Inflammation & Allergy-Drug Targets (v.12, #4)

Prevalence and Risk Factors of Vitamin D Deficiency in Critically Ill Patients by Bertrand Sauneuf, Jennifer Brunet, Olivier Lucidarme, Damien du Cheyron (223-229).
Vitamin D (Vit D) is well known for its traditional role in calcium and bone homeostasis. Sun exposure anddiet are essential for Vit D synthesis and intake. However, the association of Vit D deficiency with various diseases hasheld the attention of clinicians. Of note, Vit D has pleiotropic effects that could be involved in the optimal functioning ofmany organ systems. Several epidemiologic studies have documented widespread Vit D deficiency worldwide. Vit Ddeficiency is also frequent in hospitalized patients. Recently, publications have suggested a high prevalence of Vit Ddeficiency in critically ill patients, which might have a clinical impact in this specific population. However, few studieshave specifically investigated the prevalence and risk factors of Vit D deficiency in intensive care units. The availabledata indicate a Vit D deficiency prevalence of 80% to 100% in critically ill patients. The risk factors associated with Vit Ddeficiency include variables dependent on demographic characteristics, such as ethnicity, age and sex, lifestyle and diet,medical history and medications, and acute critical illness. Of note, the presence of a systemic inflammatory response andthe severity of acute illness may affect the Vit D status. This review presents the current knowledge on the prevalence ofVit D deficiency in the critically ill and the associated risk factors.

Vitamin D deficiency, as measured by a random level of 25-hydroxyvitamin D is very prevalent in critically illpatients admitted to the ICU and is associated with adverse outcomes. Both 25(OH)vitamin D and 1α,25(OH)2D3 aredifficult to analyse because of their lipophilic nature, affinity for VDBP and small concentrations. Also, the various testsused to estimate vitamin D levels show significant inter- and intra-assay variability, which significantly affect the veracityof the results obtained and confound their interpretation. The two main types of assays include those that directly estimatevitamin D levels (HPLC, LC-MS/MS) and competitive binding assays (RIA, EIA). The former methods require skilledoperators, with prolonged assay times and increased cost, whereas the latter are cheaper and easy to perform, but withdecreased accuracy. The direct assays are not affected by lipophilic substances in plasma and heterophile antibodies, butmay overestimate vitamin D levels by measuring the 3-epimers. These problems can be eliminated by adequatestandardization of the test using SRMs provided by NIST, as well as participating in proficiency schemes like DEQAS. Itis therefore important to consider the test employed as well as laboratory quality control, while interpreting vitamin Dresults. A single random measurement may not be reflective of the vitamin D status in ICU patients because of changeswith fluid administration, and intra-day variation in 25-hydroxyvitamin D levels. 1α,25(OH)2D3 may behave differently to25-hydroxyvitamin D, both in plasma and at tissue level, in inflammatory states. Measurement of tissue 1α,25(OH)2D3levels may provide the true estimate of vitamin D activity.

The Role of Vitamin D in Prevention and Treatment of Infection by Cameron F. Gunville, Peter M. Mourani, Adit A. Ginde (239-245).
Vitamin D is well known for its classic role in the maintenance of bone mineral density. However, vitamin Dalso has an important “non-classic” influence on the body’s immune system by modulating the innate and adaptiveimmune system, influencing the production of important endogenous antimicrobial peptides such as cathelicidin, andregulating the inflammatory cascade. Multiple epidemiological studies in adults and children have demonstrated thatvitamin D deficiency is associated with increased risk and greater severity of infection, particularly of the respiratory tract.Although the exact mechanisms by which vitamin D may improve immune responses to infection continue to beevaluated, vitamin D supplementation trials of prevention and adjunct therapy for infection are underway. Given itsinfluence on the immune system and inflammatory cascade, vitamin D may have an important future role in theprevention and treatment of infection.

Vitamin D and Sepsis: From Associations to Causal Connections by Jordan A. Kempker, Greg S. Martin (246-252).
The physiological roles of vitamin D in the functioning of the immune and inflammatory systems have been thesubject of intense research over the past decade and have stimulated interest in the connections between this steroidhormone and sepsis. While the science directly examining the relationship between sepsis and vitamin D is still emerging,many inferences can be made from current literature from various scientific disciplines looking at the seasonal,geographical and racial patterns of infections and vitamin D deficiency. This review will explore these associations,drawing from the fields of ecology, epidemiology and clinical research and describe the potential causal relationshipsimplicated by the basic sciences.

Vitamin D Deficiency and Acute Lung Injury by Dhruv Parekh, David R. Thickett, Alice M. Turner (253-261).
Acute Lung Injury (ALI) and the more severe form Acute Respiratory Distress Syndrome (ARDS) remain asignificant cause of morbidity and mortality in the critically ill patient. It is characterised by a severe inflammatoryprocess resulting in diffuse alveolar damage, influx of neutrophils, macrophages and a protein rich exudate in the alveolarspaces caused by endothelial and epithelial injury. Improvements in outcomes are in part due to restrictive fluidmanagement and protective lung ventilation however successful therapeutic strategies remain elusive with promisingtherapies failing to translate positively in human studies.</p>;The evidence for the role of vitamin D in lung disease is growing - deficiency has been associated with impairedpulmonary function, increased incidence of viral and bacterial infections and inflammatory disease including asthma andCOPD. Studies have also reported a high prevalence of vitamin D deficiency in the critically ill and an association withadverse outcomes. Although exact mechanisms are yet to be discerned, vitamin D appears to impact on a variety ofinflammatory and structural cells within the lung including macrophages, lymphocytes and epithelial cells. To date thereare few directly supportive clinical studies in ALI; this review explores the compelling evidence suggesting arole forvitamin D in ALI and the mechanisms by which it could contribute to pathogenesis.

Vitamin D in Acute Kidney Injury by Andrea B. Braun, Kenneth B. Christopher (262-272).
Vitamin D deficiency is common in critically ill patients and associated with increased mortality, as well as anincreased risk of acute kidney injury. The occurrence of acute kidney injury by itself substantially increases critical caremortality. In addition to regulating calcium and phosphorus homeostasis and bone metabolism, vitamin D has pleotropiceffects on the immune response. Potential mechanisms of how a deficiency in vitamin D could predispose individuals toincreased risk of acute renal failure include dysregulation of the immune system, predisposing patients to sepsis,endothelial dysfunction and prevention of healing of renal ischemia-reperfusion injury. Toll-like receptors, NF-κB and therenin-angiotensin-aldosterone system are mediators of vitamin D effects.

Vitamin D deficiency and its adverse skeletal sequelae are well recognized in the general population. Recentobservation of high prevalence of low vitamin D states and their associations with worse clinical outcomes in critically illpopulations have sparked interest in the role of supplementation for these patients. High-dose vitamin D efficaciouslyincreases serum levels, but its impact on clinical outcome has not been examined. This article will review results fromobservational studies on prevalence and outcomes of hypovitaminosis D in critically ill patients, as well as caveats ofvitamin D interventional trials. Improved understanding of vitamin D metabolism in critical illness will clarify thetherapeutic potential of this pleiotropic hormone and facilitate implementation of cost-effective clinical trials.

Vitamin D Intervention Trials in Critical Illness by Christian Schnedl, Thomas R. Pieber, Karin Amrein (282-287).
Vitamin D deficiency is common in critically ill patients and has been associated with adverse outcomes.Although many interesting observational studies have been published, only four small randomized controlled trials havebeen conducted in this vulnerable population. Endpoints included bone turnover, inflammatory markers andsafety/efficacy issues. However, all of these trials were underpowered to detect clinically relevant endpoints due to theirsmall sample size. Therefore, future studies focusing on morbidity and mortality endpoints are necessary in order toclarify whether vitamin D deficiency is only a surrogate marker for disease severity or whether treatment with sufficientlylarge doses of vitamin D may improve patient outcome in an intensive care setting.

Disease-Modifying Effect of Anthraquinone Prodrug with Boswellic Acid on Collagenase-Induced Osteoarthritis in Wistar Rats by Dhaneshwar Suneela, Patil Dipmala, Harsulkar Abhay, Bhondave Prashant (288-295).
Diacerein and its active metabolite rhein are promising disease modifying agents for osteoarthritis (OA).Boswellic acid is an active ingredient of Gugglu; a herbal medicine commonly administered in osteoarthritis. Both ofthem possess excellent anti-inflammatory and anti-arthritic activities. It was thought interesting to conjugate rhein andboswellic acid into a mutual prodrug (DSRB) and evaluate its efficacy on collagenase-induced osteoarthritis in ratswherein the conjugate, rhein, boswellic acid and their physical mixture, were tested based on various parameters. Oraladministration of 3.85 mg of rhein, 12.36 mg of boswellic acid and 15.73 mg of DSRB which would release equimolaramounts of rhein and boswellic acid, exhibited significant restoration in rat body weight as compared to the untreatedarthritic control group. Increase in knee diameter (mm), due to edema was observed in group injected with collagenase,which reduced significantly with the treatment of conjugate. The hematological parameters (Hb, RBC, WBC and ESR)and biochemical parameters (CRP, SALP, SGOT and SGPT) in the osteoarthritic rats were significantly brought back tonormal values on treatment with conjugate. It also showed better anti-ulcer activity than rhein. Further thehistopathological studies revealed significant anti-arthritic activity of conjugate when compared with the arthritic controlgroup. In conclusion, the conjugate at the specified dose level of 15.73 mg/kg, p. o. (BID) showed reduction in kneediameter and it could significantly normalize the hematological and biochemical abnormalities in collagenase-inducedosteoarthritis in rats. Further the histopathological studies confirmed the additive anti-arthritic effect of DSRB ascompared to plain rhein.