Vitamin D Levels: Associations with Acute Pain Events and Self-Reported Pain in Children with Sickle Cell Disease

Abstract Background/Aims: Individuals with sickle cell disease (SCD) are at high risk for vitamin D deficiency due to dark skin color, limited physical activity, poor nutrition, and renal dysfunction. In smaller retrospective studies, vitamin D deficiency in SCD was associated with increased frequency of acute pain events and higher opioid use, however the impact of vitamin D deficiency on pain related patient reported outcomes has not been described . Supplementation with high dose vitamin D is shown to be associated with fewer pain days per week and higher physical activity scores in patients with chronic pain. Thus, the objective of our study was to evaluate relationship between vitamin D levels, acute health care utilization and self-reported pain among children with SCD. We hypothesized that vitamin D deficiency is associated with increase health care utilization for pain and patient-reported outcomes for pain. Methods: Patients with SCD (1 to 18 years of age), enrolled in Sickle Cell Clinical Research and Intervention Program (SCCRIP), at St. Jude Children's Research Hospital were included in the study (Hankins et.al., Pediatric Blood and Cancer, 2018). Demographic, clinical and laboratory data were extracted from SCCRIP database. Prospective pain event leading to a hospital visit was analyzed. We analyzed pain-related hospitalizations in two ways: the number of pain-related hospitalizations within 2 years prior to and after vitamin D measurement in a cross-sectional design and longitudinally. Generalized linear regression model was used to examine associations between vitamin D and cross-sectional pain events with adjusting for hydroxyurea use. Generalized linear mixed effect model was used to assess the associations between vitamin D and longitudinal pain events, with adjusting for SCD genotype, sex, age, hydroxyurea use and interaction between age and hydroxyurea use. Pediatric Quality of Life Inventory™ Sickle Cell Disease Module (PedsQL™ SCD) was used to measure pain and pain interference using 1) Pain and Hurt and 2) Pain Impact scales. PedsQL™ SCD assessments include a Likert response scale. Items are reverse -scored and transformed to a 0-100 scale where higher scores indicate better health related quality of life in that scale. Two sample t-test or Wilcoxon rank sum test was used to compare mean scores between the two groups. Results: A total of 799 patients (females, n=398; males, n=401) were included in the study. Mean age (Standard Deviation [SD]), range at time of first vitamin D measurement for entire cohort was 8.7 (4.7), (0.8-18 years). Mean (SD) initial vitamin D level for entire cohort was 19.0 (9.4) ng/dl. Mean (SD) number of pain-related hospitalizations within two years of first vitamin D measurement was higher in the vitamin D deficient group as compared to non deficient group [0.81(1.97) vs 0.66 (1.2), (p=0.0034)]. Longitudinal data analyses showed vitamin D deficiency was associated with increased number of pain related hospitalizations (p=0.0091), after adjusting for covariates listed above (Figure 1a). Mean (SD) scores for Pain and Hurt in vitamin D deficient versus non deficient group were [74.5.7(18.2) versus 83.5(15.6), p < 0.001]. Mean (SD) scores for Pain Impact in vitamin D deficient group as compared to non deficient group were [(66.7 (22.7) versus 75.5 (22.3), p <0.001] (Figure 1b) Conclusion: Results indicated that low vitamin D levels predicted higher frequency of painful events leading to a hospital visit and were associated with higher prevalence of self-reported pain and pain interference. Further studies evaluating mechanisms by which vitamin D influences sickle cell pain are warranted and larger controlled trials can help evaluate the therapeutic efficacy of vitamin D for sickle cell pain. Figure 1 Figure 1. Disclosures Hankins: UpToDate: Consultancy; Bluebird Bio: Consultancy; Vindico Medical Education: Consultancy; Global Blood Therapeutics: Consultancy.

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Vitamin D and Nonskeletal Complications among Egyptian Sickle Cell Disease Patients

Advances in Hematology ◽

10.1155/2018/3867283 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Mona Hamdy ◽

Niveen Salama ◽

Ghada Maher ◽

Amira Elrefaee

Keyword(s):

Vitamin D ◽

Sickle Cell Disease ◽

Vitamin D Deficiency ◽

Sickle Cell ◽

Standard Of Care ◽

Enzyme Linked Immunosorbent Assay ◽

Cell Disease ◽

P Values ◽

Indirect Bilirubin ◽

Deficient Group

Lower levels of vitamin D have been documented in many patients with sickle cell disease (SCD), but data are still inconclusive regarding the association between vitamin D deficiency (VDD) and the occurrence or the severity of various SCD complications. Our study aimed to detect the prevalence of vitamin D deficiency among Egyptian patients with SCD and to associate it with the clinical course of the disease. We measured the level of 25-hydroxy vitamin D in 140 children (age from 4.3 to 15.5years), 80 patients with SCD and 60 controls using enzyme-linked immunosorbent assay. Vitamin D was deficient in 60% of SCD compared to 26.7% of controls. Severe VDD was significantly higher in SCD patients than controls. Patients were divided into 2 groups; Normal group (32 patients) and Deficient group (48 patients). There were statistically significant differences between the 2 groups regarding their age, height percentile, the presence of clinical jaundice, and osseous changes (P values 0.043, 0.024, 0.001, and 0.015, respectively). Hemoglobin and hematocrit values were significantly lower in Deficient group (P values 0.022 and 0.004, respectively) while the levels of aspartate aminotransferase, lactate dehydrogenase, and total and indirect bilirubin were significantly higher in the same group (P values 0.006, 0.001, 0.038, and 0.016, respectively). The frequency of blood transfusions, hospitalization, and vasoocclusive crisis previous year as well as the history of bone fracture and recurrent infections proved to be significantly higher in Deficient group. These findings suggest that VDD may play a role in the pathogenesis of hemolysis and other complication of SCD. Vitamin D monitoring and supplementation in patients with SCD should be implemented as a standard of care to potentially improve health outcomes in these affected patients.

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Vitamin Deficiency, CD40L and VEGF in a Young Population with Sickle Cell Disease

Blood ◽

10.1182/blood.v120.21.4768.4768 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4768-4768

Author(s):

E. Leila Jerome Clay ◽

Julia Brittain ◽

Rupa Redding-Lallinger

Keyword(s):

Vitamin D ◽

Platelet Count ◽

Sickle Cell Disease ◽

Vitamin D Deficiency ◽

Sickle Cell ◽

Inflammatory Markers ◽

Young Population ◽

Cell Disease ◽

Vitamin D Levels ◽

25 Oh Vitamin D

Abstract Abstract 4768 Introduction: Vitamin D deficiency is known to be common in patients with sickle cell disease (SCD). Vitamin D is important in multiple aspects of health, including the cardiovascular, immune and skeletal systems and its effects are mediated through the vitamin D receptor. The systems affected by vitamin D are also perturbed by SCD. Vitamin D deficiency is common in SCD, but its contribution to disease manifestations is being investigated. Vitamin D modulates the immune response and may have an effect on the levels of increased inflammation seen in individuals with SCD. In children and young adults with SCD at UNC Hospitals, we sought to determine the prevalence of vitamin D deficiency and its association with inflammatory markers and the influence of VDR haplotype. We report here on vitamin D status and several markers of inflammation. Methods: We recruited pediatric and young adult SCD patients in their steady state attending routine periodic evaluations at the Pediatric and Adult Sickle Cell Clinics at the University of North Carolina Hospitals between February and June 2012. After consent, patients had their blood collected for inflammatory markers, 25-OH vitamin D and DNA. Patients with active pain crisis or recent illness were excluded. A chart review was done for the last 5 years to obtain SCD genotype, baseline white blood cell count, hemoglobin, platelets, calcium, phosphate and alkaline phosphatase. We measured inflammatory markers IL2, IL6, CD40L, TNFa, plasma VEGF and CD40L levels using ELISA (R&D Systems). At present only the VEGF and CD40L levels, along with baseline clinical laboratory data are available with the other inflammatory marker data expected shortly. Spearman's regression was used to examine potential correlations between continuous variables. A p value of < 0.05 was considered significant. P-values are considered nominal and are uncorrected for multiple analyses. Results: Vitamin D levels were measured in 78 patients, ages ranging from 2 to 26 years, with 55% males. The SCD genotypes were SS and Sb°Thal at 80%, SC and Sb+Thal at 20%. Thirty percent of patients were on hydroxyurea and ten percent of patients were on chronic exchange transfusions. Severe vitamin D deficiency (<10 ng/mL) was present in 18%, mild to moderate deficiency (10–24 ng/mL) in 54% and only 28% were sufficient (>25 ng/mL). VEGF mean was 110.1 pg/mL (SD 125.8). CD40L mean was 642.2 pg/mL (SD 378.2). For the group as a whole, there were no correlations between the inflammatory markers and 25-OH vitamin D levels. However, when the group who was vitamin D deficient (< 25 ng/mL) was examined (n=39), vitamin D levels were inversely correlated with platelet count (rho= −0.3596, p =0.0246). Platelet count was positively correlated with CD40L level (rho= 0.3176, p= 0.0488). VEGF and CD40L levels were positively correlated (rho= 0.4520, p= 0.0039). Vitamin D levels are negatively correlated with age (rho= −0.3794, p = 0.0172). Restricting the analyses by age and gender did not change the results, nor did removing the individuals on hydroxyurea or chronic transfusions. Discussion: As has been noted previously, vitamin D deficiency is very common in people with sickle cell disease, including this young population, with mean age of 14 years. Inflammation is common as well, as reflected by the markedly elevated CD40L levels as well as the high-normal distribution of white cell count and platelet count. VEGF levels in adults with SCD appear to be elevated although are quite variable; VEGF appears to be a marker of inflammation in this disease. Little is known about VEGF levels in children with SCD. No associations between vitamin D levels and CD40L or VEGF levels were seen, however an inverse correlation between vitamin D level and platelet count was found. As platelets are a marker of inflammation, this suggests that further investigation of the relationship between vitamin D deficiency and inflammation could be fruitful. We anticipate having data concerning vitamin D and IL2, IL6 and TNFa in this group in the near future, as well as the ability to stratify the individuals by VDR haplotype. Disclosures: Redding-Lallinger: Eli Lilly and Company: Research Funding.

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Vitamin D Deficiency In Pediatric Patients with Sickle Cell Disease Correlates with Reticulocytosis but Not with Clinical Disease Severity

Blood ◽

10.1182/blood.v116.21.4820.4820 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4820-4820

Author(s):

Amanda C Winters ◽

Rebecca Kruse-Jarres ◽

Julie Kanter

Keyword(s):

Vitamin D ◽

Sickle Cell Disease ◽

Blood Cell ◽

Vitamin D Deficiency ◽

Sickle Cell ◽

Red Blood Cell ◽

Pediatric Patients ◽

Cell Turnover ◽

Cell Disease ◽

Vitamin D Levels

Abstract Abstract 4820 Vitamin D deficiency is an established phenomenon in both adult and pediatric patients with sickle cell disease. Between 33% and 78% of children and between 60% and 100% of adults with sickle cell disease (HbSS, HbSC, and HbSβ-thalassemia) have been found to have low serum levels of 25-hydroxyvitamin D, the form most clinically useful for measuring total body levels of vitamin D. Proposed factors contributing to low vitamin D levels in these patients include decreased exposure to sunlight secondary to chronic illness and frequent hospitalizations, malnutrition or malabsorption of vitamin D, higher requirements for vitamin D in sickle cell disease, and impaired metabolism of vitamin D. However, very little data has been published demonstrating a correlation between vitamin D deficiency and burden of disease in patients with sickle cell disease. In addition, there is no published data regarding the effect of vitamin D supplementation on patient-oriented outcomes. We retrospectively reviewed the medical records of pediatric patients with sickle cell disease (ages 0–18 years) to evaluate their serum vitamin D levels as a function of red blood cell turnover, patient's age, and factors relating to burden of disease such as number of emergency room visits and hospital admissions related to vaso-occlusive crises. As expected, we found that essentially all of our patients have insufficient levels of vitamin D at baseline. Although no correlation was seen between vitamin D levels and either age or number of hospital visits related to pain crises, reticulocytosis was significantly correlated (p=0.017) with degree of vitamin D deficiency in our patient population in multiple regression analysis. Based on these preliminary data, vitamin D deficiency in patients with sickle cell disease is more likely the result of the disease process as measured by red blood cell turnover as opposed to the previously hypothesized environmental constraints associated with pain crises and frequent hospitalization. Future analysis will be directed at confirming these findings in adult patients and at evaluating the effects of vitamin D supplementation in both adult and pediatric sickle cell patients. Additional studies should also evaluate the pathogenesis of vitamin D deficiency in states of high red blood cell turnover. Disclosures: No relevant conflicts of interest to declare.

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2. Vitamin D deficiency and bone fragility in sickle cell disease

Handbook of nutrition and diet in therapy of bone diseases - Human Health Handbooks ◽

10.3920/978-90-8686-823-0_2 ◽

2016 ◽

pp. 53-66

Author(s):

J.-B. Arlet ◽

J. Pouchot

Keyword(s):

Vitamin D ◽

Sickle Cell Disease ◽

Vitamin D Deficiency ◽

Sickle Cell ◽

Bone Fragility ◽

Cell Disease

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STATUS OF VITAMIN-D DEFICIENCY IN SICKLE CELL DISEASE IN ADULTS

Journal of Evidence Based Medicine and Healthcare ◽

10.18410/jebmh/2018/639 ◽

2018 ◽

Vol 5 (45) ◽

pp. 3137-3143

Author(s):

Manoj Gupta ◽

Dharmendra Katariya

Keyword(s):

Vitamin D ◽

Sickle Cell Disease ◽

Vitamin D Deficiency ◽

Sickle Cell ◽

Cell Disease

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Average Chronic Pain Medication Needed in Adult Patient with Sickle Cell Disease and Its Relation to Vitamin D Level

Blood ◽

10.1182/blood.v128.22.4857.4857 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4857-4857

Author(s):

Samip Master ◽

Shajadi Patan ◽

Shashank Cingam ◽

Runhua Shi ◽

Richard Preston Mansour

Keyword(s):

Vitamin D ◽

Chronic Pain ◽

Standard Deviation ◽

Sickle Cell Disease ◽

Adult Patient ◽

Retrospective Analysis ◽

Sickle Cell ◽

Pain Medication ◽

Cell Disease ◽

Vitamin D Levels

Abstract Introduction: The chronic pain in sickle cell disease (SCD) arises from chronic bone damage as a consequence of bone marrow infraction during vaso-occulsive events. There are certain barriers to adequate pain management in adult patients with SCD, namely, limited knowledge among the clinicians, inadequate assessment, concerns about addiction, and biases against opioid use. We did retrospective analysis to investigate the average pain medication needed by adult patient with SCD. We also did analysis to see if there was a relation between plasma vitamin D level and amount of pain medication needed. Methods: We take care of approximately 300 active adult SCD at Hematology clinic at our institute. We did a retrospective analysis of 458 adult patients with SCD seen at our clinic between 2001 and 2016. We collected data on type of SCD, plasma 25 -hydroxyvitamin d level and amount of opioid pain medication in mg. To get uniform units of opiates, we converted all the different opiates into morphine. Results: The average morphine dose in a 24 hours period needed to manage chronic pain in an adult patient with SS type was 84 mg with standard deviation of 72, for SC type was 60 mg with standard deviation of 72 and for sickle beta thal type was 72 mg with standard deviation of 71. There were 4 patients with SS with hereditary persistence of hemoglobin F and average opiate dose in them was 84 mg. We obtained vitamin d level on 223 patients and out of them, 47 had vitamin d level of <4.2 ng/ml (lowest level reportable by our lab). We also found negative correlation between amount of pain medication and vitamin D level. The spearman correlation coefficient was -0.2 and p value was <0.01. Conclusion: Because we were unable to find any previous reports of the correlation of vitamin D levels and opiate use in an adult population with SCD, we believe that this is the first study to report this correlation. It also provides a rough estimate regarding average amount of opiates that an adult patient with SCD needs. This correlation between Vitamin D levels and opiate requirement supports our current practice of screening all patients for Vitamin D deficiency using 25hydroxy vitamin D levels and treating all patients who are found to be deficient. We do not know if this Vitamin D replacement will reduce pain, bone health or the amount of opiate medication needed in the future. Disclosures No relevant conflicts of interest to declare.

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Age As an Independent Clinical Predictor for Vitamin D Deficiency in Sickle Cell Disease

Blood ◽

10.1182/blood.v124.21.1385.1385 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1385-1385

Author(s):

Jin Han ◽

Santosh L. Saraf ◽

Taimur Abbasi ◽

Xu Zhang ◽

Robert E. Molokie ◽

...

Keyword(s):

Vitamin D ◽

Sickle Cell Disease ◽

Blood Cell ◽

Creatinine Clearance ◽

Vitamin D Deficiency ◽

Sickle Cell ◽

Vitamin D Supplementation ◽

Small Sample ◽

Cell Disease

Abstract Background: Vitamin D deficiency (VDD) is highly prevalent among patients with sickle cell disease (SCD). Although little is known about the risk factors for VDD in SCD, it has been shown that VDD is associated with chronic pain, bone fragility, and pulmonary function in SCD. In this study we investigated the potential clinical predictors for VDD in patients with SCD. Method: In a retrospective, cross-sectional analysis, a total of 167 adults with SCD treated at the University of Illinois Medical Center with a baseline 25-hydroxy vitamin D (25-OHD) measurement were screened. Clinical variables were recorded from a clinic visit at least four weeks from a vaso-occlusive pain episode or red blood cell transfusion. Statistical association between 25-OHD and other clinical parameters were investigated. Results: After stratifying the patients based on 25-OHD levels, we observed the median age was significantly younger in patients with lower 25-OHD levels (Table 1). When analyzing different age groups by Kruskal Wallis analysis, 25-OHD levels were significantly elevated in patients ≥ 40 years old (Figure 1). When using Spearman correlation analysis, the 25-OHD levels as a continuous variable positively correlated with increasing age (p<0.001); they also showed a significant negative relationships with creatinine clearance, total bilirubin, platelet count, and white blood cell count (Table 2). Using ordinal logistic regression, age was an independent predictor of 25-OHD levels, as a three-categorical variable, in SCD (OR 0.55, 95% CI: 0.38 – 0.81; p =0.002) after adjusting for gender, creatinine clearance, and vitamin D supplementation (Table 3), which means that younger patients has higher chance of VDD. In the patients with VDD (25-OHD <20 ng/mL), weekly supplementation with oral ergocalciferol (50,000 units for twelve weeks) substantially improved 25-OHD levels (9.9 vs 23.7 ng/mL, p<0.0001, N=24). During a median of 40-month follow-up (range 0 to 96 months), thirteen patients died, but the log rank test or multivariate Cox regression analysis failed to show statistical significance between 25-OHD levels and mortality after adjusting ESRD and baseline vitamin D supplementation, likely due to a short follow-up period and a small sample size. Summary: Lower 25-OHD levels were associated with younger age in patients with SCD, especially patients younger than 40 years old. One possible explanation is that lower 25-OHD levels may be linked to higher mortality in SCD, but future research is needed to clarify the association between VDD and mortality in SCD. Disclosures No relevant conflicts of interest to declare.

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Prevalence of vitamin D deficiency in patients with sickle cell disease in Bahrain

International Journal of Medicine ◽

10.14419/ijm.v1i2.1126 ◽

2013 ◽

Vol 1 (2) ◽

Author(s):

Adla H Bakri ◽

Taysir S Garadah ◽

Ahmed A Jaradat ◽

Abdulla Al Ajmi ◽

Mohamed E Alawi ◽

...

Keyword(s):

Vitamin D ◽

Sickle Cell Disease ◽

Vitamin D Deficiency ◽

Sickle Cell ◽

Cell Disease

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Vitamin D Level and Its Correlation With Hemoglobin In Pediatric Sickle Cell Disease Patients

Blood ◽

10.1182/blood.v122.21.4677.4677 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4677-4677 ◽

Cited By ~ 3

Author(s):

Jennifer Alison Busse ◽

Kranthi Nandan Seelaboyina ◽

Grace Malonga ◽

Madhuri Jakkam Setty ◽

Thomas Moulton

Keyword(s):

Bone Marrow ◽

Vitamin D ◽

Sickle Cell Disease ◽

Vitamin D Deficiency ◽

Sickle Cell ◽

Blood Levels ◽

Cell Type ◽

Cell Disease ◽

Erythroid Precursor ◽

Over Time

Introduction It has been well characterized that people living with sickle cell disease are more likely than the general population to be vitamin D deficient. New literature suggests there is an association between vitamin D deficiency and increased anemia in patients with chronic anemia. To date, this has been examined only in patients with end stage renal disease, heart failure, and anemia of other chronic diseases, but not in sickle cell disease, a chronic inflammatory disease with an elevation in inflammatory markers. Vitamin D has been shown to increase erythroid precursor proliferation by increasing erythropoietin sensitivity. It is also thought that vitamin D has pleiotropic effects, which may have influence on the bone marrow. Additionally, vitamin D has been shown to suppress pro-inflammatory cytokines, which causes a decrease in the anemia of chronic inflammation. Severe vitamin D deficiency also causes hyperparathyroidism, which leads to an inhibition of endogenous production of erythropoietin. Our hypothesis implies supplementation of vitamin D will improve anemia of vitamin D deficient sickle cell patients. Methods We utilized laboratory and demographic data from the Bronx Lebanon Hospital Center's patient electronic medical record between November 2009 and July 2013. Our sample included a population of 50 sickle cell disease patients aged 0 to 21 who were vitamin D deficient (serum 25-hydroxyvitamin D (25-OHD) <30ng/ml). Sickle cell disease types included SS (64%), SC (32%), Sβ+ thalassemia and Sβ0 thalassemia (4%). Using a linear mixed model with an autoregressive correlation structure to account for variance within the subject, we examined the association between time dependent 25-OHD level (ng/ml) and hemoglobin in (g/dl), as well as between 25-OHD and reticulocyte percentage over time in days. We began at the time of first supplementation of 25-OHD to the most recent blood levels in each patient. Results After adjusting for mean corpuscular volume (MCV), hemoglobin, sickle cell type and hydroxyurea (Table 1), there was a linear increase in reticulocyte percentage over time associated with increasing 25-OHD levels (β = 0.000060, SE = 0.000030, p =0.050). However, after controlling for MCV, gender, race, sickle cell type, and hydroxyurea (Table 2), we found trend of a negative association between 25-OHD and hemoglobin levels, which was statistically significant (β = -0.000017, SE = 0.000007, p =0.017). Conclusion Our results did not support our original hypothesis, which stated that supplementation of vitamin D in vitamin D deficient sickle cell patients would lead to an improvement in anemia. However, a trend was noted of a decrease in hemoglobin with increasing 25-OHD. In turn, there was a statistically significant increase in reticulocyte percentage with increasing 25-OHD. This is suggestive that there is increased hemolysis with increased erythropoiesis caused by increasing 25-OHD. This is seen even when controlling for patients taking hydroxyurea. Further study is required to elucidate this possible correlation. It is important to examine this relationship further, as supplementing vitamin D in vitamin D deficient sickle cell disease patients is becoming standard of care for improvement in bone density. It is unclear what potential implications this may have on increased production of sickle cells from the bone marrow, including a possible increase in hemolysis and a worsened anemia. Disclosures: Seelaboyina: Bronx Lebanon Hospital: Employment.

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