Abstract
Background:
Individuals with cystic fibrosis (CF) have difficulty maintaining optimal vitamin D status due to pancreatic insufficiency-induced malabsorption, inadequate sunlight exposure, and poor intake of vitamin D containing foods. Vitamin D deficiency may increase the risk of pulmonary exacerbations of CF. The objective of this study was to assess factors impacting vitamin D status in patients with CF recently hospitalized for a pulmonary exacerbation of CF.
Methods:
This was a pre-planned analysis of vitamin D intake in patients enrolled in a multi-center, double-blind, randomized controlled study examining vitamin D therapy for pulmonary exacerbation of CF. Demographic information, responses from a habitual sun exposure questionnaire and food frequency questionnaire, and vitamin D supplement usage were queried and compared to serum 25-hydroxyvitamin D (25(OH)D) concentrations.
Results:
A total of 48 subjects were included in this analysis. Total mean vitamin D intake of the subjects was approximately 1,200 IU daily. Reported vitamin D intake, age, race, employment, and education were not significantly associated with vitamin D status in this population. However, smoking status, sunlight exposure in the last 3 years, and skin type (in the bivariate model) were all significantly associated with vitamin D status (all p<0.05).
Conclusions:
Sunlight exposure was the most predictive determinant of vitamin D status in patients with CF prior to pulmonary exacerbation. Reported vitamin D intake was below recommended amounts. The role and mode of optimizing vitamin D status prior to a pulmonary exacerbation needs further investigation.
Keywords: Vitamin D, nutrition, cystic fibrosis, pulmonary exacerbation
Introduction
Cystic fibrosis (CF) is an autosomal recessive disease characterized by chronic inflammation in the respiratory and gastrointestinal system leading to malabsorption, malnutrition, and recurrent lung infections.1 Because of pancreatic insufficiency-induced malabsorption, inadequate dietary intake, and decreased sunlight exposure, up to 90% of patients with CF exhibit vitamin D deficiency which may adversely impact skeletal, respiratory, and general health of these patients.2 It has been demonstrated that vitamin D deficiency is associated with a higher risk of pulmonary exacerbation in both adults and children with CF.3,4,5 Some small pilot studies in individuals with CF have demonstrated improved recovery after a pulmonary exacerbation of CF with vitamin D repletion,6,7,8 although larger multi-center studies have not been able to confirm this effect.9 While maintaining optimal levels of vitamin D status is desired in patients with CF, the mechanism of this beneficial effect is not entirely understood. Improved antioxidant status, lung remodeling, and induction of antimicrobial peptides are hypothesized to contribute to this effect.10,11,12
Vitamin D is a unique nutrient as it can be obtained both through oral consumption of ergocalciferol or chloecalciferol in food or dietary supplements, as well as by production in skin through exposure to sunlight.13 At this time, there have been no large studies evaluating the sources of vitamin D that may contribute to vitamin D status in patients with CF at the time of pulmonary exacerbation. Since vitamin D may have an important role in the maintenance of health in CF, particularly in optimizing lung health, it is important to further evaluate the contributing factors for vitamin D status in patients with CF in this clinical setting. Therefore, the purpose of this study was to evaluate factors contributing to vitamin D status upon hospital admission for pulmonary exacerbation in adults with CF.
Methods
Study Protocol
This was a sub study of a double-blind, multicenter, randomized, placebo-controlled clinical trial examining the effect of high dose vitamin D supplementation on outcomes in patients with CF hospitalized for pulmonary exacerbation. The study methods for the Vitamin D for the Immune System in Cystic Fibrosis (DISC) trial were detailed previously.14 Only subjects recruited at the Emory University site with baseline serum 25-hydroxyvitamin D concentrations were enrolled in this sub-study (n=48). The study received IRB approval and all subjects signed informed consent for participation. The study was registered at clinicaltrials.gov under registration #NCT01426256. Basic demographic information collected during the time of enrollment into the study was analyzed, including lifestyle and behavioral factors such as employment, alcohol, smoking, education, and time spent outdoors.
Vitamin D Intake through Supplements and Diet
Subjects were queried about their supplemental vitamin D intake upon entry into the trial. The amount of supplemental vitamin D from (1) vitamin D supplementation alone, (2) calcium supplementation also containing vitamin D, and/or (3) multivitamin supplementation also containing vitamin D was recorded. The total amount of supplemental vitamin D was calculated from all the supplemental sources.
Oral vitamin D intake from diet was also assessed using the short, structured DISC Food Frequency Questionnaire (FFQ), modified from a previous questionnaire assessing intake from calcium and vitamin D.15 The FFQ focused on frequency and typical serving sizes of consumption of vitamin D containing foods over the past year. Estimates of vitamin D content from foods were derived from the US Department of Agriculture (USDA) Nutrient Database for Standard Reference.16 The FFQ was administered at month 1 and month 12. Total vitamin D intake was derived from the summation of supplemental intake and dietary intake.
Assessment of Sun Exposure
Subjects were queried about sun exposure to evaluate cutaneous production of vitamin D using the DISC Sun Exposure History forms. Subjects completed these standardized surveys regarding skin type based on the Fitzpatrick scale,17 along with usual and vacation sun exposure over the past year and over the past 3 years. Sun exposure questions were modified from a validated survey that queried about time spent in the sun during weekends and holidays (less than 1 hour, 1–2 hours, 2–3 hours, 3–4 hours, >4 hours) and about frequency of outside activities (not that often, a moderate amount, quite a lot, almost all the time) over the past three years during both summers and winters.18 Additional questions were asked about sunscreen use and time spent in the sun to get a tan (never, rarely, sometimes, often, always). The surveys were completed within seven days of hospital admission and month 12 after enrollment in the primary study. The results of the baseline and 12 month sun exposure survey were not statistically different, and therefore the baseline sun exposure survey completed during hospital admission was used for analysis.
Measurement of Vitamin D Status
Serum total 25-hydroxyvitamin D (25(OH)D) was measured using a chemiluminescent assay (Catalog Number IS-2700S, IDS-iSYS, Immunodiagnostic Systems, Scottsdale, AZ) on an automated Immunoassay system (IDS-iSYS). The IDS-iSYS machine was calibrated using manufacturer controls of known concentration levels, and the study samples were run with internal house controls of known concentrations of 25(OH)D. Levels below 30 ng/mL were considered insufficient, with levels below 20 ng/mL considered vitamin D deficient. The laboratory performing the 25(OH)D concentrations participated in the vitamin D external quality assessment scheme (DEQAS) to ensure accuracy of these measurements.
Statistical Analysis
The distribution and percentage of the demographics of the study population were summarized. R Studio Version 3.5.2 (Boston, Massachusetts) was used to perform all analyses. The odds ratios between potential factors and 25-hydroxyvitamin D insufficiency were summarized with 95% confidence interval. The potential influence of various factors on vitamin D status were then evaluated separately with regression analysis and summarized in one table, including education, employment, time outdoors, smoking status, and alcohol consumption. The analysis was conducted separately so that each of the groups for a specified variable was compared to the responding intercept group. The interception in each part represents the reference group.
Multiple linear regression models were introduced to investigate the potential associations between 25-hydroxyvitamin D concentration and other potential factors. In this study, skin type, frequency of sunscreen usage, and sunlight exposure were categorized. Three bivariate models were conducted containing the variables separately and controlling for each. Wald p-values were reported for all models.
Results
Study Subjects
Forty-eight subjects were included in the final analysis. The demographics of the study subjects are listed in Table 1. The subjects were primarily of Caucasian race, approximately half were female, and the mean age was 27 ± 0.93 years (mean ± SEM). Ninety percent of subjects had pancreatic exocrine insufficiency and taking enzymes. Mean blood 25(OH)D concentrations were 26.4 ± 1.37 ng/mL. Mean lung function was measured by a mean FEV1 percent predicted of 49 ± 2.5%, while the mean BMI (20.8 ± 0.516 kg/m2) of the subjects was below the recommended target of the CF Foundation.19 (Table 1) Vitamin D intake came primarily from multivitamin supplements with about 80% of the subjects taking a multivitamin, a fat-soluble vitamin containing vitamins A, D, E, and K, calcium with vitamin D, or a combination of these supplements, with about 20% of the subjects also taking a separate vitamin D only supplement. In combination with dietary vitamin D intake seen in the FFQ, this equated to a total calculated mean vitamin D intake of approximately 1200 IU daily (Table 1).
Table 1.
Demographics of Study Population of Adults Hospitalized for a Pulmonary Exacerbation of Cystic Fibrosis
| Study Population (n) | Total | 48 |
|---|---|---|
| Age (years) | 27 ± 0.93 | |
| Race, n (%) | ||
| Caucasian | 41 (85) | |
| African American | 6 (13) | |
| Asian | 1 (2) | |
| Sex, n (%) | ||
| Male | 21 (44) | |
| Female | 27 (56) | |
| Body mass index (kg/m2) | 20.8 ± 0.516 | |
| FEV1 % Predicted (%) | 49 ± 2.5 | |
| Reported multivitamin use, n (%) | 20 (42) | |
| Reported fat-soluble vitamin use, n (%) | 12 (25) | |
| Reported calcium supplement use, n (%) | 11 (23) | |
| Reported vitamin D supplement use, n (%) | 9 (19) | |
| Reported total supplement use, n (%) | 37 (77) | |
| Supplemental daily vitamin D intake (IU) | 912 ±102 | |
| Nutritional daily vitamin D intake (IU) | 262 ± 66.2 | |
| Total vitamin D daily intake (IU) | 1174 ± 110.7 | |
| Reported pancreatic enzymes use, n (%) | 43 (90) | |
| Blood 25(OH)D concentrations (ng/mL) | 26.4 ± 1.37 |
A representation of the study population. Data is presented as mean ± standard error, or with percentages for standardization purposes.
Supplemental and Demographic Factors Associated with 25(OH)D Concentration Level
The use of acid reducing medications did not have any impact on vitamin D status, nor did the use of multivitamin, calcium, or fat-soluble vitamin supplements that also contained vitamin D (Table 2). Further, subjects who identified as Caucasian and those over the age of 30 were not significantly associated with higher or lower odds for vitamin D insufficiency compared to other races/ethnicities or ages (Table 2).
Table 2.
Risk Factors Associated with Vitamin D Insufficiency (25-hydroxyvitamin D < 30 ng/mL)
| Factors | Odds ratio | 95% CI |
|---|---|---|
| Age (>30) | 0.36 | (0.08, 1.50) |
| Race (Caucasian) | 3.11 | (0.34, 28.45) |
| Use of supplement containing vitamin D only | 1.12 | (0.24, 5.26) |
| Use of multivitamin containing vitamin D | 0.90 | (0.26, 3.13) |
| Use of acid reducing medicine | 0.75 | (0.20, 2.80) |
| Use of fat-soluble vitamins | 0.37 | (0.07, 1.99) |
| Use of calcium supplement containing vitamin D | 0.78 | (0.17, 3.48) |
| High vitamin D daily intake (> 2,000 IU) | 0.69 | (0.12, 3.91) |
| Hemoglobin A1C value (> 7%) | 1.00 | (0.27, 3.65) |
A univariate odds ratio table with a >1 value indicating higher chance of a factor being associated with vitamin D insufficiency and a <1 value indicating a higher chance of a factor being associated with vitamin D sufficiency. An odds ratio of 1 displays that there are no higher odds of either vitamin D insufficiency or sufficiency. A 95% confidence interval is given for levels of uncertainty, with confidence intervals containing 1 indicating an insignificant odds ratio.
Lifestyle Indicators of Vitamin D Status
Lifestyle factors including outdoor time, education, employment, and alcohol history were not significantly associated with vitamin D status. Current smoking status was associated with a significantly higher risk for vitamin D insufficiency (β=−19.62 ng/mL, P=0.041) compared to no smoking history (Table 3).
Table 3.
Impact of Lifestyle on Vitamin D Status
| Variable | Regression coefficient (ng/mL) | SE | P | |
|---|---|---|---|---|
| Education | ||||
| Reference | Completed grade school (n=5) | 31.185 | 4.280 | |
| Completed high school (n=19) | −4.404 | 4.811 | 0.37 | |
| Associates degree or specialized training (n=6) | −8.128 | 5.796 | 0.17 | |
| Standard college or university (n=15) | −4.451 | 4.943 | 0.37 | |
| Graduate school (n=3) | −10.159 | 6.990 | 0.15 | |
| Employment | ||||
| Reference | Employed (n=20) | 29.254 | 2.112 | |
| Unemployed (n=9) | −5.256 | 3.792 | 0.17 | |
| Student (n=8) | −7.252 | 3.952 | 0.07 | |
| Disability (n=10) | −2.672 | 3.659 | 0.47 | |
| Homemaker or equivalent (n=1) | −4.954 | 9.680 | 0.61 | |
| Outdoors | ||||
| Reference | < 30 minutes (n=8) | 24.92228 | 3.32104 | |
| 30 min - 1 hour (n=18) | 4.91222 | 3.99139 | 0.23 | |
| 1–2 hours (n=12) | −2.34672 | 4.28744 | 0.59 | |
| 2–4 hours (n=5) | 2.10684 | 5.35501 | 0.70 | |
| > 4 hours (n=5) | 0.02945 | 5.35501 | 0.996 | |
| Smoking History | ||||
| Reference | Never smoked (n=42) | 26.724 | 1.423 | |
| Previous smoker (n=5) | 0.817 | 4.364 | 0.85 | |
| Current smoker (n=1) | −19.624 | 9.333 | 0.04 | |
| Alcohol History | ||||
| Reference | No (n=25) | 27.980 | 1.964 | |
| Yes (n=23) | −3.297 | 2.722 | 0.232 | |
A regression analysis based on an initial group (interception point) for each variable, with subsequent groups being compared to the reference. The regression coefficient showing the direction of correlation, as well as the standard error and p-value, are given for each variable and category. A p-value of <0.05 represents significance.
Sun Survey Questionnaire Analysis
Skin type, use of sunscreen, tanning activity, and sunlight exposure during non-vacation periods were not associated with vitamin D status (Table 4). The questions that were associated with higher vitamin D status included sunlight exposure in the last 3 summers (P=0.03) and winters (P=0.03), and sunlight exposure in the past winter (P=0.01), all during holidays and vacation (Table 4).
Table 4.
Impact of Skin Type and Sunlight Exposure on Vitamin D Levels
| Variable | Regression coefficient (ng/mL) | SE | P |
|---|---|---|---|
| Skin Type (Q1) | |||
| Reference1 | 27.073 | 1.471 | |
| Brown (tan easily) or Black (get darker) | −7.567 | 4.462 | 0.097 |
| Sunscreen (Q2) | |||
| Reference2 | 26.703 | 1.771 | 0.67 |
| Often and Always | −1.302 | 3.003 | |
| Tanning (Q3) | |||
| Reference3 | 25.842 | 1.507 | |
| Sometimes, Often, and Always | 3.754 | 4.570 | 0.42 |
|
Sunlight Exposure (Q4) (last 3 summers during vacation) |
|||
| Reference4A | 24.383 | 1.574 | |
| > 4 hours/day | 7.158 | 3.081 | 0.03 |
|
Sunlight Exposure (Q5) (last 3 winters during vacation) |
|||
| Reference4B | 25.204 | 1.441 | |
| > 3 hours/day | 9.624 | 4.371 | 0.03 |
|
Outside Activities (Q6) (last 3 summers during non-vacation) |
|||
| Reference5A,B,C | 25.810 | 1.504 | |
| Almost all the time | 4.131 | 4.563 | 0.37 |
|
Outside Activities (Q7) (last 3 winters during non-vacation) |
|||
| Reference5A,B | 25.476 | 1.477 | |
| Quite a lot or almost all the time | 7.120 | 4.479 | 0.12 |
|
Sunlight Exposure (Q8) (in the last summer during vacation) |
|||
| Reference4A | 25.316 | 1.592 | |
| > 4 hours/day | 4.298 | 3.414 | 0.22 |
|
Sunlight Exposure (Q9) (in the last winter during vacation) |
|||
| Reference4C | 24.797 | 1.452 | |
| >2 hours/day | 9.552 | 3.722 | 0.01 |
|
Outside Activities (Q10) (in the last summer during non-vacation) |
|||
| Reference5A,B,C | 25.801 | 1.504 | |
| Almost all the time | 4.131 | 4.563 | 0.37 |
|
Outside Activities (Q11) (in the last winter during non-vacation) |
|||
| Reference5A,B | 25.703 | 1.474 | |
| Quite a lot or almost all the time | 6.297 | 4.998 | 0.21 |
| Bivariate Relationships | |||
| Q1 & Q4 | |||
| Reference1,4A | 225.159 | ||
| Skin type | −8.79 | 4.216 | 0.04 |
| Sunlight exposure | 7.847 | 2.988 | 0.01 |
| (in the last 3 summers during vacation) | |||
| Q1 & Q5 | |||
| Reference1,4B | 26.047 | ||
| Skin type | −8.643 | 4.245 | 0.048 |
| Sunlight Exposure | 10.509 | 4.245 | 0.02 |
| (in the last 3 winters during vacation) | |||
| Q1 & Q9 | |||
| Reference1,4C | 25.627 | ||
| Skin type | −8.097 | 4.171 | 0.06 |
| Sunlight Exposure | 9.878 | 3.614 | 0.009 |
| (in the last winter during vacation) | |||
Skin types including pale white (do not tan, burn easily), white (tan with difficulty, burn easily), white (tan after initial sunburn), and light brown (tan easily)
Never, rarely, or sometimes wear sunscreen
Never or rarely spend time in the sun to get a tan
Less than or equal to 2C, 3B, or 4A hours/day spent in the sun during weekend/holidays
Not that oftenA, a moderate amountB, quite a lotC, or almost all the timeD being outside for activities
A univariate regression analysis based on sun survey questions, with the specified group being compared to a reference group as designated above. A bivariate analysis was also done to allow for the control of either variable in question. The regression coefficient shows direction of correlation, with the standard error and p-value given for each variable and category. A p-value of <0.05 represents significance.
All skin types based on Fitzpatrick scale.15
To determine the impact on vitamin D status if one question (factor) was known, with another question (factor) unknown, bivariate models were completed to hold a variable constant (Table 4). When combining questions 1 and 4 [Please check the skin type that best describes you] and [In the last 3 years, during weekend and holidays/vacations in the summer, how much time would you normally have spent in the sun], this indicated a very significant relationship between skin type and sunlight exposure in the last 3 years during the summer. The serum 25(OH)D concentration can be determined by both skin type and sunlight (during the summer) as given by the equation 25(OH)D = 25.159 – 8.792 (Skin Type) + 7.847 (Sunlight Exposure), where skin type = 1 if brown or black, and skin type = 0 if a lighter skin tone, and sunlight exposure in the last 3 years during the summer = 1 if >4 hours, and sunlight exposure = 0 if ≤ 4 hours.
Similarly, another significant bivariate model was completed (Table 4) combining questions 1 and 5 [Please check the skin type that best describes you] and [In the last 3 years, during weekend and holidays/vacations in the winter, how much time would you normally have spent in the sun]. In this model, vitamin D levels can again be determined in any given subject by skin type and sunlight (during the winter) as given by the equation 25(OH)D = 26.047 – 8.643 (Skin Type) + 10.509 (Sunlight Exposure), where skin type = 1 if brown or black, and skin type = 0 if a lighter skin tone, and sunlight exposure in the last three years during the winter = 1 if >3 hours, and sunlight exposure = 0 if ≤ 3 hours.
Discussion
Vitamin D status can be influenced by diet, supplement use, sun exposure, age, obesity, and chronic illness.20 Our study examined the multiple factors contributing to vitamin D status in adults with CF leading up to a pulmonary exacerbation. We found that total oral intake of vitamin D was not significantly associated with vitamin D status. However, sunlight exposure, particularly in the previous winter and during the previous three summers and winters during vacation/weekends, along with skin type in the combined model, were the most predictive of vitamin D status, as determined by serum 25(OH)D levels. We found that smoking status was also predictive of vitamin D status; however, there was only 1 self-identified smoker. Other factors such as employment, education, age, and race/ethnicity were not predictive.
In this cohort, vitamin D intake leading up to hospitalization for pulmonary exacerbation of CF was inadequate (~1,200 IU daily), according to the CF Foundation guidelines on vitamin D.21 Many of the subjects in this study experienced several days of illness prior to enrollment due to the pulmonary exacerbation of CF which may have influenced reporting of usual food intake on the FFQ. However, oral intake of vitamin D during this illness period did not influence vitamin D status. We found that the reported sun exposure, especially during vacation and holiday periods, was significantly associated with higher vitamin D status leading up to this illness period. This finding indicates that exposure to sunlight is the major source of vitamin D production, especially in patients with malabsorption as in adults with CF. Further, it may be noted that those able to take outdoor sunny vacations, perhaps those with more resources, are also able to see their physicians regularly and have closer follow up regarding their vitamin D status. This finding is consistent with studies demonstrating better vitamin D status in healthy adolescents with outdoor activity,22 as well as studies reporting better vitamin D status with outdoor activity in adults and children with CF.23 Tobacco use was also associated with vitamin D status. Tobacco use among adults has been associated with vitamin D insufficiency in other studies, potentially due to an altered hepatic metabolism or accumulation of cadmium in the kidneys.24,25 It is possible that adults with CF who use tobacco products may represent individuals who are less compliant with health recommendations, such as adherence to pancreatic enzymes, which may adversely impact vitamin D status.
The amount of reported total vitamin D intake in this study was very low for individuals with CF. According to one study, a daily vitamin D intake of 1100–1700 IU is recommended for healthy adult individuals without CF to maintain adequate blood levels, with vitamin D deficient individuals requiring almost 5,000 IU in order to reach sufficient blood levels.26 A 25(OH)D concentration of over 30 ng/mL is considered optimal for healthy individuals.27 The CFF recommends repletion of individuals with vitamin D deficiency with oral weekly vitamin D of 50,000 IU for 8–12 weeks followed by maintenance therapy of 1500–2000 IU/day.21 The CFF further recommends that all individuals with CF greater than 10 years of age take at least 1000–2000 IU of vitamin D a day and adjust upwards until serum 25(OH)D levels reach above 30 ng/mL.21 This is particularly important because vitamin D deficiency has shown to be associated with increased risk of pulmonary exacerbations, particularly in children with CF.3,4 Achieving these recommended levels require much higher amounts of vitamin D in individuals with CF compared to individuals without CF.28,29 Therefore, the subjects in this study consumed well below the recommended intake of vitamin D. Whether increasing vitamin D intake prior to a pulmonary exacerbation would translate into higher vitamin D status and reduce the rates of hospitalization for pulmonary exacerbation has not been well studied.
Maintaining a sufficient vitamin D status is necessary as vitamin D deficiency, as seen in those with CF, may have other deleterious effects besides increased risk for pulmonary exacerbation. Low vitamin D levels in blood have been associated with lower bone mineral density in CF and increased bone turnover.30 Lower bone density increases the risk of vertebral fractures which can further compromise lung function due to restrictive physiology.31 Recent studies have indicated that correction of vitamin D status may favorably alter gut microbiota in adults with CF.32 Vitamin D may also have immunomodularity effects in patients with CF, by reducing frequent inflammatory responses that lead to significant lung damage.33,34
Our study examined dietary, sunlight exposure and other demographic variables accounting for vitamin D status in subjects prior to pulmonary exacerbation of CF but had some limitations. The results of this study are not generalizable to patients with CF during times of stable health. Our relatively small sample size may have limited our ability to determine the effect of certain lifestyle factors, including specific outdoor activities that provided sunlight exposure. Further limitations include our inability to directly assess adherence to vitamin D supplements and/or pancreatic enzyme use, as well as not adjusting for income status among the study subjects. This study provides new data on variables affecting vitamin D sufficiency and insufficiency at hospital admission for pulmonary exacerbation in adults with CF and can inform larger, prospective studies.
Conclusions
In conclusion, vitamin D status is often sub-optimal at the time of pulmonary exacerbation. We find that vitamin D intake appears to be inadequate at the time of pulmonary exacerbation and that sunlight exposure is most associated with higher vitamin D status. The parent multi-center DISC study demonstrated that rapid correction of vitamin D status at the time of pulmonary exacerbation did not alter clinical outcomes in adults with CF over the subsequent 12 months.9 Therefore, attention to achieving and maintaining optimal vitamin D status as opposed to rapid correction of vitamin D deficiency may be indicated as an approach to improve clinical outcomes in adults with CF. Physicians and their healthcare teams need to better identify those individuals with CF who have vitamin D insufficiency and utilize improved protocols to restore vitamin D status. Whether maintaining optimal vitamin D status during clinical stability prevents subsequent pulmonary exacerbations of CF, particularly in the new era of highly effective CFTR modulator therapies, needs to be tested in future clinical studies.
Funding:
This work was supported by grants from NIH/NCATS UL1 TR002378 (Georgia Clinical and Translational Science Alliance), NIH R03 DK117246, and the Cystic Fibrosis Foundation Clinical Research Award #TANGPR11A0. This project partially fulfilled the requirements of the Emory Discovery Program for Marta Bean.
Footnotes
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References
- 1.Elborn JS. Cystic fibrosis. The Lancet. 2016;388(10059):2519–2531. [DOI] [PubMed] [Google Scholar]
- 2.Grossmann RE, Tangpricha V. Evaluation of vehicle substances on vitamin D bioavailability: a systematic review. Mol Nutr Food Res. 2010;54(8):1055–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Mccauley LA, Thomas W, Laguna TA, Regelmann WE, Moran A, Polgreen LE. Vitamin D deficiency is associated with pulmonary exacerbations in children with cystic fibrosis. Ann Am Thorac Soc. 2014;11(2):198–204. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Vanstone MB, Egan ME, Zhang JH, Carpenter TO. Association between serum 25-hydroxyvitamin D level and pulmonary exacerbations in cystic fibrosis. Pediatr Pulmonol. 2015;50(5):441–6. [DOI] [PubMed] [Google Scholar]
- 5.Sexauer WP, Hadeh A, Ohman-Strickland PA, Zanni RL, Varlotta L, Holsclaw D, Fiel S, Graff GR, Atlas A, Bisberg D, et al. Vitamin D deficiency is associated with pulmonary dysfunction in cystic fibrosis. J Cyst Fibros 2015;14(4):497–506. [DOI] [PubMed] [Google Scholar]
- 6.Pincikova T, Paquin-Proulx D, Sandberg JK, Flodström-Tullberg M, Hjelte L. Clinical impact of vitamin D treatment in cystic fibrosis: a pilot randomized, controlled trial. Eur J Clin Nutr 2017;71(2):203–5. [DOI] [PubMed] [Google Scholar]
- 7.Grossmann RE, Zughaier SM, Liu S, Lyles RH, Tangpricha V. Impact of vitamin D supplementation on markers of inflammation in adults with cystic fibrosis hospitalized for a pulmonary exacerbation. Eur J Clin Nutr 2012;66(9):1072–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Grossmann RE, Zughaier SM, Kumari M, Seydafkan S, Lyles RH, Liu S, Sueblinvong V, Schechter MS, Stecenko AA, Ziegler TR, et al. Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: a randomized, controlled trial. Dermatoendocrinol 2012;4(2):191–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Tangpricha V, Lukemire J, Chen Y, et al. Vitamin D for the Immune System in Cystic Fibrosis (DISC): a double-blind, multicenter, randomized, placebo-controlled clinical trial. Am J Clin Nutr. 2019;109(3):544–553. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Dimitrov V, White JH. Species-specific regulation of innate immunity by vitamin D signaling. J Steroid Biochem Mol Biol. 2016;164:246–253. [DOI] [PubMed] [Google Scholar]
- 11.Alvarez JA, Chowdhury R, Jones DP, et al. Vitamin D status is independently associated with plasma glutathione and cysteine thiol/disulphide redox status in adults. Clin Endocrinol (Oxf). 2014;81(3):458–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Foong RE, Bosco A, Jones AC, et al. The effects of in utero vitamin D deficiency on airway smooth muscle mass and lung function. Am J Respir Cell Mol Biol. 2015;53(5):664–75. [DOI] [PubMed] [Google Scholar]
- 13.Chesdachai S, Tangpricha V. Treatment of vitamin D deficiency in cystic fibrosis. J Steroid Biochem Mol Biol. 2016;164:36–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Tangpricha V, Smith EM, Binongo J, et al. The Vitamin D for Enhancing the Immune System in Cystic Fibrosis (DISC) trial: Rationale and design of a multi-center, double-blind, placebo-controlled trial of high dose bolus administration of vitamin D3 during acute pulmonary exacerbation of cystic fibrosis. Contemp Clin Trials Commun. 2017;6:39–45. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Blalock SJ, Norton LL, Patel RA, Cabral K, Thomas CL. Development and assessment of a short instrument for assessing dietary intakes of calcium and vitamin D. J Am Pharm Assoc (2003). 2003;43(6):685–693. [DOI] [PubMed] [Google Scholar]
- 16.Haytowitz DB, Ahuja JK, Wu X, et al. USDA National Nutrient Database for Standard Reference [database online]. Beltsville, MD: Nutrient Data Laboratory, Beltsville Human Nutrition Research Center, ARS, USDA; 2018. http://www.ars.usda.gov/nutrientdata. Accessed September 23, 2018. [Google Scholar]
- 17.Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol. 1988;124(6):869–871. [DOI] [PubMed] [Google Scholar]
- 18.van der Mei IA, Blizzard L, Ponsonby AL, Dwyer T. Validity and reliability of adult recall of past sun exposure in a case-control study of multiple sclerosis. Cancer Epidemiol Biomarkers Prev. 2006;15(8):1538–1544. [DOI] [PubMed] [Google Scholar]
- 19.Stallings VA, Stark LJ, Robinson KA, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc. 2008;108(5):832–839. [DOI] [PubMed] [Google Scholar]
- 20.Tsiaras WG, Weinstock MA. Factors influencing vitamin D status. Acta Derm Venereol. 2011;91(2):115–124. [DOI] [PubMed] [Google Scholar]
- 21.Tangpricha V, Kelly A, Stephenson A, et al. An update on the screening, diagnosis, management, and treatment of vitamin D deficiency in individuals with cystic fibrosis: evidence-based recommendations from the Cystic Fibrosis Foundation. J Clin Endocrinol Metab. 2012;97(4):1082–1093. [DOI] [PubMed] [Google Scholar]
- 22.Wu T, Luo H, Wang R, Jia L, Li P, Zhu P. Effect of vitamin D supplementation and outdoor time on the 25(OH)D level in adolescents. Journal of Hygiene Research. 2017;46(2):207–212. [PubMed] [Google Scholar]
- 23.Robberecht E, Vandewalle S, Wehlou C, Kaufman JM, De Schepper J. Sunlight is an important determinant of vitamin D serum concentrations in cystic fibrosis. Eur J Clin Nutr. 2011;65(5):574–579. [DOI] [PubMed] [Google Scholar]
- 24.Brot C, Jorgensen NR, Sorensen OH. The influence of smoking on vitamin D status and calcium metabolism. Eur J Clin Nutr. 1999;53(12):920–926. [DOI] [PubMed] [Google Scholar]
- 25.Ren W, Gu Y, Zhu L, et al. The effect of cigarette smoking on vitamin D level and depression in male patients with acute ischemic stroke. Compr Psychiatry. 2016;65:9–14. [DOI] [PubMed] [Google Scholar]
- 26.Aloia JF, Patel M, Dimaano R, et al. Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Am J Clin Nutr. 2008;87(6):1952–1958. [DOI] [PubMed] [Google Scholar]
- 27.Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: when to test and how to treat. Mayo Clin Proc. 2010;85(8):752–757; quiz 757–758. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Khazai NB, Judd SE, Jeng L, et al. Treatment and prevention of vitamin D insufficiency in cystic fibrosis patients: comparative efficacy of ergocalciferol, cholecalciferol, and UV light. J Clin Endocrinol Metab. 2009;94(6):2037–2043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Regalado Lam Chew Tun R, Porhownik N, Taback S, Oleschuk C. Effect of high dose vitamin D3 therapy on serum vitamin D3 levels in vitamin D insufficient adults with cystic fibrosis. Clin Nutr ESPEN. 2018;23:84–88. [DOI] [PubMed] [Google Scholar]
- 30.Hall WB, Sparks AA, Aris RM. Vitamin d deficiency in cystic fibrosis. Int J Endocrinol. 2010;2010:218691. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Wolfenden LL, Judd SE, Shah R, Sanyal R, Ziegler TR, Tangpricha V. Vitamin D and bone health in adults with cystic fibrosis. Clin Endocrinol (Oxf). 2008;69(3):374–381. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Kanhere M, He J, Chassaing B, et al. Bolus Weekly Vitamin D3 Supplementation Impacts Gut and Airway Microbiota in Adults With Cystic Fibrosis: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial. J Clin Endocrinol Metab. 2018;103(2):564–574. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Pincikova T, Paquin-Proulx D, Sandberg JK, Flodstrom-Tullberg M, Hjelte L. Vitamin D treatment modulates immune activation in cystic fibrosis. Clin Exp Immunol. 2017;189(3):359–371. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Herscovitch K, Dauletbaev N, Lands LC. Vitamin D as an anti-microbial and anti-inflammatory therapy for Cystic Fibrosis. Paediatr Respir Rev. 2014;15(2):154–162. [DOI] [PubMed] [Google Scholar]