Vitamin D for Sepsis prevention – June 2018

Applications of Vitamin D in Sepsis Prevention
DiscovMed , June 25, 2018

Author: Fernanda A.C. Takeuti
Specialty: Microbiology, Immunology
Institution: Pontifical Catholic University of Paraná School of Medicine
Address: Curitiba, Paraná, Brazil

Author: Fernando Souza-Fonseca-Guimaraes
Specialty: Immunology, Oncology
Institution: Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research
Address: Parkville, Victoria, 3052, Australia

Author: Paulo S.F. Guimaraes
Specialty: Microbiology, Immunology
Institution: Pontifical Catholic University of Paraná School of Medicine
Address: Curitiba, Paraná, Brazil
Institution: Department of Nutrology, Cajuru University
Address: Curitiba, Paraná, Brazil

Abstract

Vitamin D (VD) is a steroid prohormone that regulates the body's calcium and phosphate levels in bone mineralization. It is also well described as a fat-soluble vitamin playing an important role in immunomodulation, regulation of cytokines, and cell proliferation. Thus, VD is a powerful hormone with pleiotropic effects, which acts to maintain optimal health. Recent studies demonstrate that VD deficiency is associated with the development of cardiovascular diseases, autoimmune disorders, and various types of cancer, each associated with increased mortality rates. VD deficiency is commonly seen in the intensive care unit (ICU); it aggravates the incidence and outcome of infectious complications in critically ill patients. In particular, VD deficiency is associated with an increased risk of sepsis and more severe clinical outcomes in patients with sepsis. These patients have dysregulated VD metabolism and frequently present insufficient plasma VD levels, which contribute to the deterioration of their clinical state. In this review, we summarize the role of VD in the immune system, the consequences of its deficiency and we discuss potential perspectives on VD supplementation in preventing sepsis and enhancing patient recovery. Although the relevance of the applications of VD in sepsis is stated, further studies are required to elucidate the optimal VD plasma levels and the recommended daily intake.

Introduction

Sepsis is a leading cause of morbidity and mortality in critically ill patients worldwide (Vipul et al., 2017). It accounts for more than 210,000 deaths annually in the United States, and similar death rates have been reported for other countries (Angus et al., 2001; Prucha et al., 2018). The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) Task Force define sepsis as a “life threatening organ dysfunction caused by a dysregulated host response to infection” (Singer et al., 2016). Organ dysfunction is characterized by the acute increase of at least two points in the Sequential (Sepsis-related) Organ Failure Assessment (SOFA) score (Finkelsztein et al., 2017; Singer et al., 2016). Given that SOFA scores require laboratory testing and are mostly used inside the ICU, the Sepsis-3 Task Force introduced a simpler algorithm for patients in a non-ICU setting, named “quick SOFA” (qSOFA) (Finkelsztein et al., 2017; Singer et al., 2016). This score is a modified version of the SOFA score, consisting of three clinical components (namely hypotension, tachypnea, and altered consciousness), where each element is allocated one point. A qSOFA score of ≥2 points indicates organ dysfunction (Finkelsztein et al., 2017; Paul and Taeb, 2017; Singer et al., 2016).

If untreated, sepsis may progress to severe sepsis and lead to further complications such as multiple organ failure (MOF) (Annane et al., 2005). Patients with untreated sepsis have an increased risk of advancing into septic shock, which presents as acute circulatory failure and persistent hypotension despite intravenous fluid resuscitation. Both MOF and septic shock will eventually lead to a patient’s death (Annane et al., 2005; Bone et al., 1992). Studies suggest that many trace elements and nutrients, such as VD, have a positive effect on health status, improving prognosis in septic patients. In addition to the regulation of calcium homeostasis, it has been demonstrated that VD also has a role in the regulation of inflammatory responses against infection (Greulich et al., 2017; Vipul et al., 2017). The mechanism underlying this process involves the upregulation of endogenous antimicrobial peptide (AMP) cathelicidin (LL-37) in human skin, plasma, monocytes, and macrophages. LL-37 and other AMPs exhibit direct antimicrobial effects against microorganisms and modulate numerous innate and adaptive immune functions (Haan et al., 2014; Han et al., 2017; Rech et al., 2014).

VD deficiency has been reported to be widely prevalent in critically ill patients. Morbidity and mortality are increased amongst these patients due to the negative clinical outcomes associated with VD deficiency (Greulich et al., 2017; Mathews et al., 2014). The potential benefit of VD administration in critically ill patients is currently being investigated. Recently, a number of randomized clinical trials have studied various high-dose regimens of cholecalciferol (VD3) and reported benefits on clinical outcomes, including increased total 25-hydroxyvitamin D [25(OH)D, or calcidiol] levels in blood, reduced mortality (Schndel et al., 2014), and reduced hospital length of stay (Han et al. 2016; Quraishi et al., 2015). This review summarizes the role of VD in the immune system and the consequences of its deficiency. It also discusses the correlation of VD with sepsis and perspectives on its supplementation in preventing sepsis and enhancing patient recovery.

Vitamin D and the Immune System

VD may be obtained from three potential sources: nutritional sources, UVB- dependent endogenous production, and supplements. In humans, up to 90% of VD is synthesized in the skin after exposure to ultraviolet B (UVB), whereas only a minor part is derived from dietary sources. To ensure adequate levels of VD, at least three hours of direct sunlight are required every day (Calle and Torrejon, 2012; Izadpanah and Khalili, 2013; Shuler et al., 2013).

In the human skin, cholecalciferol is synthesized from 7-dihydrocholesterol when exposed to UVB. Cholecalciferol is biologically inactive and immediately binds to VD binding proteins (VDBP) (Prietl et al., 2013), before entering the circulation and moving to the liver for hydroxylation. Hydroxylation is performed by cytochrome P450 CYP27A1 (25-hydroxylase) to form 25(OH)D, its storage form. 25(OH)D is then converted — either in an autocrine manner or in response to cytokines — to the active form 1,25-dihydroxyvitamin D [1,25(OH)2D or calcitriol] by CYP27B1 (1α-hydroxylase). CYP27B1 is an enzyme expressed in many cell types, including intestinal, pancreatic, prostatic, and immune cells. This conversion can take place in the peripheral, but most 1,25(OH)2D is produced by the kidneys, predominantly in response to parathyroid hormone secretion, as part of the classic pathway (Calle and Torrejon, 2012; Izadpanah and Khalili, 2013; Kearns et al., 2015; Shuler et al., 2013). Furthermore, VD can enter cells and act as a steroid hormone to protect the organism against various diseases and modulate the immune system using its various pleiotropic effects (Jeng et al., 2009; Jovanovich et al., 2014). Figure 1 illustrates the metabolic availability of VD and its effects on mineral homeostasis.

Figure 1. VD can be made endogenously in the epidermis after exposure to UVB rays. VD binds to VDBP, which distributes it throughout the body, and undergoes hydroxylation by CYP27A1 to form 25(OH)D. 20(OH)D is then converted to the active form 1,25(OH)2D by CYP27B1.

The association between VD status and immunity has been supported by a number of studies (Lasky-Su et al., 2017; Prietl, 2013). VD regulates both innate and adaptive immune systems. Its deficiency leads to immune dysregulation and infection by pathogens (Haan, 2014). Experiments on VD supplementation in critically ill patients demonstrated that VD prevents the excessive production of proinflammatory cytokines [such as interleukin-6 (IL-6) and C-reactive protein], increases production of anti-inflammatory mediators (such as IL-10), and can act as an antibacterial peptide (such as cathelicidin) (Trongtrakul and Feemuchang, 2017). VD can also activate endothelial cells and increase the antibacterial capacity of macrophages, influencing the activation of toll-like receptors (TLRs), leukocyte migration, local inflammation, and innate immune responses against bacteria (Al Nozha, 2016; Moromizato et al., 2014; Su et al., 2013).

The enzyme CYP27B1 is expressed in most cells in the immune system. These cells also express the vitamin D receptor (VDR), a nuclear receptor that modulates the expression of genes involved in cytokine production by antigen-presenting cells (APCs), such as monocytes, macrophages, dendritic cells, and T lymphocytes (Cantorna et al., 2015; Murdoch et al., 2012; Youssef et al., 2011). VD tends to stimulate innate immune cells to respond to infection. After VD binds its receptor, it is converted into its active form. This active form regulates B-cell homeostasis and facilitates neutrophil motility and function, as well as increasing macrophage oxidative burst potential and inducing macrophages to mature and produce acid phosphatase and hydrogen peroxide. These compounds are responsible for the antimicrobial function of these cells (Rech et al., 2014; Gerke et al., 2014).

Consequences of Vitamin D Deficiency

The primary and most established role of VD is the maintenance of calcium and phosphorus homeostasis in bone mineralization; deficiency of these minerals can lead to rickets, osteomalacia, and osteoporosis (Caccamo et al., 2018; Izadpanah and Khalili, 2013). As VD is liposoluble, it can enter cells as a steroid hormone and initiate its pleiotropic effects, protecting the organism against infection, heart disease, cancer, hypertension, autoimmune disease, and diabetes (Al Nozha, 2016; Flynn et al., 2012; Goldsmith, 2015).

Most VD metabolites have a very short plasma half-life; however, 25(OH)D, the most abundant and stable form, has a half-life of approximately three weeks and is the most established indicator of vitamin D nutritional status (Caccamo et al., 2018; Shuler et al., 2013). Measurement of serum VD is recommended for certain conditions, including osteoporosis, chronic kidney disease, liver disease, mal-absorptive diseases such as cystic fibrosis and inflammatory bowel disease, hyperparathyroidism, granulomatous diseases such as sarcoidosis, tuberculosis, histoplasmosis, lymphomas, and following bariatric surgery and radiotherapy. A serum VD level of ≤20 ng/mL is interpreted as deficiency, 21 to 29 ng/mL as insufficiency, and ≥30 ng/mL as sufficiency. A serum level between 30 and 100 ng/mL is considered normal (Izadpanah and Khalili, 2013; Moromizato et al., 2014; Watkins et al., 2011). Approximately 1 billion people have VD insufficiency or deficiency worldwide, and its deficiency is commonly associated with death in critically ill patients with sepsis (Kempker et al., 2012a).

Individuals of African descent are more likely to develop sepsis and organ dysfunction associated with VD deficiency. This is due to greater skin pigmentation, which reduces VD production in the skin as melanin competes with the VD precursor 7-dehydrocholesterol to absorb UVB photons (Kempker et al., 2012b; Shuler et al., 2013; Watkins and Lively, 2012). Furthermore, obese individuals have more clinical complications and a greater prevalence of severe sepsis. Furthermore, these individuals have reduced plasma VD levels and produce 57% less VD in the skin compared with healthy weight individuals. Obese individuals also have lower rates of intestinal absorption of VD (Watkins and Lively, 2012). The elderly have reduced serum VD levels and synthesize less than half as much VD as twenty-year-olds. Lower levels of VD in both the elderly and the obese may be related to reduced photoproduction of VD in the skin by UVB as well as reduced physical activity and time spent outside (Caccamo et al., 2018; Watkins and Lively, 2012). Other risk factors for VD deficiency include intestinal absorption difficulties in inflammatory bowel disease and treatment with medications including anticonvulsants, glucocorticoids, antifungal agents, and antiretroviral agents. Young infants, pregnant women, and breastfeeding mothers are also at greater risk of VD deficiency (Abe et al., 2016; Principi et al., 2013).

Vitamin D and Sepsis

VD metabolic enzymes and VDRs have a wide tissue distribution, reflecting the involvement of VD in the metabolism and function of many cell types (Kearns et al., 2015). Indeed, differential metabolic profiles are demonstrated in ambulatory patients who respond to VD supplementation, relative to those who do not (Raygan et al., 2018). Since metabolic homeostasis is often disrupted in critical illness, substantial modifications of numerous intrinsic pathways can be expected in septic patients (Lasky-Su et al., 2017).

Patients who are hospitalized with a serious condition more frequently have lower levels of 25(OH)D than healthy individuals. Recent evidence suggests that sufficient levels of VD can play an important protective role in these patients, particularly those with sepsis (Izadpanah and Khalili, 2013; Upala et al., 2015; Watkins et al., 2011). Low VD levels in sepsis patients may be due to protein catabolism with consequent reduced levels of VDBP, a key protein and predictor of mortality in intensive care units that is associated with early sepsis and a worse prognosis when present in reduced absolute levels (Izadpanah and Khalili, 2013; Watkins et al., 2011). However, as the immune assay used to detect 25(OH)D depends on VDBP, and levels of VDBP are reduced with sepsis, hypoalbuminemia, and hemodilution (serum concentrations of VDBP can be reduced by 35% during the first 24 hours of intravenous fluid replacement), it remains unclear whether there is a correlation between sepsis and reduced 25(OH)D levels (Kempker et al., 2012b; Moromizato et al., 2014; Watkins et al., 2011). Furthermore, critically ill patients have less exposure to sunlight and do not receive sufficient VD in their diet to have beneficial effects on the immune system (Flynn et al., 2012). Seasonal variation can also influence VD deficiency, as plasma 25(OH)D levels vary throughout the year, reaching a maximum in autumn and a minimum after winter. This may explain the finding that mortality rates due to sepsis are reduced during summer (Al Nozha, 2016).

VD deficiency prior to hospitalization is associated with a greater mortality and a greater prevalence of bacteria-positive blood cultures in critically ill patients (Ginde et al., 2011; Parekh et al., 2017). Scores of illness severity such as the Acute Physiology Age Chronic Health Evaluation (APACHE) II, Sepsis-related Organ Failure Assessment (SOFA), and Simplified Acute Physiology Score 3 (SAPS 3) are frequently used to measure the severity of medical illness and infection (Singer et al., 2016). Although there is no statistically significant correlation between VD levels and the scores, the risk of mortality is 1.9 times greater in individuals with a VD deficiency (Braun et al., 2011; 2012; Murdoch et al., 2012). In patients with a severe condition (APACHE II >18), VD deficiency presented worse outcomes, with longer hospitalization, increased hospital costs, higher predisposition to Staphylococcus aureus and Clostridium difficile infections, and increased mortality (Flynn et al., 2012; Kempker et al., 2012a; Quraishi et al., 2013; Su et al., 2013). The exact association is yet to be understood; however, there is a known increase in proinflammatory interleukin production, alongside adverse effects such as excessive oxidative stress and increased expression of endothelial adhesion molecules, which have a significant contribution to the pathogenesis of sepsis (de Haan et al., 2014; Herr et al., 2011; Jovanovich et al., 2014). The effects of 1,25(OH)2D include inhibition of T cell proliferation, a reduction in proinflammatory cytokines [tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), IL-1β, IL-2, IL-6, IL-8, and IL-17] and an increase in anti-inflammatory cytokines (IL-4 and IL-10) (Calton et al., 2015; Cantorna et al., 2015).

Vitamin D Supplementation in Sepsis

Critically ill septic patients suffer from VD metabolism and parathyroid disorders (Dancer et al., 2015; Su et al., 2013). In these patients, plasma VD levels and the production of AMPs decreased, leading to a reduced capacity of mounting a sufficient response to insult, injury, or infection. Although reduced plasma VD levels are associated with increased susceptibility to infection and development of hospital-acquired bloodstream infections, multiple studies have investigated potentially modifiable host factors that could reduce these risks (Dancer et al., 2015; Lehouck et al., 2012). It has been reported that after pretreatment with VD, endothelial cells are able to reduce production of proinflammatory cytokines (IL-6 and IL-8) induced by LPS and inhibit activation of the NF-κβ pathway (Parekh et al., 2017; Xu et al., 2015a; 2015b).

A recent randomized controlled clinical trial on VD supplementation in critically ill patients demonstrated that hospital mortality was lower among patients who received VD supplementation (4%) in comparison to those who did not (28%). Length of stay in intensive care units was also shorter in the former group. Ergocalciferol (VD2) or VD3 supplementation can be used to achieve these benefits and should be administered during the first thirty days of hospitalization (Quraishi et al., 2013). Parenteral supplementation should be considered in critically ill patients as it allows the immunomodulatory action of VD to be exerted more effectively, given the reduced oral absorption of many nutrients and medications in these patients, which causes complications associated with absorption, hydroxylation, and transport of VD, and conversion of 25(OH)D into 1,25(OH2)D. VD supplementation is associated with lower levels of C-reactive protein, IL-6, and TNF-α, indicating that it leads to positive immunomodulatory effects, such as a dose-dependent reduction in proinflammatory cytokines, and immunosuppressive effects. Further interventional studies are required to determine the optimal dosing regime and timing of dosage for VD supplementation (Dancer et al., 2015; Izadpanah and Khalili, 2013; Lehouck et al., 2012).

The exact level that constitutes VD sufficiency is controversial in critically ill patients and its measurement should be interpreted with caution. In these patients, albumin concentrations can fluctuate, and the dilution effect of intravenous volume resuscitation and loss of transport proteins require close evaluation (Lee, 2011; Watkins et al., 2011). There is also a lack of consensus regarding the plasma concentration required to ensure the extra-skeletal pleiotropic effects of VD, although it has been suggested that higher serum concentrations of 40 to 50 ng/mL are required. Moreover, the number of studies regarding the effects of VD supplementation and the reduced risk of infection is limited (Braun et al., 2012; Herr et al., 2011; Jovanovich et al., 2014; Lee, 2011). Ergocalciferol (VD2) can be used as a replacement or supplement, but cholecalciferol (VD3) is more effective in maintaining and boosting 25(OH)D levels. The recommended daily intake of VD is 600 IU for individuals under 70 years of age and 800 IU for older individuals. These values should be at least 50% greater for susceptible individuals and 150% greater for pregnant and breastfeeding women (Principi et al., 2013).

Recent studies support VD as a potential therapeutic agent in hospitalized patients (Lasky-Su et al., 2017). Its supplementation could therefore improve clinical response and reduce prescriptions of antibiotics, as there is evidence that maintenance of VD levels around 45 ng/mL may significantly reduce mortality and the incidence of infections in the upper respiratory tract (Gois et al., 2017).

The multiple roles of VD in the immune system’s response to infection suggest that its supplementation could contribute to the fight against sepsis (Goldsmith, 2015). Supplementation is cheap, safe, and may provide a significant impact on public health, and hence is recommended for sepsis prevention and treatment of septic patients. Although its importance is stated, further studies on optimal plasma VD levels and the recommended daily intake are needed.

Conclusion

The mechanism linking VD deficiency with increased mortality in septic patients may potentially involve regulation of the adaptive and innate immune responses, both of which involve VDR expression. The potential role of VD in critically ill patients is yet to be defined, as there is no consensus to date on the relationship between its serum levels and its immunomodulatory actions in septic patients. Recent findings will contribute to improving clinical results for critically ill patients and patients suffering from VD deficiency/sepsis. In addition, there is a need to identify the risk factors associated with VD deficiency in sepsis and the correlation between serum levels of 25(OH)D and 1,25(OH2)D. Finally, the effects of comorbidities on serum VD concentration in critically ill patients requires further investigation, as well as the best supplementation dose and the duration of treatment for critically ill patients.

Acknowledgments: We thank Robert Hennessy for editing, discussion, comments, and advice on this review.

Disclosure: Authors declare no conflicts of interest.

Corresponding Author: Paulo de S.F. Guimaraes, M.D., Ph.D., Pontifícal Catholic University of Paraná School of Medicine, Curitiba, Paraná, Brazil.

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