Introduction

Vitamin D deficiency has reached pandemic proportions [1] and is linked to increased health expenditures [2]. Vitamin D has potential benefits on innate immunity [3] and it appears to potentiate antimicrobial actions through a variety of mechanisms, including expression of potent antimicrobial peptides, such as beta defensin 2 and cathelicidin [4, 5]. Moreover, the antimicrobial actions of vitamin D cover a wide range of organisms, such as bacteria (including Mycobacterium tuberculosis) [6], viruses [7], and fungi [8]. Vitamin D deficiency is also associated with an increased risk of MRSA nasal carriage [9].

Methicillin resistant Staphylococcus aureus (MRSA) is endemic in many hospitals, with prevalence rates approaching 30% of all Staphylococcus aureus (S. aureus) infections [10]. Eradication has been difficult, with inappropriate antibiotic use contributing to its prevalence [11]. In New York City, the attributable infection cost of a patient with MRSA was approximately $2,500 higher than the attributable cost of a patient with methicillin sensitive Staphylococcus aureus (MSSA) [12]. The higher cost of MRSA infections versus MSSA infections appears to be due to the higher cost of vancomycin, longer hospital stay, cost of patient isolation procedures, enteral feeding and intensive care [12, 13]. Increased mortality associated with MRSA infection has been documented globally across all age groups [14]. The costs associated with MRSA in Canadian hospitals have been estimated to be $42 to $59 million annually [15].

Similarly, P. aeruginosa is also associated with higher mortality, morbidity and cost of care, and could be community or nosocomially acquired [16]. Pseudomonas septicemia is a significant contributor to mortality in patients with burns [17]. P. aeruginosa is among the most common contributors to intravenous catheter sepsis [18] and a significant contributor to urinary tract infections [19]. Cystic fibrosis patients are susceptible to this pathogen [20], which also contributes frequently to ventilator-associated pneumonia [21]. Patients involved in an outbreak of P. aeruginosa in an intensive care unit had 66% higher adjusted hospital costs than non-affected patients, and had 70 days excess length of ICU stay [22]. Multidrug resistance complicates effective treatment of P. aeruginosa and contributes to increased mortality and costs [23–25]. In one prospective study, bloodstream infections due to P. aeruginosa had a greater risk of hospital mortality compared to bloodstream infections due to S. aureus despite adequate antibiotic treatment [26]. In the 2001 SENTRY Surveillance Program report, P. aeruginosa was the second most common pathogen isolated from ICU patients, trailing only S. aureus [27].

Given the economic burden of the infections related to S. aureus, and P. Aeruginosa, and the emerging evidence of the antimicrobial role of vitamin D, the present study was conducted to determine if vitamin D status is related to increased healthcare costs associated with infections with these two organisms.

Methods

This study was conducted at James H. Quillen Veterans Medical Facility in the southeastern United States. The Research and Development Committee at the Veterans Affairs Medical Center (VAMC) and the Institutional Review Board at the affiliated university approved the study. Data were obtained electronically through retrospective review after personal information was removed. The sample included all patients within the veterans integrated service network-9 (VISN 9) diagnosed with either methicillin resistant Staphylococcus aureus (MRSA) or P. aeruginosa infections from 2000 to 2008, and that also had serum 25-hydroxyvitamin D [25(OH)D] analysis run within 3 months of the initial diagnosis. VISN-9 comprises six VA hospitals in the southeast, including sites in Huntington, WV, Lexington, KY, Louisville, KY, Memphis, TN, Mountain Home, TN and Tennessee Valley, TN. The 25(OH)D assay was peformed by immunochemiluminometric assay (Labcorp, USA).

Patient healthcare costs incurred within one year of diagnosis were estimated. They were estimated by the technical guidelines via the Decision Support System and clinical National Data Extracts standardized by the VA [28]. Costs in the year following diagnosis were broken down into separate inpatient and outpatient categories (i.e. laboratory, pharmacy, radiology, surgery, primary care, emergency room, etc.). For each of the cost categories, a total amount (US$) was analyzed. Fees refer to costs incurred by the VA as a result of consultation and/or procedures performed in the private sector utilizing diagnosis and procedure codes specified in the International Classification of Diseases, Ninth Revision, and Clinical Modification (ICD-9) [29]. Additionally, the total number of inpatient stays, and the number of days of each inpatient stay, represented service utilization and were also recorded for each patient. The database was queried for patients with a discharge diagnosis code of 008.42 reflecting Pseudomonas enteritis, 038.43 for Pseudomonas septicemia, 041.7 for Pseudomonas infections, and 482.1 for Pseudomonal pneumonia; patients with MRSA infections were identified using the ICD-9 code of 038.12 for MRSA septicemia, and 041.12 for other MRSA infections.

Statistical analysis

The 25(OH)D level was analyzed as a dichotomous variable, with vitamin D deficiency defined as 25(OH)D <20 ng/ml [1]. Statistical analyses were performed using SPSS software, version 14.0 (SPSS Inc., USA). All variables were checked for outliers and normality of distribution before analyses were performed. Correlations and χ2 analysis were used to examine associations between type of infection and 25(OH)D level and deficiency status. Student t-tests were used to examine associations between vitamin D status and cost and service utilization.

Results

The final sample contained 58 patients, and as described above, included all patients diagnosed with either MRSA or Pseudomonas infections that had a 25(OH) D within 3 months of the diagnosis, and had at least one year of cost data available. There were 510 MRSA patients and 2,482 Pseudomonas patients without a 25(OH) D level checked within 3 months of diagnosis. Of the 58 patients that had a 25(OH)D level, 14 were diagnosed with MRSA and 44 with Pseudomonas. Of the total sample, 31 were vitamin D deficient (25(OH)D < 20 ng/ml).

Sample background characteristics, in total and by vitamin D status, are presented in Table 1. As can be seen, there were no demographic differences by vitamin D status. In addition, vitamin D status was not significantly different between the MRSA (57.1% deficient) and the Pseudomonas (52.3%) groups (p > 0.05). Since the two diagnosis groups did not differ significantly in vitamin D levels, all analyses were run for the combined group of 58 patients.

Table 1 Sample characteristics by vitamin D status
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As shown in Table 2, the vitamin D deficient group as a whole (i.e. regardless of diagnosis) had higher costs and service utilization. Those that were vitamin D deficient had significantly higher inpatient costs across most categories, despite the fact that those with vitamin D deficiency did not have significantly more inpatient stays or total number of inpatient days (there was a non-significant trend for total number of days). Interestingly, vitamin D deficiency status was not significantly associated with any of the outpatient costs or service utilization variables. In fact, the trend was for those who were deficient to have lower costs and to have fewer visits compared with those who were not deficient.

Table 2 Associations between vitamin D status and cost/service parameters in veterans (N = 58) with MRSA or Pseudomonas infections
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Discussion

Veterans with vitamin D deficiency and either P. aeruginosa or MRSA infections have increased healthcare utilization and expenses. The expenses associated with these infections were significantly higher in hospitalized patients. This report is, to the best of our knowledge, the first to indicate that vitamin D deficiency may be an important and under-recognized contributor to increased hospitalization costs incurred among patients with these two costly infections. Given the increased morbidity and mortality of these infections and the presence of significant vitamin D deficiency among many veterans [2], vitamin D may have a potential role in assisting standard antimicrobial therapies.

Increasing evidence indicates that vitamin D may have an important antimicrobial role. For example, rickets was found to be a significant predictor of reduced success in the treatment of very severe pneumonia, as seen in a prospective cohort study conducted in Yemen [30]. In this Yemeni study, vitamin D deficiency also predicted reduced neutrophil counts and 5-day hypoxemia. In one double-blind, randomized, placebo-controlled study in inner city children in Kabul, a single high dose treatment (100,000 IU) of vitamin D3 along with antibiotic treatment reduced repeated pneumonia episodes by approximately 22% [31]. This is possibly secondary to the fact that vitamin D3 proved inhibitory to S. aureus, Streptococcus pyogenes, Klebsiella pneumoniae, Escherichia coli, and other bacteria in vitro studies [32]. Similarly, in an experimental model of turkey osteomyelitis, vitamin D treatment resulted in reduced bacterial presence in tissue and improved mortality [33]. In addition, vitamin D may reduce the risk of caries and periodontal disease by anti-bacterial action against Streptococcus mutans [34].

The antimicrobial effects of vitamin D are not confined solely to bacterial infections. There is evidence that vitamin D may have a protective role in influenza [7] and other viral diseases, such as AIDS in HIV [35], hepatitis infection [36, 37], Avian flu [38] and other viruses. Recent discoveries indicate the importance of vitamin D-dependent generation of antimicrobial peptides in human host defense against Mycobacterium tuberculosis [6]. Low vitamin D levels were associated with a 5-fold increased risk for progression to tuberculosis [39]. Vitamin D may also play a role in the control of fungal infections such as candidiasis [40], chromoblastomycosis [8] and histoplasmosis [41]. In addition, studies on parasitic infections revealed that enriched vitamin D supplements hinder growth of P. falciparum [42], decrease the rate of reinfection with Schistosoma mansoni [43], and exert a toxic effect on Hymenolepis microstoma [44].

The antimicrobial effects of vitamin D may work through a multitude of complex mechanisms which are becoming better delineated. The vitamin D receptor is ubiquitous, including a presence on B and T lymphocytes, monocytes and dendritic cells [45]. Circulating vitamin D levels have a direct influence on macrophages, increasing their oxidative burst potential [7]. It also facilitates neutrophil motility and phagocytic function [46]. Vitamin D stimulates the expression of potent antimicrobial peptides, such as beta defensin and cathelicidin [4], which exist in neutrophils, natural killer cells, and in epithelial cells lining the respiratory tract [5]. Schauber et al. revealed that vitamin D3 induced cathelicidin expression in keratinocytes and monocytes, and enhanced antimicrobial activity against S. aureus [47]. Human cathelicidin has antimicrobial as well as anti-endotoxin activity [48]. The potential boost in innate immunity by vitamin D may also help recovery from acute illness such as the case of patients in intensive care units [49]. In patients with cystic fibrosis, an inverse relationship between vitamin D and serum immunoglobulin G has been reported [50]. Vitamin D also reduces both local and systemic inflammatory responses as a result of modulating cytokine responses and reducing toll-like receptor activation [4]. Clinical evidence from ICU studies indicates that lower vitamin D levels may be associated with an approximate doubling of length of stay and mortality in intensive care units [51].

The current study does have certain inherent limitations. Given the retrospective nature of our investigation, not all factors which could have influenced outcomes could be controlled. Our sample size is small and we believe this reflects inadequate testing in veteran populations, as has been noted previously [52]. Only about 1% of patients with MRSA and Pseudomonas aeruginosa had 25(OH)D levels done. We could not assess the extent to which vitamin D was replaced; however, we do not believe this would have significant impact on our study since prior studies were consistent with inadequate monitoring and replacement of vitamin D in veterans [52, 53].

It is also possible that because the patients with the infections of interest were acutely ill, this in itself could have resulted in lower vitamin D levels. We do not believe this likely, however, since the levels of 25(OH)D observed in this study are comparable to 25(OH)D values previously reported in many different populations [54–56]. More importantly, acute infections such as falciparum malaria infection do not appear to lower vitamin D levels [57].

Underlying conditions could be responsible for the findings, and a selection bias could be present in that testing was done in sicker patients or patients more likely to be vitamin D deficient. However, the sample size was too small to statistically control for underlying conditions. It is also possible that underlying illness rather than vitamin D deficiency could have contributed to costs. However, preadmission vitamin D levels were linked to adverse outcomes [58], and potentially increased costs. Data for BMI, age and comorbidities were available, and while they may confound the findings, the sample size was just too small to control for them statistically. Future studies should include larger study groups and factors that could account for vitamin D deficiency including co-morbid conditions, seasonality, race and obesity. Large study populations may enable a greater in-depth look at specific infections; we were unable to do this on account of our sample size.

In conclusion, we believe that achieving a vitamin D replete state should be given high priority when treating P. aeruginosa and MRSA infections. The present study confirms and extends similar findings found in veterans with Clostridium difficile and Methicillin sensitive staphylococcus aureus (MSSA) infections. This suggests that vitamin D deficiency may be a significant factor in increasing costs not only in MSSA and Clostridium difficile, but also in MRSA and Pseudomonas infections, and possibly other bacterial infections [59]. Inappropriate antibiotic therapy along with overzealous antibiotic use enhances the development of such pathogens as MRSA, with concomitant increases in mortality, length of stay and hospital costs [60–62]. Higher doses of vitamin D than currently recommended may be needed to achieve and maintain 25(OH)D levels in the therapeutic range [55] and have the benefit of negligible costs compared to many antibiotics. An exciting area for further exploration is the potential for brief, very high dose therapy in acute infectious illness. In any event, these potential antimicrobial benefits may be added to the long list of health benefits associated with adequate vitamin D reserves, including improved well-being and enhanced longevity [63], with a projected significant savings in global healthcare costs [64]. Our findings in this current study should provide an impetus to initiate additional prospective controlled studies to evaluate the important antibacterial benefits of vitamin D supplementation.