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Update on vitamin D role in severe infections and sepsis
Journal of Anesthesia, Analgesia and Critical Care volume 4, Article number: 4 (2024)
Abstract
Severe infections frequently require admission to the intensive care unit and cause life-threatening complications in critically ill patients. In this setting, severe infections are acknowledged as prerequisites for the development of sepsis, whose pathophysiology implies a dysregulated host response to pathogens, leading to disability and mortality worldwide.
Vitamin D is a secosteroid hormone that plays a pivotal role to maintain immune system homeostasis, which is of paramount importance to resolve infection and modulate the burden of sepsis. Specifically, vitamin D deficiency has been widely reported in critically ill patients and represents a risk factor for the development of severe infections, sepsis and worse clinical outcomes. Several studies have demonstrated the feasibility, safety and effectiveness of vitamin D supplementation strategies to improve vitamin D body content, but conflictual results support its benefit in general populations of critically ill patients. In contrast, small randomised clinical trials reported that vitamin D supplementation may improve host-defence to pathogen invasion via the production of cathelicidin and specific cytokines. Nonetheless, no large scale investigations have been designed to specifically assess the impact of vitamin D supplementation on the outcome of critically ill septic patients admitted to the intensive care unit.
Background
Sepsis is a leading cause of disability and mortality worldwide, thus representing a global challenge and a research priority for clinicians and health care systems [1]. The pathophysiology of sepsis implies a dysregulated host response to severe infection leading to multi-organ dysfunction and worse clinical outcomes [2]. The 2021 Surviving Sepsis Campaign guidelines [3] recommended the timely implementation of several interventions with the aim to lighten the burden of sepsis, which include early patient recognition, identification and effective control of the infective source, appropriate antimicrobial therapy and adequate multi-organ support. However, no therapies directly targeting the immune system dysfunction [4,5,6,7,8] have been suggested beyond the systemic administration of corticosteroids in specific clinical settings [9,10,11,12,13].
In this context, an increasing amount of research revealed the theoretic role of vitamin D to restore the immune system homeostasis and potentially limiting the consequences of inflammatory dysregulation [14,15,16]. Vitamin D is a secosteroid hormone, whose metabolism relies on diet, sun exposure, and liver and kidney functions, being altered by acute or chronic diseases affecting these organs [15]. Epidemiologic reports highlighted the wide diffusion of vitamin D deficiency in the community [17, 18] and its large prevalence (about 70%) among critically ill patients admitted to the intensive care unit (ICU) [19], for whom it represents a risk factor for the development of severe infections, sepsis and worse clinical outcomes [20,21,22,23]. In order to overcome these issues, several researches have demonstrated the feasibility and safety of vitamin D supplementation in critical care, which was shown effective to improve vitamin D body content [24, 25]. However, controversial results do not support its benefit on patient prognosis [26,27,28,29].
In this narrative review, we report the epidemiology of infections in ICU patients and describe the pathophysiology of sepsis. Moreover, we discuss the physiology of vitamin D, the clinical implications of vitamin D deficiency and the effect of vitamin D supplementation in critically ill patients with severe infections and sepsis. Finally, we provide an overview of ongoing clinical investigations in this field.
Main text
Severe infection, host response and sepsis
Epidemiology of infections and sepsis in ICU
Severe infections are leading causes of admission to the ICU and represent frequent complications during the ICU stay, being acknowledged as prerequisites for the development of sepsis [30]. Vincent et al. designed a 24-h point prevalence study involving 1150 centres in 88 countries with the aim to report the prevalence of infections in critically ill patients admitted to the ICU. Among 15,202 patients included, 8135 (54%) had suspected or proven infections, 1760 (22%) of whom were acquired in the ICU and represented a predictor of higher mortality compared with the community-acquired ones. Pathogen identification was reported in 5259 (65%) patients and was characterised by gram-negative bacteria (3540 patients, 67%), gram-positive bacteria (1946 patients, 37%), fungi (864 patients, 16%), viruses (196 patients, 3.7%) and parasites (43 patients, 0.8%). In comparison with previous investigations, this study reported an increasing rate of infections, which was 45% in 1992 (the EPIC I study [31]) and 51% in 2007 (the EPIC II study [32]). This finding was explained by the authors as possibly due to improvement in surveillance programmes for the early diagnosis of infection in ICU patients. Unfortunately, this study did not provide specific information on the epidemiologic and clinical characteristics of sepsis, that was reported on a large scale by the ICON study in 2012 [33]. In this paper, Vincent et al. included 10,069 patients from 730 centres in 84 countries and found that sepsis was diagnosed in 2973 (20.5%) patients on admission or during the ICU stay [33, 34]. In comparison with the SOAP study in 2002 [35], the proportion of patients with sepsis was slightly higher in the ICON study (29.6% vs 31.9%, p = 0.03) and characterised by increased disease severity (SAPS II score 41.9 ± 18.2 vs. 36.5 ± 17.1; SOFA scores on admission 6.3 ± 4.3 vs. 5.1 ± 3.8, maximum SOFA scores during the ICU stay 7.8 ± 4.8 vs. 6.6 ± 4.4, all p < 0.001), although the adjusted odds of ICU mortality was lower [OR 0.45 (0.35–0.59), p < 0.001] [36]. Over the last decade, the reported incidence of sepsis is increasing [37], likely due to the ageing population and greater recognition, but the true incidence remains unknown [2].
Inflammatory system dysfunction and sepsis
Sepsis results from the dysregulated inflammatory response to pathogens invading sterile organs or altering microbiota homeostasis with shift from symbiosis to dysbiosis [38]. Pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) are recognised by specific receptors (e.g. the toll-like receptor, TLR), whose activation induces multiple intracellular pathways leading to the expression of specific genes, which codify for inflammatory (e.g. cytokines) and metabolic molecules (e.g. hormones) [5]. The physiological rationale of immune activation triggered by pathogen recognition aims to control such a microbial threat and is counterbalanced by immunosuppressive pathways, in order to limit tissue damage. In this setting, sepsis occurs when the balance between immune activation and immune suppression is lost, and causes both metabolic derangements and organ dysfunction [2]. Traditionally, immune activation was considered the early stage of inflammation and implied the release of tumour necrosis factor-α (TNF-α), several interleukins (e.g. IL-1β, IL-2, IL-6, IL-8) and interferon-γ (IFN-γ). In contrast, immune suppression was considered the late stage of inflammation and was mediated by the release of specific molecules (e.g. IL-10). However, recent evidence demonstrated that immune activation and immune suppression coexist during the whole inflammatory response process [39] and no specific therapies have been demonstrated effective to improve the immune system dysfunction [4,5,6,7,8]. In this setting, an increasing amount of research have shed light on the potential of vitamin D to mitigate hyperinflammation as well as foster host defence towards infections via the enhanced production of cathelicidins.
Physiology of vitamin D
Metabolism
The vitamin D family includes several lipophilic hormones characterised by a secosteroid structure [40], among those vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) exert the most biologically powerful activity. The intake of vitamin D2 comes mostly from diet (e.g. vegetables), while vitamin D3 is mostly produced in the skin by the reaction with solar ultraviolet B radiation, although it is contained in few aliments (e.g. animal-based food like fatty fish and egg) [41]. For these reasons, vitamin D production is influenced by sun exposure (e.g. season, latitude, clothing), diet and age (skin structure change with dermis reduction) [16].
Vitamin D is turned by the 25-hydroxylase of the liver (cytochrome p450, CYP2R1—endoplasmic reticulum) into the 25-hydroxyvitamin D [25(OH)D, calcidiol], which is further converted by the 1α-hydroxylase (cytochrome p450, CYP27B1- mitochondria) of the renal tubular cells into the most biologically active 1,25-dihydroxyvitamin D [1,25(OH)2D, calcitriol] [41]. Of note, the 1α-hydroxylase has been identified in several extra-renal tissues (e.g. immune and inflammatory cells), where it is supposed to contribute to intracrine and paracrine regulation pathways [42]. Vitamin D circulates into the bloodstream predominantly carried by the glycoprotein vitamin D binding protein (VDBP) [43] in a very stable complex. In contrast, free and albumin-bound compounds roughly accounts for the 10% of circulating vitamin D and are considered rapidly available for biological functions [44]. Although the 1,25-dihydroxyvitamin D is the most biologically active form of this hormone [45], the 25-dihydroxyvitamin D is characterised by greater blood level (1000 times) and longer half-life (4 h vs 2–3 weeks, respectively) [46].
Pathophysiologic implications
Vitamin D is characterised by several pleiotropic activities beyond the calcium/phosphate balance (classical metabolic pathway), which include microbial clearance, immunomodulation of innate and adaptive responses [47], anti-tumour and cardiovascular homeostasis [15]. Over the last decades, an increasing amount of evidence has reported an association between vitamin D status alterations and inflammatory diseases [16, 48]. Specifically, 1,25(OH)2D influences both innate (pathogen recognition and antigen presentation) and adaptive (T and B lymphocyte function) inflammatory pathways (Fig. 1) via the nuclear vitamin D receptor (nVDR), that acts as a transcription factor modulating inflammatory cells activation, differentiation and production of cytokines [16]. The 1,25(OH)2D reduces the production of proinflammatory cytokines (IL-12, IFN- γ, IL-6, IL-8, TNF-α, IL-17, IL-9), increases the production of anti-inflammatory cytokines (IL-4, IL-5 and IL-10), enhances the differentiation of T regulatory cells, tolerogenic dendritic cells and monocytes to macrophages [16, 49,50,51,52]. Moreover, the 1,25(OH)2D inhibits the COX-2 transcription [53]. Similarly, the 1,25(OH)2D exerts inhibitory effects on B-cells proliferation, differentiation to plasma cells, and immunoglobulin production, while it induces apoptosis of these cells [16, 54,55,56,57], thus implying a role for vitamin D to promote immune tolerance [48]. Also, the 1,25 (OH)2D exerts non-genomic effects via the membrane vitamin D receptor (mVDR), thus modulating intracellular signalling pathways [16]. In severe infections and sepsis, the Toll-like receptors (TLRs) play roles of paramount importance to early recognise and rapidly respond to pathogen invasion via the activation of several inflammatory pathways [58]. The activation of the TLRs influences the production of immunological peptides that are actively involved in the host response to infection, like cathelicidins [59]. Specifically, cathelicidins are antimicrobial peptides forming α-helices that have been identified in many mammalian species, whose C-terminal domain has antimicrobial properties by both disrupting pathogen membrane and improving immune cell signalling [60]. In humans, the sole cathelicidin found was the hCAP18, which was isolated in neutrophils, monocytes, lymphocytes and epithelial cells at the barrier level [24]. The C-terminal domain of the hCAP18, the LL-37, was demonstrated to exert potent broad-spectrum antimicrobial activities against viruses and bacteria [61,62,63,64]. In critically ill patients with sepsis, the 25-hydroxyvitamin D blood concentration was demonstrated to be directly associated with LL-37 [65]. Pre-clinical investigations showed that airway epithelial cells express both the VDR and the 1α-hydroxylase [61], thus inducing the production of antimicrobial peptides like cathelicidin and defensin β4.
Vitamin D status alterations
The 25(OH)D is the major circulating vitamin D metabolite [66] and its concentration has been widely used to assess the vitamin D status. Specifically, the Institute of Medicine [67] graded individual vitamin D status as:
-
Sufficiency: 25(OH)D ≥ 30 ng/ml
-
Insufficiency: 25(OH)D = 21–29 ng/ml
-
Deficiency: 25(OH)D ≤ 20 ng/ml
In this context, a cut-off of 25(OH)D ≤ 12 ng/ml is considered the threshold for severe vitamin D deficiency [68] and a post-hoc analysis of the VITdAL-ICU trial [26] reported lower hospital mortality among critically with severe vitamin D deficiency who received vitamin D supplementation compared with placebo. The results of the VITdAL-ICU trial [26] will be discussed further on this manuscript.
The vitamin D deficiency is widely diffused among Western communities (40% of the subjects) [17, 18, 46], and seems to be prevalent in lower-middle income countries according to spare evidence [69], although the global epidemiology of this condition has never been investigated.
A comprehensive analysis of risk factors for vitamin D deficiency was presented elsewhere [15]. Critically ill patients represent a subgroup of the population particularly vulnerable to vitamin D deficiency, which has been reported in 40–70% of patients at the admission to the ICU [19]. In this setting, vitamin D deficiency is commonly diagnosed in patients with infection and sepsis, although the nature of this association is poorly understood and does not imply causation.
Severe infections and sepsis
In severe hospitalised patients, vitamin D deficiency represents a risk factor for the development of sepsis and a predictor of higher mortality [70,71,72,73]. Specifically, Moromizato et al. [74] observed that the 25(OH)D blood levels ≤ 15 ng/mL before hospital admission were predictive for the risk of sepsis and 90-day mortality in 3386 patients. In 2016, De Pascale et al. [75] conducted an observational study including 107 critically ill adults with sepsis reported Vitamin D deficiency in 93.5% of the patients, of which 53.3% showed extremely low 25(OH)D bloodstream concentration (≤ 7 ng/mL) [75]. Specifically, extremely low 25(OH)D bloodstream concentration and higher mean SAPS 2 score were independent predictors of sepsis-related mortality. Moreover, patients with extremely low 25(OH)D bloodstream concentration had a higher rate of microbiologically confirmed infections (80.7% vs 58%, p = 0.02) and a lower percentage of microbiological eradication (35.3% vs 68%, p 0.03) compared with those with 25(OH)D > 7 ng/ml [75]. Furthermore, patients with extremely low 25(OH)D bloodstream concentration required a longer duration of mechanical ventilation when affected by pneumonia, and vasopressor administration for septic shock, in comparison with those with compared with those with 25(OH)D > 7 ng/ml [75]. In 2018, Zhou et al. conducted a systematic review and a meta-analysis [76] of 24 studies to explore the association between vitamin D levels and sepsis. The authors found that the vitamin D level was lower in patients with sepsis compared to those without sepsis, but vitamin D deficiency had no significant association with sepsis-related death. Conversely, a recent systematic review and meta-analysis [77] of 8 studies (1736 patients) found that lower 25(OH)D levels were independently associated with a higher risk of mortality in patients with sepsis (adjusted relative risk: 1.93, p < 0.001). Subgroup analyses showed that only severe vitamin D deficiency, defined as 25(OH)D < 10 ng/ml, was significantly associated with increased risk of death in sepsis, while this relationship was not reproduced for higher 25(OH)D level [77]. Further research is warranted to clarify whether vitamin D deficiency is involved in the pathophysiology of severe infections and sepsis or should be acknowledged as a marker of patient severity.
Coronavirus disease-19
The coronavirus disease 19 (COVID-19) is a severe clinical condition caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), whose pathophysiology has not been completely understood and mostly relies on the immune system dysfunction caused by the SARS-CoV-2 infection [78].
In this context, an observational study on 191,779 patients found that SARS-CoV-2 positivity was higher among patients with vitamin D deficiency and inversely associated with circulating 25(OH)D levels, independently of latitude, ethnicity, age and sex [79]. A possible explanation of these findings relies on the immunomodulating function of vitamin D, especially for what concerns hyperinflammatory cytokines like TNF, whose soluble receptor was demonstrated as an independent predictor of 30-day mortality in COVID-19 patients [80]. Nevertheless, the pathophysiological implication of vitamin D deficiency in COVID-19 patients remains unknown and warrants to be clarified by future investigations.
Rationale and clinical evidence of vitamin D supplementation in ICU
Vitamin D compounds are available for enteral, parenteral and intramuscular routes of administration. Enteral formulations have been widely used in clinical trials, being characterised by ease of administration and large vitamin D bioavailability. Specifically, some studies reported a greater increase of 25-dihydroxyvitamin D blood level in patients who received oral formulations, compared with those who received the same dose of vitamin D-based compound by intramuscular administration [81]. Parenteral and intramuscular administrations of vitamin D-based compounds should be indicated for patients with malabsorption due to enteral diseases, gastrointestinal bypass surgery and medications that reduce lipid absorption. In clinical practice, vitamin D2 and vitamin D3 represent the most widely used isoforms of this molecule and may plausibly be considered “native vitamin D”. Although both compounds are characterised by low stability in moist air [82], vitamin D3 administration was associated with a greater increase of 25-hydroxyvitamin D blood level, compared to vitamin D2 [83]. In recent years, several vitamin D analogues have been manufactured with the aim to produce specific compounds with enhanced pharmacokinetic and pharmacodynamic properties. As an example, paricalcitol does not require enzymatic activation, doxercalciferol has a prolonged half-life and maxacalcitrol specifically acts on non-classical vitamin D-associated pathways [84, 85]. However, the effect of these drugs on vitamin D status and patient clinical outcomes has never been tested in large-scale investigations.
Vitamin D supplementation is feasible, safe and effective to improve body content of this compound within a few days in critically ill patients admitted to the ICU [24, 25]. Several observational studies reported an association between vitamin D supplementation and improved clinical outcomes in hospitalised patients with severe infection [86, 87]. A recent meta-analysis pooling the results of 9 randomised controlled trials on 1867 critically ill patients [88] found no benefit of vitamin D supplementation on the 28-day mortality compared with placebo (20.4% vs 21.7%, respectively). In contrast, Menger et al. [89] conduced a larger systematic review and meta-analysis on 2449 critically ill patients from 16 randomised controlled trials and found lower mortality in critically ill patients who received vitamin D supplementation. However, both systematic reviews and meta-analyses had important limitations that hampered the generalizability of results, mostly due to the wide degree of inhomogeneity among the studies included. The only two large scale clinical investigations were the VITdAL-ICU [26] and the VIOLET [27] trials (Table 1), whose specific peculiarities warrant to be discussed in detail.
The VITdAL-ICU trial [26] was conducted in 5 ICUs of an Austrian hospital and enrolled 475 critically ill patients with vitamin D deficiency, who were randomised to receive oral vitamin D supplementation (vitamin D3: loading dose of 540,000 IU, followed by monthly maintenance dose of 90,000 IU for 5 months) or placebo. In patients receiving vitamin D supplementation the deficiency status improved within 7 days from the inclusion and remained stable for the 28 days afterwards respect to the placebo. Although Vitamin D supplementation had no effect on patient clinical outcomes, a subgroup analysis including patients with severe vitamin D deficiency [25(OH)D levels ≤ 12 ng/mL)] showed that vitamin D supplementation reduced the risk of hospital mortality compared with placebo (28.6% vs 46.1%, respectively). In the light of this finding, the VIOLET trial [27] enrolled 1358 severe patients with vitamin D deficiency from 44 hospitals in the United States, who were randomised to receive enteral vitamin D supplementation (vitamin D3: loading dose of 540,000 IU, administered even before ICU admission and not followed by maintenance dose) or placebo. Although vitamin D status improved in patients who received vitamin D supplementation compared with placebo, this intervention had no impact on patient clinical outcomes. Accordingly, this study was stopped for futility after the first interim analysis. Unfortunately, the prevalence of sepsis in the VITdAL-ICU [26] and VIOLET [27] trials was low (7.7% and 33.3%), thus impairing to evaluation of the effect of vitamin D supplementation in this patient population.
During the COVID-19 pandemic, Murai et al. [29] investigated the effect of vitamin D3 supplementation (single dose: 200,000 IU) vs placebo in 240 hospitalised patients (most of whom were not critically ill) with moderate to severe COVID-19 from 2 centres and found no difference of hospital length of stay between study groups. In this setting, Mariani et al. [90] randomised 218 hospitalised patients with mild-to-moderate COVID-19 and risk factors for disease progression from 17 centres to receive vitamin D3 (single dose: 500,000 IU) vs placebo and found no difference in terms of respiratory SOFA score changes between the baseline and the highest value within the following 7 days. In both of these studies, the increase of vitamin D blood levels in patients who received vitamin D supplementation compared to placebo did not correspond to any improvement of secondary outcomes as ICU admission, need for mechanical ventilation, and hospital mortality.
In contrast, Leaf et al. randomised 67 critically ill patients with sepsis to receive 2 μg of intravenous calcitriol or placebo [28], with the aim to investigate whether vitamin D supplementation may improve cathelicidin blood levels within 24 h (primary outcome), increase 1,25-dihydroxyvitamin D blood level within 6 h, influence cytokines mRNA expression and cytokines levels into the bloodstream within 24 h and reduce urinary markers of kidney injury within 48 h (secondary outcomes). Although vitamin D blood levels increased in patients who received vitamin D supplementation, it was only associated with an increase of cathelicidin and IL-10 mRNA expression within 24 h compared with placebo. Vitamin D supplementation was not associated with 28-day, ICU and hospital mortality compared with placebo, whereas this trial was not powered to assess these outcomes. Moreover, Quraishi et al. randomised 30 critically ill septic patients to receive enteral vitamin D3 400,000 IU versus of vitamin D3 200,000 IU versus placebo. They found that the administration of higher doses of vitamin D3 led to an improvement of 25(OH)D body content and bioavailability at day 5, which corresponded with a concomitant increase of LL-37 [24].
Future directions
The VITDALIZE study (NCT03188796) [66] is an international (Austria, Germany, Belgium, Switzerland and UK), multicentre (more than 30 sites), placebo-controlled, double-blind, phase 3 randomised trial, that has started in 2017 and aims to include 2400 adult critically ill patients with severe vitamin D deficiency, within the first 72 h of ICU admission. Patients randomised in the treatment group receive vitamin D3 540,000 IU at the enrolment, followed by 4000 IU daily for 90 days. The primary outcome of the study is 28-day mortality, while the development of infections requiring antibiotics at day 90 is accounted among other secondary outcomes (e.g. progression of organ dysfunction, hospital, ICU, 90-day and 1-year mortality).
Conversely, there are no researches recorded in ClinicalTrial.gov currently ongoing with the aim to assess the effect of vitamin D supplementation to prevent the development of infection or sepsis as well as improve the outcome of critically ill patients suffering from these conditions. Due to the clinical relevance of vitamin D deficiency and the potential of vitamin D supplementation to improve the outcome of critically ill patients with severe infections and sepsis, future multicentre clinical trials in this context appear clinically justified and urgently advocated.
Conclusion
Severe infections and sepsis are widely diagnosed in ICU patients, for whom vitamin D deficiency is frequent and associated with the development of these conditions. Vitamin D was demonstrated to modulate the immune system and vitamin D deficiency may represent a target for future therapy, in order to control infection and ameliorate inflammatory dysfunction and sepsis. Although small randomised clinical trials demonstrated a benefit of vitamin D supplementation to improve immunologic features of in critically ill septic patients, no large scale randomised controlled trials have been designed to specifically assess the effect of this therapy on patient-related clinical outcomes. Accordingly, future high-quality research is urgently advocated in this field.
Availability of data and materials
Not applicable.
Abbreviations
- COVID-19:
-
Coronavirus disease 19
- DAMPs:
-
Danger-associated molecular patterns
- 25(OH)D:
-
25-Hydroxyvitamin D
- 1,25(OH)2D:
-
1,25-Dihydroxyvitamin D
- IFN-γ:
-
Interferon-γ
- ILs:
-
Interleukins
- ICU:
-
Intensive care unit
- IU:
-
International unit
- nVDR:
-
Nuclear vitamin D receptor
- PAMPs:
-
Pathogen-associated molecular patterns
- SOFA:
-
Sequential Organ Failure Assessment
- SARS-CoV-2:
-
Severe acute respiratory syndrome coronavirus 2
- SAPS II:
-
Simplified Acute Physiology Score II
- TLR:
-
Toll-like receptor
- TNF-α:
-
Tumour necrosis factor-α
- VDBP:
-
Vitamin D binding protein
References
Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S (2017) Recognizing sepsis as a global health priority - a WHO resolution. N Engl J Med 377(5):414–417
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M et al (2016) The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315(8):801–810
Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith C, French C et al (2021) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med 47(11):1181–1247
Cutuli S, Grieco D, De Pascale G, Antonelli M (2021) Hemadsorption. Curr Opin Anaesthesiol 34(2):113–118
Cutuli S, Carelli S, Grieco D, De Pascale G (2021) Immune modulation in critically ill septic patients. Medicina 57(6):552
Cascarano L, Cutuli SL, Pintaudi G, Tanzarella ES, Carelli S, Anzellotti G et al (2021) Extracorporeal immune modulation in COVID-19 induced immune dysfunction and secondary infections: the role of oXiris(R) membrane. Minerva Anestesiol 87(3):384–385
De Rosa S, Cutuli SL, Ferrer R, Antonelli M, Ronco C, Group C-EC (2021) Polymyxin B hemoperfusion in coronavirus disease 2019 patients with endotoxic shock: case series from EUPHAS2 registry. Artif Organs 45(6):E187–E94
Yanase F, Bitker L, Hessels L, Osawa E, Naorungroj T, Cutuli SL et al (2020) A pilot, double-blind, randomized, controlled trial of high-dose intravenous vitamin C for vasoplegia after cardiac surgery. J Cardiothorac Vasc Anesth 34(2):409–416
de Gans J, van de Beek D, European Dexamethasone in Adulthood Bacterial Meningitis Study I (2002) Dexamethasone in adults with bacterial meningitis. N Engl J Med 347(20):1549–56
Torres A, Sibila O, Ferrer M, Polverino E, Menendez R, Mensa J et al (2015) Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA 313(7):677–686
Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S et al (2018) Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med 378(9):809–818
Recovery Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL et al (2021) Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 384(8):693–704
Dequin PF, Meziani F, Quenot JP, Kamel T, Ricard JD, Badie J et al (2023) Hydrocortisone in severe community-acquired pneumonia. N Engl J Med 388(21):1931–1941
Cao M, He C, Gong M, Wu S, He J (2023) The effects of vitamin D on all-cause mortality in different diseases: an evidence-map and umbrella review of 116 randomized controlled trials. Front Nutr 10:1132528
Cutuli SL, Cascarano L, Tanzarella ES, Lombardi G, Carelli S, Pintaudi G et al (2022) Vitamin D status and potential therapeutic options in critically ill patients: a narrative review of the clinical evidence. Diagnostics (Basel) 12(11):2719
Colotta F, Jansson B, Bonelli F (2017) Modulation of inflammatory and immune responses by vitamin D. J Autoimmun 85:78–97
Cashman K, Dowling K, Škrabáková Z, Gonzalez-Gross M, Valtueña J, Henauw SD et al (2016) Vitamin D deficiency in Europe: pandemic? Am J Clin Nutr 103(4):1033–1044
Herrick K, Storandt R, Afful J, Pfeiffer C, Schleicher R, Gahche J et al (2019) Vitamin D status in the United States, 2011–2014. Am J Clin Nutr 110(1):150–157
Amrein K, Papinutti A, Mathew E, Vila G, Parekh D (2018) Vitamin D and critical illness: what endocrinology can learn from intensive care and vice versa. Endocr Connect 7(12):R304–R315
de Haan K, Groeneveld A, Geus Hd, Egal M, Struijs A (2014) Vitamin D deficiency as a risk factor for infection, sepsis and mortality in the critically ill: systematic review and meta-analysis. Crit Care 18(6):660
McNally J, Nama N, O’Hearn K, Sampson M, Amrein K, Iliriani K et al (2017) Vitamin D deficiency in critically ill children: a systematic review and meta-analysis. Crit Care 21(1):287
Parekh D, Patel J, Scott A, Lax S, Dancer R, D’Souza V et al (2017) Vitamin D deficiency in human and murine sepsis. Crit Care Med 45(2):282–289
De Pascale G, Vallecoccia M, Schiattarella A, Di Gravio V, Cutuli S, Bello G et al (2016) Clinical and microbiological outcome in septic patients with extremely low 25-hydroxyvitamin D levels at initiation of critical care. Clin Microbiol Infect 22(5):456.e7-e13
Quraishi S, De Pascale G, Needleman J, Nakazawa H, Kaneki M, Bajwa E et al (2015) Effect of cholecalciferol supplementation on vitamin D status and cathelicidin levels in sepsis: a randomized, placebo-controlled trial. Crit Care Med 43(9):1928–1937
Amrein K, Sourij H, Wagner G, Holl A, Pieber T, Smolle K et al (2011) Short-term effects of high-dose oral vitamin D3 in critically ill vitamin D deficient patients: a randomized, double-blind, placebo-controlled pilot study. Crit Care 15(2):R104
Amrein K, Schnedl C, Holl A, Riedl R, Christopher K, Pachler C et al (2014) Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA 312(15):1520–30
National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Ginde A, Brower R, Caterino J, Finck L, Banner-Goodspeed V et al (2019) Early high-dose vitamin D 3 for critically ill, vitamin D-deficient patients. N Engl J Med 381(26):2529–40
Leaf D, Raed A, Donnino M, Ginde A, Waikar S (2014) Randomized controlled trial of calcitriol in severe sepsis. Am J Respir Crit Care Med 190(5):533–541
Murai I, Fernandes A, Sales L, Pinto A, Goessler K, Duran C et al (2021) Effect of a single high dose of vitamin D3 on hospital length of stay in patients with moderate to severe COVID-19: a randomized clinical trial. JAMA 325(11):1053–1060
Vincent JL, Sakr Y, Singer M, Martin-Loeches I, Machado FR, Marshall JC et al (2020) Prevalence and outcomes of infection among patients in intensive care units in 2017. JAMA 323(15):1478–1487
Vincent JL, Bihari DJ, Suter PM, Bruining HA, White J, Nicolas-Chanoin MH et al (1995) The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. JAMA 274(8):639–44
Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD et al (2009) International study of the prevalence and outcomes of infection in intensive care units. JAMA 302(21):2323–2329
Vincent JL, Marshall JC, Namendys-Silva SA, Francois B, Martin-Loeches I, Lipman J et al (2014) Assessment of the worldwide burden of critical illness: the intensive care over nations (ICON) audit. Lancet Respir Med 2(5):380–386
Sakr Y, Jaschinski U, Wittebole X, Szakmany T, Lipman J, Namendys-Silva SA et al (2018) Sepsis in intensive care unit patients: worldwide data from the intensive care over nations audit. Open Forum Infect Dis 5(12):ofy313
Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H et al (2006) Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 34(2):344–353
Vincent JL, Lefrant JY, Kotfis K, Nanchal R, Martin-Loeches I, Wittebole X et al (2018) Comparison of European ICU patients in 2012 (ICON) versus 2002 (SOAP). Intensive Care Med 44(3):337–344
Gaieski DF, Edwards JM, Kallan MJ, Carr BG (2013) Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med 41(5):1167–1174
Cutuli S, Carelli S, De Pascale G (2020) The gut in critically ill patients: how unrecognized “7th organ dysfunction” feeds sepsis. Minerva Anestesiol 86(6):595–597
Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL (2016) Sepsis and septic shock. Nat Rev Dis Primers 2:16045
Demer L, Hsu J, Tintut Y (2018) Steroid hormone vitamin D: implications for cardiovascular disease. Circ Res 122(11):1576–1585
Szymczak-Pajor I, Śliwińska A (2019) Analysis of association between vitamin D deficiency and insulin resistance. Nutrients 11(4):794
Hewison M, Burke F, Evans KN, Lammas DA, Sansom DM, Liu P et al (2007) Extra-renal 25-hydroxyvitamin D3–1alpha-hydroxylase in human health and disease. J Steroid Biochem Mol Biol 103(3–5):316–321
Speeckaert MM, Speeckaert R, van Geel N, Delanghe JR (2014) Vitamin D binding protein: a multifunctional protein of clinical importance. Adv Clin Chem 63:1–57
Quraishi SA, Bittner EA, Blum L, McCarthy CM, Bhan I, Camargo CA Jr (2014) Prospective study of vitamin D status at initiation of care in critically ill surgical patients and risk of 90-day mortality. Crit Care Med 42(6):1365–1371
Rosen C (2011) Clinical practice. Vitamin D insufficiency. N Engl J Med 364(3):248–54
Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP et al (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96(7):1911–1930
Trochoutsou AI, Kloukina V, Samitas K, Xanthou G (2015) Vitamin-D in the immune system: genomic and non-genomic actions. Mini Rev Med Chem 15(11):953–963
Holick M (2007) Vitamin D deficiency. N Engl J Med 357(3):266–281
Lemire JM, Archer DC, Beck L, Spiegelberg HL (1995) Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr 125(6 Suppl):1704S-S1708
Zhang Y, Leung DY, Richers BN, Liu Y, Remigio LK, Riches DW et al (2012) Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol 188(5):2127–2135
Van Belle TL, Gysemans C, Mathieu C (2011) Vitamin D in autoimmune, infectious and allergic diseases: a vital player? Best Pract Res Clin Endocrinol Metab 25(4):617–632
Jeffery LE, Burke F, Mura M, Zheng Y, Qureshi OS, Hewison M et al (2009) 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol 183(9):5458–5467
Wang Q, He Y, Shen Y, Zhang Q, Chen D, Zuo C et al (2014) Vitamin D inhibits COX-2 expression and inflammatory response by targeting thioesterase superfamily member 4. J Biol Chem 289(17):11681–11694
Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE (2007) Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 179(3):1634–1647
Lemire JM, Adams JS, Sakai R, Jordan SC (1984) 1 alpha,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest 74(2):657–661
Iho S, Takahashi T, Kura F, Sugiyama H, Hoshino T (1986) The effect of 1,25-dihydroxyvitamin D3 on in vitro immunoglobulin production in human B cells. J Immunol 136(12):4427–4431
Shirakawa AK, Nagakubo D, Hieshima K, Nakayama T, Jin Z, Yoshie O (2008) 1,25-dihydroxyvitamin D3 induces CCR10 expression in terminally differentiating human B cells. J Immunol 180(5):2786–2795
Barton GM, Medzhitov R (2003) Toll-like receptor signaling pathways. Science 300(5625):1524–1525
Quraishi SA, Camargo CA Jr (2012) Vitamin D in acute stress and critical illness. Curr Opin Clin Nutr Metab Care 15(6):625–634
Pinheiro da Silva F, Machado MC (2012) Antimicrobial peptides: clinical relevance and therapeutic implications. Peptides. 36(2):308–14
Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW (2008) Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol 181(10):7090–7099
Tripathi S, Tecle T, Verma A, Crouch E, White M, Hartshorn KL (2013) The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins. J Gen Virol 94(Pt 1):40–49
Kho AT, Sharma S, Qiu W, Gaedigk R, Klanderman B, Niu S et al (2013) Vitamin D related genes in lung development and asthma pathogenesis. BMC Med Genomics 6:47
Mendez-Samperio P (2010) The human cathelicidin hCAP18/LL-37: a multifunctional peptide involved in mycobacterial infections. Peptides 31(9):1791–1798
Jeng L, Yamshchikov AV, Judd SE, Blumberg HM, Martin GS, Ziegler TR et al (2009) Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med 7:28
Amrein K, Parekh D, Westphal S, Preiser JC, Berghold A, Riedl R et al (2019) Effect of high-dose vitamin D3 on 28-day mortality in adult critically ill patients with severe vitamin D deficiency: a study protocol of a multicentre, placebo-controlled double-blind phase III RCT (the VITDALIZE study). BMJ Open 9(11):e031083
Institute of Medicine (US) (2011) Committee to review dietary reference intakes for vitamin D and calcium. Dietary reference intakes for calcium and vitamin D. Ross C, Taylor C, Yaktine A, Valle HD, editors. Washington: National Academies Press (US)
Ross AC (2011) The 2011 report on dietary reference intakes for calcium and vitamin D. Public Health Nutr 14(5):938–939
Fuleihan GE-H, Nabulsi M, Choucair M, Salamoun M, Shahine CH, Kizirian A et al (2001) Hypovitaminosis D in healthy schoolchildren. Pediatrics 107(4):E53
Braun A, Chang D, Mahadevappa K, Gibbons FK, Liu Y, Giovannucci E et al (2011) Association of low serum 25-hydroxyvitamin D levels and mortality in the critically ill. Crit Care Med 39(4):671–677
Seok H, Kim J, Choi WS, Park DW (2023) Effects of vitamin D deficiency on sepsis. Nutrients 15(20):4309
Vanichkulbodee A, Romposra M, Inboriboon PC, Trongtrakul K (2023) Effects of vitamin D insufficiency on sepsis severity and risk of hospitalisation in emergency department patients: a cross-sectional study. BMJ Open 13(1):e064985
Malinverni S, Ochogavia Q, Lecrenier S, Scorpinniti M, Preiser JC, Cotton F et al (2023) Severe vitamin D deficiency in patients admitted to the emergency department with severe sepsis is associated with an increased 90-day mortality. Emerg Med J 40(1):36–41
Moromizato T, Litonjua A, Braun A, Gibbons F, Giovannucci E, Christopher K (2014) Association of low serum 25-hydroxyvitamin D levels and sepsis in the critically ill. Crit Care Med 42(1):97–107
De Pascale G, Vallecoccia MS, Schiattarella A, Di Gravio V, Cutuli SL, Bello G et al (2016) Clinical and microbiological outcome in septic patients with extremely low 25-hydroxyvitamin D levels at initiation of critical care. Clin Microbiol Infect 22(5):456.e7-e13
Zhou W, Mao S, Wu L, Yu J (2018) Association between vitamin D status and sepsis. Clin Lab 64(4):451–460
Li Y, Ding S (2020) Serum 25-Hydroxy vitamin D and the risk of mortality in adult patients with sepsis: a meta-analysis. BMC Infect Dis 20(1):189
Parasher A (2021) COVID-19: current understanding of its pathophysiology, clinical presentation and treatment. Postgrad Med J 97(1147):312–320
Kaufman HW, Niles JK, Kroll MH, Bi C, Holick MF (2020) SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS One 15(9):e0239252
Sancho Ferrando E, Hanslin K, Hultstrom M, Larsson A, Frithiof R, Lipcsey M et al (2022) Soluble TNF receptors predict acute kidney injury and mortality in critically ill COVID-19 patients: a prospective observational study. Cytokine 149:155727
Romagnoli E, Mascia M, Cipriani C, Fassino V, Mazzei F, D’Erasmo E et al (2008) Short and long-term variations in serum calciotropic hormones after a single very large dose of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) in the elderly. J Clin Endocrinol Metab 93(8):3015–20
Gupta R, Behera C, Paudwal G, Rawat N, Baldi A, Gupta P (2018) Recent advances in formulation strategies for efficient delivery of vitamin D. AAPS PharmSciTech 20(1):11
Heaney R, Recker R, Grote J, Horst R, Armas L (2011) Vitamin D(3) is more potent than vitamin D(2) in humans. J Clin Endocrinol Metab 96(3):E447–E452
Chen J, Tang Z, Slominski A, Li W, Żmijewski M, Liu Y, et al (2020) Vitamin D and its analogs as anticancer and anti-inflammatory agents. Eur J Med Chem. Online ahead of print
Cunningham J, Zehnder D (2011) New vitamin D analogs and changing therapeutic paradigms. Kidney Int 79(7):702–707
Yang B, Zhu Y, Zheng X, Li T, Niu K, Wang Z et al (2023) Vitamin D supplementation during intensive care unit stay is associated with improved outcomes in critically ill patients with sepsis: a cohort study. Nutrients 15(13):2924
Guan J, Shichen M, Liang Z, Yu S, Zhao M, Zhang L et al (2023) Potential benefits of vitamin D for sepsis prophylaxis in critical ill patients. Front Nutr 10:1073894
Lan S, Lai C, Chang S, Lu L, Hung S, Lin W (2020) Vitamin D supplementation and the outcomes of critically ill adult patients: a systematic review and meta-analysis of randomized controlled trials. Sci Rep 10(1):14261
Menger J, Lee Z, Notz Q, Wallqvist J, Hasan MS, Elke G et al (2022) Administration of vitamin D and its metabolites in critically ill adult patients: an updated systematic review with meta-analysis of randomized controlled trials. Crit Care 26(1):268
Mariani J, Antonietti L, Tajer C, Ferder L, Inserra F, Sanchez Cunto M et al (2022) High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: multicentre randomized controlled clinical trial. PLoS One 17(5):e0267918
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Conceptualization, S.L.C. and G.D.P.; methodology, S.L.C.; validation, M.A.; formal analysis, S.L.C. and G.D.P.; investigation, S.L.C., E.S.F., F. C., E. F., A. C., G.L., E.S.T., D.L.G., M.A., and G.D.P.; resources, S.L.C., M.A., and G.D.P.; data curation, S.L.C., F. C., E. F., A. C., G.L., E.S.T., and D.L.G; writing—original draft preparation, S.L.C. and E.S.F.; writing—review and editing, M.A. and G.D.P.; visualisation, M.A. and G.D.P; supervision, G.D.P.; project administration, S.L.C. and G.D.P. All authors have read and agreed to the published version of the manuscript.
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Cutuli, S.L., Ferrando, E.S., Cammarota, F. et al. Update on vitamin D role in severe infections and sepsis. J Anesth Analg Crit Care 4, 4 (2024). https://doi.org/10.1186/s44158-024-00139-5
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DOI: https://doi.org/10.1186/s44158-024-00139-5