefits on innate immunity and potentiates antimicrobial actions through a variety of mechanisms. Vitamin D has potential antimicrobial actions against different organisms, such as bacteria, viruses, and fungi.

It is also well known that hospital acquired infections constitute a major cause of hospital morbidity and mortality. Viewing the widespread lack of testing of 25-hydroxyvitamin D [25(OH)D] levels in the inpatient setting, and the possible beneficial effects of getting sufficient levels, we raise in this article the potential association between vitamin D deficiency and the risk of acquisition of unnecessary infections during a hospital stay.

Burden of Hospital-Acquired Infections

Hospital-acquired infections (HAIs) are a leading cause of death in the US health care arena, with an overall estimated annual incidence of 1.7 million cases1 and 100,000 deaths.2 As a result, HAIs have given rise to state laws, legislative proposals at the federal level, public–private initiatives, and work at the hospital system and individual hospital level.2 They constitute a substantial cause of morbidity and mortality. Pneumonia was the most likely disease, followed by bacteremias, urinary tract infections, surgical site infections, and others.3 On the basis of published medical and economic literature, HAIs in US hospitals generate an estimated $28.4 billion–$45 billion in excess health care costs annually.4

Similarly, 12.7% of admitted patients developed HAIs, doubling the cost of these patients’ hospital stays. The totals for 159 patients were $1.48 million–$3.34 million in medical costs and $5.27 million for premature death, and excess length of stay (LOS) totaled 844–1,373 hospital days.5 Patients with sepsis had a nearly 6-fold higher odds of death than patients without an HAI. Patients with other HAIs had a 1.5- to 1.9-fold higher odds of mortality than control subjects. Patients with HAIs had costs that were approximately 2- to 2.5-fold higher than those of patients without HAIs. The median LOS was approximately 2-fold higher in patients with HAIs than in patients without HAIs.6 For example, results from a population-based data set indicated that mortality and LOS are increased among inflammatory bowel disease patients who develop HAIs. Most HAIs were from catheter-associated urinary tract infections (UTIs).7HAIs increase morbidity and mortality in intensive-care units (ICUs) not only for adults (including the elderly) but also for newborn infants.8

Multiple challenges stand against the implementation of HAI reduction plans: poor adherence, insufficient resources, staffing problems, lack of culture change, no impetus to change, and issues related to staff and patient education.9 The rates of hospital-acquired bacterial infection can be reduced by restricting the admission of patients colonized with resistant bacteria, increasing the rate of patient turnover, reducing transmission by infection control measures, and the use of second-line drugs for which there is no resistance.10 Many simple measures can decrease infection rates, such as adequate hand hygiene11 and, most recently, vitamin D supplementation.

Antimicrobial Role of Vitamin D

Vitamin D modulates the immune system12 and appears to have systemic antimicrobial effects13 that may be crucial in a variety of both acute and chronic illness. Moreover, vitamin D deficiency may predispose patients to hypocalcemia, which by itself impairs normal lymphocyte and neutrophil function.14 It also decreases the barrier protective function of cells.15 Vitamin 1,25-D3 inhibits proliferation of T helper 1(Th1) cells (consequently impairing production of IL-2, tumor necrosis factor ? and interferon [IFN]), as well as T helper 17 (Th17) cells, skewing cytokine production toward a T helper 2 (Th2) phenotype.16 Most cells, such as B and T lymphocytes, monocytes, and dendritic cells, have specific vitamin D receptors (VDRs).16 Vitamin D exerts its immunomodulatory effects on these cell lines through its effects on the VDR.17 Vitamin D tends to favor a mononuclear phenotype, increasing VDR expression on monocytes and macrophages.18,19 Vitamin D increases the oxidative burst of macrophages20 and facilitates neutrophilic motility and phagocytic function.21

Vitamin D reduces local and systemic inflammatory responses as a result of modulating cytokine responses and reducing Toll-like receptor activation.22 It directly affects T-cell activation and the phenotype and function of antigen-presenting cells, especially dendritic cells.23 Furthermore, vitamin D stimulates the expression of potent antimicrobial peptides, such as cathelicidin and ?-defensin 2.24

Cathelicidins are a family of peptides thought to provide an innate defensive barrier against a variety of potential microbial pathogens, such as gram-positive and gram-negative bacteria, fungi, and mycobacteria, at multiple entry sites, including skin and mucosal linings of the respiratory and gastrointestinal systems,24 as well as viruses.25 These antimicrobial peptides are expressed on epithelial surfaces and in neutrophils, are inducible in keratinocytes in response to infection, and act as natural antibiotics. In earlier studies, cathelicidins (LL-37 and CRAMP) were expressed at select epithelial interfaces and may kill bacteria such as group A Streptococcus.26,27 Studies in mice showed that deletion of the cathelicidin gene, Cnlp, results in increased susceptibility to group A Streptococcus infection. Keratinocytes inhibit the growth of S. aureus, due partially to their ability to synthesize and activate cathelicidin.28 The human cathelicidin, hCAP18, is a component of the innate immune system and has broad antimicrobial activity conferred by its C-terminal fragment, LL-37. hCAP18 is produced in leukocytes and is induced in barrier organs upon inflammation and infection; hCAP18 also works in the reepithelialization of skin wounds.29 To resist innate immunity, bacteria can develop enzymes that inactivate cathelicidins. Thus, streptococcal cysteine protease SpeB-mediated inactivation of LL-37 is noted in patients with severe group A Streptococcus tissue infections.30 However, addition of cathelicidins by combining synthetic cathelicidin peptides in vitro, by producing human keratinocytes that overexpress cathelicidins in culture, showed increased resistance to infections with group A Streptococcus.31 In case of prolonged deficiency of both dietary vitamin D and calcium, vitamin D deficiency may predispose to hypocalcemia, which impairs normal lymphocyte and neutrophil function and potentially increases the risk of acquiring infectious diseases.32 Vitamin D–deficient patients are susceptible to increased nosocomial infections, such as pneumonia, sepsis, and central line infections.16,33

Neutrophils, macrophages, lymphocytes, monocytes, and natural killer cells increase the expression of these antimicrobial peptides with 25(OH)D stimulation.34 Human ?-defensin 2 (HBD-2) is beneficial in multidrug-resistant microbes in vitro.35 Human ?-defensin 3 (HBD-3) is an antimicrobial peptide that exhibits broad-spectrum antimicrobial activity against gram-positive/negative bacteria and fungi.36 It could be more potent than HBD-2 in S. aureus skin infections.37 Moreover, the bacterial protein flagellin stimulates the mucosal surface innate immunity by production of antimicrobial peptides and may generate cytoprotection and control infection in the cornea and other mucosal tissues.38 Enhanced antimicrobial peptide production may also improve skin lesions in psoriasis and atopic dermatitis.39

Use of Vitamin D in Infectious Diseases

In a previous publication, we outlined the most important actions of vitamin D against many infections, whether they are bacterial, mycobacterial, fungal, parasitic, or viral.40 We also found that vitamin D deficiency was intimately linked to adverse health outcomes and costs in veterans with staphylococcal and Clostridium difficile(C. difficile) infections. Vitamin D–deficient patients with C. difficile or staphylococcal infections had costs more than five times higher than those of nondeficient patients. The total length of hospital stay was four times greater in the vitamin D–deficient group. Also, the total number of hospitalizations was significantly greater in vitamin D–deficient patients.41 Similarly, vitamin D–deficient patients with MRSA and Pseudomonas aeruginosa infections had higher costs and service utilization than patients who were not vitamin D deficient.42 In a retrospective study by McKinney and colleagues, ICU survivors had a significantly lower rate of vitamin D deficiency than did nonsurvivors (28% vs. 53%). The risk of death was significantly higher in ICU patients with vitamin D deficiency.43 Most recently, Higgins et al. conducted a prospective study to evaluate the burden of vitamin D deficiency in intensive care unit patients. Serum 25(OH)D was checked upon admission and at 10 d after admission and the patients were followed up at 28 d. 26% were deficient and 56% were insufficient. 25(OH)D status was not significantly associated with 28-d all-cause mortality. However, higher levels of 25(OH)D were associated with a shorter time-to-alive ICU discharge. 25(OH)D-deficient patients showed a trend toward a higher infection rate.44 Vitamin D therefore appears to be important for patients with critical illness. On the basis of US epidemiologic studies, Grant hypothesized that solar UVB light and vitamin D could reduce the risk of septicemia.45 Grant also stated that supplementation with vitamin D to mothers and infants may reduce the risk of sepsis in premature infants.46 One study by Jeng and colleagues in critically ill patients pointed at the important correlation between 25(OH)D levels, vitamin D–binding protein, and LL-37 levels. These patients had significantly lower plasma 25(OH)D concentrations and LL-37 levels than did healthy control subjects. Vitamin D–binding protein levels in plasma were significantly lower in critically ill subjects with sepsis than in critically ill subjects without sepsis.47 Therapy with vitamin D in animal models of sepsis improves blood coagulation parameters in disseminated intravascular coagulation and modulates levels of systemic inflammatory cytokines, including tumor necrosis factor ? and interleukin 6.48

Vitamin D deficiency is also more prevalent in blacks than in whites.49,50 Severe sepsis occurs more often and leads to more deaths in black than in white individuals. Racial differences in severe sepsis are explained by both a higher infection rate and a higher risk of acute organ dysfunction in black than in white individuals.51

Currently, prescribing traditional antimicrobials for infectious processes is customary in medicine. The current use of antimicrobials in the United States costs billions of dollars, and the overuse of antibiotics persists and contributes to the emergence of resistant organisms.52 Vitamin D is likely to emerge as a powerful and hitherto unrecognized antimicrobial agent. Evidence is mounting that vitamin D could help to manage infectious illnesses. But does vitamin D deficiency cause infections? This question remains. Hill proposed one way to determine causality in a biological system,53 on the basis of nine criteria: strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy. The more criteria that are elicited, the better the case for causality. Some examples of applying Hill’s criteria include the relationship between vitamin D as a risk-reduction factor for several types of cancer54 and that of vitamin D deficiency and periodontal disease.55 Below we discuss the most common HAIs and the beneficial role of vitamin D. Table 1 summarizes the effects of vitamin D on each entity.

Table 1. Effects of vitamin D on HAIs

HAI Effect Reference
Intensive care unit infections Higher levels of 25(OH)D were associated with a shorter time-to-alive ICU discharge. 25(OH)D-deficient patients had higher infection rate 44
Bacteremia Increased prevalence of pneumococcal sepsis in wintertime 60
Bacteremia, dialysis patients Increased risk of infections, sepsis and bacteremia in deficiency 61
Bacterial sepsis 66% higher mortality rate for low vs. high serum 25(OH)D 62
Community acquired pneumonia Higher 30-d mortality in case of severe deficiency 68
Pneumonia in Children Higher oxygen supplements and ventilator need in deficiency 69,70
Pneumonia Supplementation with 1000–2000 IU/d for five days – no effect 74
Pneumonia associated with influenza Case-fatality rate was significantly reduced in regions with higher solar UVB doses 79
Clostridium difficile Vitamin D protects macrophages against death.Deficiency was associated with higher costs 8641
Catheter-associated urinary tract infections VDR ApaI polymorphism seems to be protective. Tt and tt genotypes have higher risk of UTI.
   Vitamin D3 supplementation increased cathelicidin production in bladders infected with uropathogenic Escherichia coli. 90–92
Surgical site infections 50,000 IU dose eliminated wound infections Donald Miller (Personal communication)
Virulent organisms such as MRSA S. aureus colonization decreased by 6.6% for each 5-nmol/l increase in 25(OH)D 105

Bacteremias and Central Vascular Catheter–Associated Bloodstream Infections

Patients with health care–associated, community-acquired bacteremia have more malignancies, open wounds at admission, and intravascular catheter–related infections.56 Most pneumococcal bloodstream infections (BSIs) are community acquired, although HAIs are common in neutropenic patients.57 Critically ill patients who develop ICU-acquired BSIs suffer excess morbidity and mortality and incur significantly increased health care costs.58 According to the latest News and Numbers from the Agency for Healthcare Research and Quality, septicemia was the single most expensive condition treated in US hospitals, at nearly $15.4 billion in 2009, including community- and hospital-acquired cases. The federal agency also found that the number of hospital stays principally for septicemia more than doubled between 2000 and 2009, making it the sixth most common principal reason for hospitalization in 2009. Also, the in-hospital death rate for septicemia was 16% in 2009, more than eight times as high as for all other hospital stays.59

Streptococcus pneumoniae is a common cause of community-acquired pneumonia and bacteremia. White and colleagues confirmed that the wintertime predominance of invasive pneumococcal disease in Philadelphia is related to extended periods of low UV radiation. They suggested that the mechanism of action of diminished sunlight exposure on disease occurrence may be due to direct effects on pathogen survival or host immune function via altered 1,25(OH)2D production.60

In dialysis patients, vitamin D deficiency was among several pathophysiologic factors that enhance the risk of infections in this population. Twenty to 30% of dialysis patients develop infection, and 20–30% of these die from their infection. Sepsis and bacteremia are significantly more frequent, and their mortality is 50 times higher than in the healthy population.61

In a study by Lee and colleagues, 17% of intensive care unit patients had undetectable levels of 25-hydroxyvitamin D [25(OH)D].32 In a different study, 20% of critically ill patients with bacterial sepsis had hypocalcemia, and their mortality rate was significantly higher (50%) than that of normocalcemic patients with sepsis (29%).62 Vitamin D deficiency in the obese may have a role in the pathogenesis of endotoxemia and adipose inflammation.63

Health Care–Associated Pneumonia and Hospital-Acquired Pneumonia

Health care–associated pneumonia (HCAP) usually develops in patients in outpatient facilities, such as nursing homes, long-term care facilities, and dialysis centers. HCAP should be dealt with as if it is hospital-acquired pneumonia (HAP) and should be treated as such until final cultures are available. Analysis of multi-institutional clinical data showed that mortality associated with HCAP is higher than that with community-acquired pneumonia.64 Postoperative HAP is a major risk associated with surgery. In one study, 10.7% of patients with HAP after intra-abdominal surgery died before discharge. HAP was independently associated with a 4.13-fold increase in risk to be discharged to a skilled nursing facility. The mean length of hospital stay of these patients was significantly greater than that of intra-abdominal surgery patients who did not develop HAP. HAP was independently associated with a 75% mean increase in total hospital charges.65 In children younger than 1 y and those with chronic medical conditions, hospital-acquired febrile respiratory illness is caused mainly by viruses such as respiratory syncytial virus and is associated with increased mortality.66

Vitamin D promotes lung and bone health.67 Upon evaluating the associations between mortality and serum 25(OH)D in patients with community-acquired pneumonia, Leow and colleagues verified that severe 25(OH)D deficiency was common and associated with a higher 30-d mortality rate than that of patients with sufficient 25(OH)D during winter.68 Similar findings were noted in children with acute lower respiratory infection. Patients needing more supplementary oxygen and ventilator management were those with vitamin D deficiency.69 Also, in a case–control study in Nigerian children with pneumonia, those with hypovitaminosis D and hypocalcemia had more complications and worse outcomes than those without deficiency.70 Moreover, rickets was a significant predictor of reduced success in treating severe pneumonia in Yemen.71 In ICU-admitted veterans, a longer stay was significantly linked to lower vitamin D status.43 Two recent reviews describe the role of vitamin D and susceptibility to chronic lung diseases and thus risk for superimposed infections.72,73

Given the relationship between 25(OH)D levels and community-acquired pneumonia, we think that the association is likely to be even stronger for HAIs. However, in one randomized, double-blind, placebo-controlled trial in India that involved children admitted for pneumonia, supplementation with oral vitamin D of 1,000–2,000 IU per day for 5 d was not beneficial in resolving severe pneumonia.74 The dose and especially the duration of vitamin D treatment may have been insufficient to influence outcome. Cannell and colleagues have advocated much higher short-term doses for acute illness.75

Influenza was associated with a higher tendency to develop superimposed bacterial pneumonia, and prevention may avoid the higher risk of pneumonia, especially in elderly and chronic lung disease patients. Whether vitamin D should be implemented as a mandatory vitamin to prevent pandemic influenza is the question.76 Juzeniene et al. studied pandemic and nonpandemic influenzas in Sweden, Norway, the United States, Singapore, and Japan. The higher exposure to UVB radiation in summer and consequently higher 25(OH)D levels protect against influenza.77 Hayes hypothesizes that influenza pandemics are associated with solar control of 25(OH)D levels in humans, which increase or decrease with solar cycle–dependent UV radiation.78 Studying the 1918–1919 influenza pandemic, Grant and Giovannucci determined that vitamin D, by producing antimicrobial peptides and reducing production of proinflammatory cytokines, decreases the development of pneumonia after infection with influenza virus.79 Also one randomized controlled trial involving Japanese schoolchildren found a relative risk of influenza of 0.36 in those taking 1,200 IU/day compared with those taking 200 IU/day.80 However, Shaman et al. studied levels of 25(OH)D to see if it can be used to simulate influenza rates. They found it unlikely that seasonal variations in vitamin D levels principally determine the seasonality of influenza in temperate regions.81

We believe that this finding also applies to patients in the hospital, especially those infected with the influenza virus, and the subsequent development of HAP.

Clostridium Difficile Infections

Clostridium difficile is the most common cause of nosocomial infectious diarrhea in the United States. C. difficile–associated disease (CDAD) can be severe and fatal. C. difficile infection (CDI) is a major cause of hospital-acquired diarrhea and is most commonly associated with changes in normal intestinal flora caused by administration of antibiotics. In Massachusetts, between 1999 and 2003, CDAD management consumed 55,380 inpatient-days and cost $51.2 million. Based on this study, a conservative estimate of the annual US cost for CDAD management was expected to be $3.2 billion.82 In one institution, over a 5-y period, the economic burden of CDAD was increasing to the point that its associated medical expenditures approached $1 million per year.83 An analysis by the Centers for Disease Control and Prevention revealed that, in the United States, CDI continues to increase, with more than 250,000 US hospitalizations in 2005 associated with it.84

Vitamin D has been found to play a protective role in the gut. Vitamin D and the VDR are required for the development and function of two regulatory populations of T cells: the iNKT cells and CD4/CD8?? intraepithelial lymphocytes (IEL). Protective immune responses that depend on iNKT cells or CD8?? IEL are therefore impaired in the vitamin D or VDR deficient host and the mice are more susceptible to immune-mediated diseases in the gut.85 Also, vitamin D protects macrophages against death induced by Cdif toxin (TcdA/B)-induced intestinal injury.86 In one study undertaken in Weill Cornell College of Medicine and New York Hospital Queens, 30 d clearance rates were 53% in those with normal serum levels of 25(OH)D vs. 26% in those with levels below 21 ng/dL. Mortality rates were also higher in the patients with low vitamin D, at 56% compared with 33% for those with serum 25(OH)D levels of 21 ng/dL or above.87 We discussed previously the health care costs of patients with CDI associated with vitamin D deficiency. In the outpatient setting, vitamin D deficiency in patients with C. difficile and staphylococcal infections were associated with significantly increased total outpatient costs and fee-based consultation.

In addition the total number of hospitalizations was also significantly greater in the vitamin D-deficient group. In the inpatient setting, vitamin D–deficient patients had higher laboratory, pharmacy, and radiology costs. These deficient patients had five times higher costs than the non-deficient patients, manifested by four times greater length of hospital stay and more hospitalizations.41

Catheter-Associated Urinary Tract Infections

Almost 60% of patients having a foley catheter in the hospital do not need it. Twenty-six percent of patients using indwelling catheters for 2–10 d get bacteriuria. Among those, symptoms of urinary tract infections (UTIs) develop in an estimated 24%, and bacteremia in 3.6%. Each episode of UTI is expected to cost an additional $676, and catheter-related bacteremia at least $2,836.88 Changes in reimbursement policies have focused attention on the use of indwelling catheters in the critical care unit as well as their role in hospital-acquired UTIs. Implementation of an evidence-based prevention program can significantly reduce both the prevalence of indwelling catheterization and the incidence of hospital-acquired, catheter-associated UTIs.89 One review discussed the role of vitamin D in the prevention of infections, including UTIs.90 A study evaluated the different vitamin D receptor polymorphisms in children with UTIs and those with a history of UTI. The ApaI polymorphism was significantly increased in the control group and considered a protective factor. Comparing with the TaqI, the study found that both the Tt and tt genotypes carried minimal increased risk of UTI.91 To prove the activity of vitamin D in protecting against UTIs, Hertting and colleagues demonstrated a significant increase in the production of cathelicidin after vitamin D3 supplementation in bladders infected with uropathogenic Escherichia coli. The authors recommended that vitamin D be considered as a potential preventive measure for UTIs.92

Surgical Site Infections

The first report of a group A Streptococcus hospital outbreak was reported in an acute care facility in Texas. The wound care team was the means of transmission: a member of this team was colonized with the matching type.93 Surgical site infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are increasing significantly and are independently associated with higher mortality, increased length of stay, and higher cost.94

In a personal communication with Seattle cardiothoracic surgeon Donald Miller, MD, he indicated that the postpericardiotomy syndrome occurring in veterans after coronary artery bypass surgery virtually disappeared, as did sternotomy wound infections, after a preoperative dose of 50,000 IU of cholecalciferol.

Vitamin D enhances antimicrobial peptide production in the skin. Deficiency in antimicrobial peptide production contributes to the increased susceptibility of S. aureus skin infections in patients with atopic dermatitis.95 Antimicrobial peptides may contribute to host defense through wound repair96 and clearance of bacteria at various barrier sites.97 Applying topical vitamin D would result in faster recovery from many skin disorders, both infectious and noninfectious, including wounds, bacterial and viral infections, diabetic ulcers, and chronic skin ulcers. Arnold and van de Kerkhof investigated the efficacy of MC903, a vitamin D3 analog, in reducing hyperproliferation as determined by levels of ornithine decarboxylase in 15 patients with chronic plaque psoriasis. Eight of 11 patients treated with MC903 showed clinical improvement.98

Several other studies showed beneficial outcomes in skin and soft tissue in the presence of vitamin D. For example, one study compared outcomes of periodontal surgery and teriparatide administration in vitamin D–sufficient and vitamin D–insufficient individuals. Placebo patients with baseline vitamin D deficiency had significantly less clinical attachment and probing depth reduction than vitamin D–sufficient individuals. At 1 y, infrabony defect resolution was greater in teriparatide-treated vitamin D–sufficient individuals.99 In an animal study, incidence of injection site lesions was lowest among animals given vitamin AD3, a water emulsifiable solution to be used as a supplemental source of Vitamins A and D3 in cattle (as calves, at both branding and weaning times) and was highest in cattle given injections of 5 mL of clostridial products at branding or of long-acting oxytetracycline antibiotic at weaning.100

Infections due to Virulent Organisms, such as MRSA

In one hospital, most MRSA infections were health care associated: 58.4% were community-onset infections, 26.6% were hospital-onset infections, and 13.7% were community-associated infections, and the rest could not be classified. The incidence rates were highest among persons aged 65 y and older, blacks, and males.101 Hospital-acquired MRSA and community-acquired MRSA are important causes of pneumonia and present diagnostic and therapeutic challenges.102

Nasal colonization with S. aureus is a significant risk factor for ICU-acquired S. aureus infections, and strategies to control these infections should target both MSSA (methicillin-susceptible S. aureus) and MRSA colonization.103 A secondary data analysis of the National Health and Nutrition Examination Survey, 2001–2004, showed that vitamin D deficiency was associated with an increased risk of MRSA nasal carriage.104 To support this finding, the Tromsø Staph and Skin Study 2007–2008 demonstrated that in nonsmoking men, the probability of S. aureus colonization and carriage, respectively, decreased by 6.6% and 6.7% for each 5-nmol/L increase in serum 25(OH)D concentration. This study also established serum 25(OH)D?thresholds of greater than?59 nmol/L and at least 75 nmol/L for ~30% and ~50% reduction in S. aureus colonization and carriage, respectively.105 Vitamin D supplementation to reach a serum 25(OH)D above 75 nmol/L may reduce the incidence of MSSA and MRSA infection and thus may be a significant synergistic step in preventing HAIs.

Appropriate Dose of Vitamin D

Vitamin D deficiency is associated with increased mortality rates.106 A meta-analysis of 11 prospective studies of serum 25(OH)D at time of enrollment found a significantly reduced mortality rate for those with serum 25(OH)D concentrations of 75 nmol/L compared with those with less than 42 nmol/L.107 Another recent paper estimated that doubling worldwide population mean serum 25(OH)D concentrations, from 50–55 nmol/L to 100–105 nmol/L, would reduce mortality rates by 7–17% and increase life expectancy by 2 y.108 Also, a recent publication of a meta-analysis of 12 prospective studies showed that a 20nmol/l increase in 25(OH)D levels was associated with an 8% lower mortality in the general elderly population.109

The optimal serum 25(OH)D concentration for bacterial and viral immunity is still a controversial matter. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine gives guidelines for the daily vitamin D needed supplementation, based on a review of randomized controlled trials that they deemed of high quality, finding strong evidence only for beneficial effects for bones.110 They recommended a daily dose of 600 IU of vitamin D. They also considered a serum level of 16 ng/mL to meet the needs for almost half the population. This report suggested that vitamin D deficiency is overdiagnosed. However, a 600-IU daily dose is inadequate to achieve the health-related goals we have described.111 And because the response to vitamin D supplementation varies among patients, many patients need higher doses.112 Norman and colleagues113 addressed the current public health needs of vitamin D. Recently, the Endocrine Society released Evaluation, Treatment, and Prevention of Vitamin D Deficiency: An Endocrine Society Clinical Practice Guideline, which recommended doses of vitamin D supplementation for each age group. Adults require at least 1,500–2,000 IU of vitamin D per day to maintain a blood level of 25(OH)D above 75 nmol/L. This dosage is similar to the requirements for those aged 50–70 y and for pregnant women.110 Moreover, results in the literature on severe respiratory infections support these findings. In an observational study, individuals with serum 25(OH)D concentrations greater than 95 nmol/L had low rates of acute viral respiratory tract infections, whereas those with lower concentrations had a 50% chance of developing such infections during a half-year observational period. In a 2009 Paris meeting, a panel of vitamin D researchers endorsed a serum 25(OH)D concentration of 75–100 nmol/L.115Sabetta et al. demonstrated that maintenance of a vitamin D serum concentration of 38 ng/mL or higher should significantly reduce the incidence of acute viral respiratory tract infections, including influenza, at least during the fall and winter in temperate zones.116

Conclusion

For HAIs, pointing to vitamin D deficiency as the sole risk factor is difficult. Patients admitted to the hospital are sicker and thus are more prone to acquire pathogens and manifest illnesses. However, vitamin D deficiency can increase this probability by decreasing the host innate defense mechanisms. We have suggested the use of vitamin D in the management of acute illness in elderly patients and those with an underlying chronic illness.117 This review aims to show the potential benefits of vitamin D in infection. Given the prevalence of vitamin D deficiency, we believe that intensive vitamin D supplementation in patients before and during hospital stays could improve health outcomes. Vitamin D is inexpensive, and adequate supplementation can be achieved at minimal cost. Vitamin D use could reduce inappropriate antibiotic prescription and boost therapeutic response when combined with appropriate antibiotic use. Although prospective double-blind studies are needed to confirm the antimicrobial effects of vitamin D, the existing evidence for an antimicrobial effect by vitamin D is compelling. We recommend that vitamin D deficiency be taken into greater consideration as a risk factor for immunodeficiency and increased susceptibility to infections. To note that most recently, Cannell announced that it has become possible to prescribe vitamin D3, as 50,000 IU once weekly, and it can also be prescribed as once every 2 weeks.118

Disclosure of Potential Conflict of Interest

WBG receives or has received funding from the UV Foundation (McLean, VA), Bio-Tech-Pharmacal (Fayetteville, AR), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada).

Acknowledgments

This material is the result of works supported with resources and the use of facilities at the Mountain Home VAMC. The contents of this report do not reflect the position of the US government and the Department of Veterans Affairs. WBG receives or has received funding from the UV Foundation (McLean, VA), Bio-Tech-Pharmacal (Fayetteville, AR), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada).

References

1. Welsh CA, Flanagan ME, Hoke SC, Doebbeling BN, Herwaldt L. Reducing health care-associated infections (HAIs): lessons learned from a national collaborative of regional HAI programs. Am J Infect Control 2012; 40:29-34; PMID: 21775022; DOI: 10.1016/j.ajic.2011.02.017.

2. Sprague L. Health care-associated infections: is there an end in sight?. Issue Brief Natl Health Policy Forum 2009; •••:1-14; PMID: 19343832.

3. Klevens RM, Edwards JR, Richards CL, Horan TC, Gaynes RP, Pollock DA, et al. Estimating health care-associated infections and deaths in U.S. hospitals, 2002. Public Health Rep 2007; 122:160-6; PMID: 17357358.

4. Scott, R.D. The direct medical costs of healthcare-associated infections in U.S. hospitals and the benefits of prevention. (Publication No. CS200891-A). Centers for Disease Control and Prevention.

5. Roberts RR, Scott RD, Hota B, Kampe LM, Abbasi F, Schabowski S, et al. Costs attributable to healthcare-acquired infection in hospitalized adults and a comparison of economic methods. Med Care 2010; 48:1026-35; PMID: 20940650; DOI: 10.1097/MLR.0b013e3181ef60a2.

6. Glance LG, Stone PW, Mukamel DB, Dick AW. Increases in mortality, length of stay, and cost associated with hospital-acquired infections in trauma patients. Arch Surg 2011; 146:794-801; PMID: 21422331; DOI: 10.1001/archsurg.2011.41.

7. Karagozian R, Johannes RS, Sun X, Burakoff R. Increased mortality and length of stay among patients with inflammatory bowel disease and hospital-acquired infections. Clin Gastroenterol Hepatol 2010; 8:961-5; PMID: 20723618; DOI: 10.1016/j.cgh.2010.07.017.

8. Higgins RD, Baker CJ, Raju TN. Executive summary of the workshop on infection in the high-risk infant. J Perinatol 2010; 30:379-83; PMID: 20072133; DOI: 10.1038/jp.2009.199.

9. Flanagan ME, Welsh CA, Kiess C, Hoke S, Doebbeling BN. A national collaborative for reducing health care?associated infections: current initiatives, challenges, and opportunities. Am J Infect Control 2011; 39:685-9; PMID: 21665329; DOI: 10.1016/j.ajic.2010.12.013.

10. Haber M, Levin BR, Kramarz P. Antibiotic control of antibiotic resistance in hospitals: a simulation study. BMC Infect Dis 2010; 10:254; PMID: 20738872; DOI: 10.1186/1471-2334-10-254.

11. Biddle C. Semmelweis revisited: hand hygiene and nosocomial disease transmission in the anesthesia workstation. AANA J 2009; 77:229-37; PMID: 19645173.

12. Feindt E, Ströder J. [Studies on the antimicrobial effect of vitamin D (author’s transl)]. Klin Wochenschr 1977; 55:507-8; PMID: 195120; DOI: 10.1007/BF01489010.

13. Toubi E, Shoenfeld Y. The role of vitamin D in regulating immune responses. Isr Med Assoc J 2010; 12:174-5; PMID: 20684184.

14. Gombart AF. The vitamin D-antimicrobial peptide pathway and its role in protection against infection. Future Microbiol 2009; 4:1151-65; PMID: 19895218; DOI: 10.2217/fmb.09.87.

15. Hewison M, Zehnder D, Chakraverty R, Adams JS. Vitamin D and barrier function: a novel role for extra-renal 1 alpha-hydroxylase. Mol Cell Endocrinol 2004; 215:31-8; PMID: 15026172; DOI: 10.1016/j.mce.2003.11.017.

16. Bikle DD. Vitamin D and the immune system: role in protection against bacterial infection. Curr Opin Nephrol Hypertens 2008; 17:348-52; PMID: 18660668; DOI: 10.1097/MNH.0b013e3282ff64a3.

17. Veldman CM, Cantorna MT, DeLuca HF. Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys 2000; 374:334-8; PMID: 10666315; DOI: 10.1006/abbi.1999.1605.

18. Eleftheriadis T, Antoniadi G, Liakopoulos V, Galaktidou G. The effect of paricalcitol on osteoprotegerin production by human peripheral blood mononuclear cells. J Rheumatol 2009; 36:856-7; PMID: 19342729; DOI: 10.3899/jrheum.080987.

19. Veldman CM, Cantorna MT, DeLuca HF. Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys 2000; 374:334-8; PMID: 10666315; DOI: 10.1006/abbi.1999.1605.

20. Rockett KA, Brookes R, Udalova I, Vidal V, Hill AV, Kwiatkowski D. 1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line. Infect Immun 1998; 66:5314-21; PMID: 9784538.

21. Lorente F, Fontan G, Jara P, Casas C, Garcia-Rodriguez MC, Ojeda JA. Defective neutrophil motility in hypovitaminosis D rickets. Acta Paediatr Scand 1976; 65:695-9; PMID: 187003.

22. Jeng L, Yamshchikov AV, Judd SE, Blumberg HM, Martin GS, Ziegler TR, et al. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med 2009; 7:28; PMID: 19389235; DOI: 10.1186/1479-5876-7-28.

23. Canning MO, Grotenhuis K, de Wit H, Ruwhof C, Drexhage HA. 1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes. Eur J Endocrinol 2001; 145:351-7; PMID: 11517017; DOI: 10.1530/eje.0.1450351.

24. Bartley J. Vitamin D: emerging roles in infection and immunity. Expert Rev Anti Infect Ther 2010; 8:1359-69; PMID: 21133662; DOI: 10.1586/eri.10.102.

25. Barlow PG, Svoboda P, Mackellar A, Nash AA, York IA, Pohl J, et al. Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37. PLoS One 2011; 6:e25333; PMID: 22031815; DOI: 10.1371/journal.pone.0025333.

26. Dorschner RA, Pestonjamasp VK, Tamakuwala S, Ohtake T, Rudisill J, Nizet V, et al. Cutaneous injury induces the release of cathelicidin anti-microbial peptides active against group A Streptococcus.. J Invest Dermatol 2001; 117:91-7; PMID: 11442754; DOI: 10.1046/j.1523-1747.2001.01340.x.

27. Nizet V, Ohtake T, Lauth X, Trowbridge J, Rudisill J, Dorschner RA, et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 2001; 414:454-7; PMID: 11719807; DOI: 10.1038/35106587.

28. Braff MH, Zaiou M, Fierer J, Nizet V, Gallo RL. Keratinocyte production of cathelicidin provides direct activity against bacterial skin pathogens. Infect Immun 2005; 73:6771-81; PMID: 16177355; DOI: 10.1128/IAI.73.10.6771-6781.2005.

29. Heilborn JD, Nilsson MF, Kratz G, Weber G, Sørensen O, Borregaard N, et al. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J Invest Dermatol 2003; 120:379-89; PMID: 12603850; DOI: 10.1046/j.1523-1747.2003.12069.x.

30. Johansson L, Thulin P, Sendi P, Hertzén E, Linder A, Akesson P, et al. Cathelicidin LL-37 in severe Streptococcus pyogenes soft tissue infections in humans. Infect Immun 2008; 76:3399-404; PMID: 18490458; DOI: 10.1128/IAI.01392-07.

31. Lee PH, Ohtake T, Zaiou M, Murakami M, Rudisill JA, Lin KH, et al. Expression of an additional cathelicidin antimicrobial peptide protects against bacterial skin infection. Proc Natl Acad Sci U S A 2005; 102:3750-5; PMID: 15728389; DOI: 10.1073/pnas.0500268102.

32. Lee P, Eisman JA, Center JR. Vitamin D deficiency in critically ill patients. N Engl J Med 2009; 360:1912-4; PMID: 19403914; DOI: 10.1056/NEJMc0809996.

33. Bowdish DM, Davidson DJ, Hancock RE. Immunomodulatory properties of defensins and cathelicidins. Curr Top Microbiol Immunol 2006; 306:27-66; PMID: 16909917; DOI: 10.1007/3-540-29916-5_2.

34. Schwalfenberg GK. A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency. Mol Nutr Food Res 2011; 55:96-108; PMID: 20824663; DOI: 10.1002/mnfr.201000174.

35. Routsias JG, Karagounis P, Parvulesku G, Legakis NJ, Tsakris A. In vitro bactericidal activity of human beta-defensin 2 against nosocomial strains. Peptides 2010; 31:1654-60; PMID: 20600430; DOI: 10.1016/j.peptides.2010.06.010.

36. Suzuki Y, Inokuchi S, Takazawa K, Umezawa K, Saito T, Kidokoro M, et al. Introduction of human ?-defensin-3 into cultured human keratinocytes and fibroblasts by infection of a recombinant adenovirus vector. Burns 2011; 37:109-16; PMID: 20884123; DOI: 10.1016/j.burns.2010.08.004.

37. Zanger P, Holzer J, Schleucher R, Scherbaum H, Schittek B, Gabrysch S. Severity of Staphylococcus aureus infection of the skin is associated with inducibility of human beta-defensin 3 but not human beta-defensin 2. Infect Immun 2010; 78:3112-7; PMID: 20404083; DOI: 10.1128/IAI.00078-10.

38. Gao N, Kumar A, Jyot J, Yu FS. Flagellin-induced corneal antimicrobial peptide production and wound repair involve a novel NF-kappaB-independent and EGFR-dependent pathway. PLoS One 2010; 5:e9351; PMID: 20195469; DOI: 10.1371/journal.pone.0009351.

39. Vähävihu K, Ala-Houhala M, Peric M, Karisola P, Kautiainen H, Hasan T, et al. Narrowband ultraviolet B treatment improves vitamin D balance and alters antimicrobial peptide expression in skin lesions of psoriasis and atopic dermatitis. Br J Dermatol 2010; 163:321-8; PMID: 20331450; DOI: 10.1111/j.1365-2133.2010.09767.x.

40. Youssef D, Miller C, El-Abbassi A, Cutchins D, Cutchins C, Grant WB, et al. Antimicrobial implications of vitamin D. Dermatoendocrinol 2011; 3:1-10; PMID: 21519401; DOI: 10.4161/derm.3.4.15027.

41. Youssef D, Bailey B, El Abbassi A, Copeland R, Adebonojo L, Manning T, et al. Healthcare costs of Staphylococcus aureus and Clostridium difficile infections in veterans: role of vitamin D deficiency. Epidemiol Infect 2010; 138:1322-7; PMID: 20056018; DOI: 10.1017/S0950268809991543.

42. Youssef D, Bailey B, El-Abbassi A, Vannoy M, Manning T, Moorman JP, et al. Healthcare costs of methicillin resistant Staphylococcus aureus and Pseudomonas aeruginosa infections in veterans: role of vitamin D deficiency. Eur J Clin Microbiol Infect Dis 2012; 31:281-6; PMID: 21695580; DOI: 10.1007/s10096-011-1308-9.

43. McKinney JD, Bailey BA, Garrett LH, Peiris P, Manning T, Peiris AN. Relationship between vitamin D status and ICU outcomes in veterans. J Am Med Dir Assoc 2011; 12:208-11; PMID: 21333923; DOI: 10.1016/j.jamda.2010.04.004.

44. Higgins DM, Wischmeyer PE, Queensland KM, Sillau SH, Sufit AJ, Heyland DK. Relationship of Vitamin D Deficiency to Clinical Outcomes in Critically Ill Patients. JPEN J Parenter Enteral Nutr 2012; ; PMID: 22523178; DOI: 10.1177/0148607112444449.

45. Grant WB. Solar ultraviolet-B irradiance and vitamin D may reduce the risk of septicemia. Dermatoendocrinol 2009; 1:37-42; PMID: 20046587; DOI: 10.4161/derm.1.1.7250.

46. Grant WB. Vitamin D supplementation of mother and infant could reduce risk of sepsis in premature infants. Early Hum Dev 2010; 86:133; PMID: 20188500; DOI: 10.1016/j.earlhumdev.2010.02.003.

47. Jeng L, Yamshchikov AV, Judd SE, Blumberg HM, Martin GS, Ziegler TR, et al. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med 2009; 7:28; PMID: 19389235; DOI: 10.1186/1479-5876-7-28.

48. Watkins RR, Yamshchikov AV, Lemonovich TL, Salata RA. The role of vitamin D deficiency in sepsis and potential therapeutic implications. J Infect 2011; 63:321-6; PMID: 21777617; DOI: 10.1016/j.jinf.2011.07.002.

49. Shea MK, Houston DK, Tooze JA, Davis CC, Johnson MA, Hausman DB, et al. Correlates and prevalence of insufficient 25-hydroxyvitamin D status in black and white older adults: the health, aging and body composition study. J Am Geriatr Soc 2011; 59:1165-74; PMID: 21668915; DOI: 10.1111/j.1532-5415.2011.03476.x.

50. Grant WB, Peiris AN. Possible role of serum 25-hydroxyvitamin D in black-white health disparities in the United States. J Am Med Dir Assoc 2010; 11:617-28; PMID: 21029996; DOI: 10.1016/j.jamda.2010.03.013.

51. Mayr FB, Yende S, Linde-Zwirble WT, Peck-Palmer OM, Barnato AE, Weissfeld LA, et al. Infection rate and acute organ dysfunction risk as explanations for racial differences in severe sepsis. JAMA 2010; 303:2495-503; PMID: 20571016; DOI: 10.1001/jama.2010.851.

52. Ranji SR, Steinman MA, Shojania KG, Gonzales R. Interventions to reduce unnecessary antibiotic prescribing: a systematic review and quantitative analysis. Med Care 2008; 46:847-62; PMID: 18665065; DOI: 10.1097/MLR.0b013e318178eabd.

53. Hill AB. The Environment and Disease: Association or Causation?. Proc R Soc Med 1965; 58:295-300; PMID: 14283879.

54. Grant WB. How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer?: An examination using Hill’s criteria for causality. Dermatoendocrinol 2009; 1:17-24; PMID: 20046584; DOI: 10.4161/derm.1.1.7388.

55. Grant WB, Boucher BJ. Are Hill’s criteria for causality satisfied for vitamin D and periodontal disease?. Dermatoendocrinol 2010; 2:30-6; PMID: 21547146; DOI: 10.4161/derm.2.1.12488.

56. Marschall J, Fraser VJ, Doherty J, Warren DK. Between community and hospital: healthcare-associated gram-negative bacteremia among hospitalized patients. Infect Control Hosp Epidemiol 2009; 30:1050-6; PMID: 19803723; DOI: 10.1086/606165.

57. Kumashi P, Girgawy E, Tarrand JJ, Rolston KV, Raad II, Safdar A. Streptococcus pneumoniae bacteremia in patients with cancer: disease characteristics and outcomes in the era of escalating drug resistance (1998-2002). Medicine (Baltimore) 2005; 84:303-12; PMID: 16148730; DOI: 10.1097/01.md.0000180045.26909.29.

58. Laupland KB, Lee H, Gregson DB, Manns BJ. Cost of intensive care unit-acquired bloodstream infections. J Hosp Infect 2006; 63:124-32; PMID: 16621137; DOI: 10.1016/j.jhin.2005.12.016.

59. Agency for Healthcare Research and Quality. “Blood Infections Most Costly Hospital Condition.” Medical News Today. MediLexicon, Intl., 7 Oct. 2011. Web. 10 Nov. 2011.

60. White AN, Ng V, Spain CV, Johnson CC, Kinlin LM, Fisman DN. Let the sun shine in: effects of ultraviolet radiation on invasive pneumococcal disease risk in Philadelphia, Pennsylvania. BMC Infect Dis 2009; 9:196; PMID: 19961583; DOI: 10.1186/1471-2334-9-196.

61. Vanholder R, Van Biesen W. Incidence of infectious morbidity and mortality in dialysis patients. Blood Purif 2002; 20:477-80; PMID: 12207097; DOI: 10.1159/000063556.

62. Zaloga GP, Chernow B, Cook D, Snyder R, Clapper M, O’Brian JT. Assessment of calcium homeostasis in the critically ill surgical patient. The diagnostic pitfalls of the McLean-Hastings nomogram. Ann Surg 1985; 202:587-94; PMID: 4051606; DOI: 10.1097/00000658-198511000-00009.

63. Lee P, Campbell LV. Vitamin D deficiency: the invisible accomplice of metabolic endotoxemia?. Curr Pharm Des 2009; 15:2751-8; PMID: 19689344; DOI: 10.2174/138161209788923895.

64. Amin A, Kollef MH. Health care-associated pneumonia. Hosp Pract (Minneap) 2010; 38:63-74; PMID: 20499775; DOI: 10.3810/hp.2010.06.317.

65. Thompson DA, Makary MA, Dorman T, Pronovost PJ. Clinical and economic outcomes of hospital acquired pneumonia in intra-abdominal surgery patients. Ann Surg 2006; 243:547-52; PMID: 16552208; DOI: 10.1097/01.sla.0000207097.38963.3b.

66. Vayalumkal JV, Gravel D, Moore D, Matlow A. Surveillance for healthcare-acquired febrile respiratory infection in pediatric hospitals participating in the Canadian Nosocomial Infection Surveillance Program. Infect Control Hosp Epidemiol 2009; 30:652-8; PMID: 19496653; DOI: 10.1086/598247.

67. Brown SM, Waterer GW. Vitamin D: stronger lungs as well as stronger bones?. Respirology 2011; 16:577-8; PMID: 21306477; DOI: 10.1111/j.1440-1843.2011.01947.x.

68. Leow L, Simpson T, Cursons R, Karalus N, Hancox RJ. Vitamin D, innate immunity and outcomes in community acquired pneumonia. Respirology 2011; 16:611-6; PMID: 21244571; DOI: 10.1111/j.1440-1843.2011.01924.x.

69. Inamo Y, Hasegawa M, Saito K, Hayashi R, Ishikawa T, Yoshino Y, et al. Serum vitamin D concentrations and associated severity of acute lower respiratory tract infections in Japanese hospitalized children. Pediatr Int 2011; 53:199-201; PMID: 21648117; DOI: 10.1111/j.1442-200X.2010.03224.x.

70. Oduwole AO, Renner JK, Disu E, Ibitoye E, Emokpae E. Relationship between vitamin D levels and outcome of pneumonia in children. West Afr J Med 2010; 29:373-8; PMID: 21465443.

71. Banajeh SM. Nutritional rickets and vitamin D deficiency--association with the outcomes of childhood very severe pneumonia: a prospective cohort study. Pediatr Pulmonol 2009; 44:1207-15; PMID: 19911367; DOI: 10.1002/ppul.21121.

72. Sundar IK, Rahman I. Vitamin d and susceptibility of chronic lung diseases: role of epigenetics. Front Pharmacol 2011; 2:50; PMID: 21941510; DOI: 10.3389/fphar.2011.00050.

73. Rubin BK, Dhand R, Ruppel GL, Branson RD, Hess DR. Respiratory care year in review 2010: part 1. asthma, COPD, pulmonary function testing, ventilator-associated pneumonia. Respir Care 2011; 56:488-502; PMID: 21496376; DOI: 10.4187/respcare.01286.

74. Choudhary N, Gupta P, Vitamin D. Vitamin D Supplementation for Severe Pneumonia A Randomized Controlled Trial. Indian Pediatr 2011; ; PMID: 21992858.

75. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, et al. Epidemic influenza and vitamin D. Epidemiol Infect 2006; 134:1129-40; PMID: 16959053; DOI: 10.1017/S0950268806007175.

76. Goldstein MR, Mascitelli L, Pezzetta F. Pandemic influenza A (H1N1): mandatory vitamin D supplementation?. Med Hypotheses 2010; 74:756; PMID: 20006449; DOI: 10.1016/j.mehy.2009.11.006.

77. Juzeniene A, Ma LW, Kwitniewski M, Polev GA, Lagunova Z, Dahlback A, et al. The seasonality of pandemic and non-pandemic influenzas: the roles of solar radiation and vitamin D. Int J Infect Dis 2010; 14:e1099-105; PMID: 21036090; DOI: 10.1016/j.ijid.2010.09.002.

78. Hayes DP. Influenza pandemics, solar activity cycles, and vitamin D. Med Hypotheses 2010; 74:831-4; PMID: 20056531; DOI: 10.1016/j.mehy.2009.12.002.

79. Grant WB, Giovannucci E. The possible roles of solar ultraviolet-B radiation and vitamin D in reducing case-fatality rates from the 1918-1919 influenza pandemic in the United States. Dermatoendocrinol 2009; 1:215-9; PMID: 20592793; DOI: 10.4161/derm.1.4.9063.

80. Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr 2010; 91:1255-60; PMID: 20219962; DOI: 10.3945/ajcn.2009.29094.

81. Shaman J, Jeon CY, Giovannucci E, Lipsitch M. Shortcomings of vitamin D-based model simulations of seasonal influenza. PLoS One 2011; 6:e20743; PMID: 21677774; DOI: 10.1371/journal.pone.0020743.

82. O’Brien JA, Lahue BJ, Caro JJ, Davidson DM. The emerging infectious challenge of clostridium difficile-associated disease in Massachusetts hospitals: clinical and economic consequences. Infect Control Hosp Epidemiol 2007; 28:1219-27; PMID: 17926270; DOI: 10.1086/522676.

83. Song X, Bartlett JG, Speck K, Naegeli A, Carroll K, Perl TM. Rising economic impact of clostridium difficile-associated disease in adult hospitalized patient population. Infect Control Hosp Epidemiol 2008; 29:823-8; PMID: 18643746; DOI: 10.1086/588756.

84. Dubberke ER, Wertheimer AI. Review of current literature on the economic burden of Clostridium difficile infection. Infect Control Hosp Epidemiol 2009; 30:57-66; PMID: 19049438; DOI: 10.1086/592981.

85. Ooi JH, Chen J, Cantorna MT. Vitamin D regulation of immune function in the gut: why do T cells have vitamin D receptors?. Mol Aspects Med 2012; 33:77-82; PMID: 22079836; DOI: 10.1016/j.mam.2011.10.014.

86. S Tulk, S Hirota, J MacDonald, P Beck. Vitamin D downregulates NLRP3 and protects against Clostridium difficile toxin-induced cell death. University of Calgary, Calgary, AB.

87. Arramraju S, et al “Higher resolution rate of clostridia difficile enteritis in hospitalized patients with normal vitamin D levels” DDW 2010; Abstract T1793.

88. Saint S. Clinical and economic consequences of nosocomial catheter-related bacteriuria. Am J Infect Control 2000; 28:68-75; PMID: 10679141; DOI: 10.1016/S0196-6553(00)90015-4.

89. Gray M. Reducing catheter-associated urinary tract infection in the critical care unit. AACN Adv Crit Care 2010; 21:247-57; PMID: 20683224; DOI: 10.1097/NCI.0b013e3181db53cb.

90. Schwalfenberg GK. A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency. Mol Nutr Food Res 2011; 55:96-108; PMID: 20824663; DOI: 10.1002/mnfr.201000174.

91. Aslan S, Akil I, Aslan G, Onay H, Ozyurt BC, Ozkinay F. Vitamin D receptor gene polymorphism in children with urinary tract infection. Pediatr Nephrol 2012; 27:417-21; PMID: 21947233; DOI: 10.1007/s00467-011-2000-0.

92. Hertting O, Holm Å, Lüthje P, Brauner H, Dyrdak R, Jonasson AF, et al. Vitamin D induction of the human antimicrobial Peptide cathelicidin in the urinary bladder. PLoS One 2010; 5:e15580; PMID: 21179490; DOI: 10.1371/journal.pone.0015580.

93. Felkner M, Pascoe N, Shupe-Ricksecker K, Goodman E. The wound care team: a new source of group a streptococcal nosocomial transmission. Infect Control Hosp Epidemiol 2005; 26:462-5; PMID: 15954484; DOI: 10.1086/502568.

94. Weigelt JA, Lipsky BA, Tabak YP, Derby KG, Kim M, Gupta V. Surgical site infections: Causative pathogens and associated outcomes. Am J Infect Control 2010; 38:112-20; PMID: 19889474; DOI: 10.1016/j.ajic.2009.06.010.

95. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002; 347:1151-60; PMID: 12374875; DOI: 10.1056/NEJMoa021481.

96. Hiemstra PS. The role of epithelial beta-defensins and cathelicidins in host defense of the lung. Exp Lung Res 2007; 33:537-42; PMID: 18075828; DOI: 10.1080/01902140701756687.

97. White JH. Vitamin D as an inducer of cathelicidin antimicrobial peptide expression: past, present and future. J Steroid Biochem Mol Biol 2010; 121:234-8; PMID: 20302931; DOI: 10.1016/j.jsbmb.2010.03.034.

98. Arnold WP, van de Kerkhof PC. The induction of epidermal ornithine decarboxylase following tape stripping is inhibited by a topical vitamin D3 analogue (MC903). Br J Dermatol 1991; 125:6-8; PMID: 1873206; DOI: 10.1111/j.1365-2133.1991.tb06029.x.

99. Bashutski JD, Eber RM, Kinney JS, Benavides E, Maitra S, Braun TM, et al. The impact of vitamin D status on periodontal surgery outcomes. J Dent Res 2011; 90:1007-12; PMID: 21555774; DOI: 10.1177/0022034511407771.

100. George MH, Heinrich PE, Dexter DR, Morgan JB, Odde KG, Glock RD, et al. Injection-site lesions in carcasses of cattle receiving injections at branding and at weaning. J Anim Sci 1995; 73:3235-40; PMID: 8586578.

101. Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 2007; 298:1763-71; PMID: 17940231; DOI: 10.1001/jama.298.15.1763.

102. Rubinstein E, Kollef MH, Nathwani D. Pneumonia caused by methicillin-resistant Staphylococcus aureus.. Clin Infect Dis 2008; 46:S378-85; PMID: 18462093; DOI: 10.1086/533594.

103. Niven DJ, Laupland KB, Gregson DB, Church DL. Epidemiology of Staphylococcus aureus nasal colonization and influence on outcome in the critically ill. J Crit Care 2009; 24:583-9; PMID: 19327313; DOI: 10.1016/j.jcrc.2008.10.004.

104. Matheson EM, Mainous AG, Hueston WJ, Diaz VA, Everett CJ. Vitamin D and methicillin-resistant Staphylococcus aureus nasal carriage. Scand J Infect Dis 2010; 42:455-60; PMID: 20210515; DOI: 10.3109/00365541003602049.

105. Olsen K, Falch BM, Danielsen K, Johannessen M, Ericson Sollid JU, Thune I, et al. Staphylococcus aureus nasal carriage is associated with serum 25-hydroxyvitamin D levels, gender and smoking status. The Tromsø Staph and Skin Study. Eur J Clin Microbiol Infect Dis 2012; 31:465-73; PMID: 21811869; DOI: 10.1007/s10096-011-1331-x.

106. Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 2007; 167:1730-7; PMID: 17846391; DOI: 10.1001/archinte.167.16.1730.

107. Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi V, Gandini S. Vitamin D deficiency and mortality risk in the general population: a meta-analysis of prospective cohort studies. Am J Clin Nutr 2012; 95:91-100; PMID: 22170374; DOI: 10.3945/ajcn.111.014779.

108. Grant WB. An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr 2011; 65:1016-26; PMID: 21731036; DOI: 10.1038/ejcn.2011.68.

109. Schöttker B, Ball D, Gellert C, Brenner H. Serum 25-hydroxyvitamin D levels and overall mortality. A systematic review and meta-analysis of prospective cohort studies. Ageing Res Rev. 2012 Feb 16. [Epub ahead of print] (in print in July)

110. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 2011; 96:53-8; PMID: 21118827; DOI: 10.1210/jc.2010-2704.

111. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr 2005; 135:317-22; PMID: 15671234.

112. Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res 2011; 31:607-11; PMID: 21378345.

113. Norman AW, Bouillon R. Vitamin D nutritional policy needs a vision for the future. Exp Biol Med (Maywood) 2010; 235:1034-45; PMID: 20667908; DOI: 10.1258/ebm.2010.010014.

114. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96:1911-30; PMID: 21646368; DOI: 10.1210/jc.2011-0385.

115. Souberbielle JC, Body JJ, Lappe JM, Plebani M, Shoenfeld Y, Wang TJ, et al. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmun Rev 2010; 9:709-15; PMID: 20601202; DOI: 10.1016/j.autrev.2010.06.009.

116. Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One 2010; 5:e11088; PMID: 20559424; DOI: 10.1371/journal.pone.0011088.

117. Youssef DA, El Abbassi AM, Cutchins DC, Chhabra S, Peiris AN. Vitamin D deficiency: implications for acute care in the elderly and in patients with chronic illness. Geriatr Gerontol Int 2011; 11:395-407; PMID: 21605301; DOI: 10.1111/j.1447-0594.2011.00716.x.

118. Cannell J. Bio-Tech 50,000 IU D3 now available for prescription. 28 Feb 2012. http://www.vitamindcouncil.org/bio-tech-50000-iu-d3-now-available-for-prescription/
- - - - - - - - - - - -