BRIEF COMMUNICATIONS Vitamin D Status in Children with Cystic Fibrosis Associations with Inflammation and Bacterial Colonization Tregony Simoneau1, Omar Bazzaz2, Gregory S. Sawicki1, and Catherine Gordon2,3 1 Children’s Hospital Boston, Division of Respiratory Diseases, Harvard Medical School, Boston, Massachusetts; 2Children’s Hospital Boston, Boston, Massachusetts; and 3Hasbro Children’s Hospital, Brown University, Providence, Rhode Island
Abstract Rationale: Patients with cystic fibrosis (CF) have high rates of vitamin D insufficiency. The relation between vitamin D status and inflammation in patients with CF is poorly understood. Objectives: To determine the prevalence of vitamin D deficiency and insufficiency in a young CF population and to examine correlations between vitamin D status, disease severity, and inflammatory markers. Methods: This was a retrospective chart review of patients with CF under the age of 12 years. Serum laboratory parameters, growth indices, pancreatic status, CFTR genetics, medications, microbiology, and presence of CF-related comorbidities were collected for patients who had fat-soluble vitamin levels measured between January 1, 2009 and December 31, 2011. Vitamin D deficiency was defined as a serum 25(OH)D less than 20 ng/ml and insufficiency as serum 25(OH)D 20 to 29.9 ng/ml. Associations between serum vitamin D concentration and clinical/inflammatory markers were assessed using Chi-square and t tests.
Measurements and Main Results: Data were collected for 148 children. The mean serum 25(OH)D concentration was 32.4 ng/ml (SD, 8.9). Seven percent (10 of 148) were vitamin D deficient, and 36% (53 of 148) were vitamin D insufficient. Among the pancreatic-sufficient patients, 50% (14 of 28) were vitamin D insufficient/deficient, whereas among pancreatic-insufficient patients, 41% (49 of 120) were vitamin D insufficient/deficient. Pseudomonas aeruginosa was a more common pathogen in the patients who were vitamin D insufficient/deficient (18 of 63 vs. 11 of 85, P = 0.018). There was no difference between vitamin D–sufficient versus –insufficient groups in terms of other bacterial colonization or inflammatory markers. Conclusions: Overall, vitamin D insufficiency is common among young children with CF. Vitamin D insufficiency is prevalent even in children who are pancreatic sufficient. In this population, vitamin D insufficiency is associated with a history of Pseudomonas colonization but not with classic markers of systemic inflammation. Keywords: cystic fibrosis; vitamin D; inflammation
(Received in original form June 14, 2013; accepted in final form December 28, 2013 ) Supported by Cystic Fibrosis Foundation Training Grant SIMONEA120 (T.S.). Author Contributions: All authors contributed to design and data collection of the study, and writing and critically editing the manuscript. Correspondence and requests for reprints should be addressed to Tregony Simoneau, M.D., Boston Children’s Hospital, Division of Respiratory Diseases, 300 Longwood Avenue, Boston, MA 02115. E-mail: [email protected] Ann Am Thorac Soc Vol 11, No 2, pp 205–210, Feb 2014 Copyright © 2014 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201306-171BC Internet address: www.atsjournals.org
Individuals with cystic fibrosis (CF) are known to be at increased risk of developing vitamin D insufficiency (1). Prior research has identified extremely high rates of insufficient vitamin D levels in CF populations, with rates higher than 80% in both adults and children (2, 3). Since many countries have adopted newborn screening programs for CF, the overall nutritional status of young children with CF
has improved, but vitamin D insufficiency remains a significant problem (4). Vitamin D insufficiency results in decreased intestinal absorption of calcium, resulting in secondary hyperparathyroidism. The elevated parathyroid hormone causes calcium resorption from bone, resulting in bone weakness, skeletal losses, and early osteoporosis (5). Perhaps related to the high
Simoneau, Bazzaz, Sawicki, et al.: Vitamin D Status in Pediatric Patients with CF
rates of vitamin D insufficiency, individuals with CF have also been shown to have low bone mineral density and a relatively high fracture prevalence rate of 20% (6). In addition to effects on bone health, vitamin D deficiency is correlated with an increased risk for the development of cancer, autoimmune diseases, infections, and cardiovascular disease among individuals without CF (5, 7–9). There is
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BRIEF COMMUNICATIONS also evidence to suggest that vitamin D plays a role in modulating the innate immune system, and vitamin D receptors have been found on Th1 cells and macrophages (5, 10). Few studies have assessed whether vitamin D status has an impact on inflammation or clinical outcomes in CF. The Scandinavian Cystic Fibrosis Nutritional Study found an inverse relationship between vitamin D and serum IgG levels (11), and a recent trial testing the effects of high-dose vitamin D supplementation on inflammation found a significant reduction in IL-6 and tumor necrosis factor-a, two inflammatory markers (12). We performed a retrospective analysis examining the associations between vitamin D status, inflammation, and disease severity in children with CF, specifically focusing on those younger than 12 years of age. We hypothesized that vitamin D insufficiency would correlate with markers of disease severity such as pulmonary function (FEV1), body mass index (BMI), and bacterial colonization.
This study was approved by the Boston Children’s Hospital (BCH) Institutional Review Board. A retrospective chart review was performed for children less than 12 years old who presented to the BCH Pediatric CF Center who had fat-soluble vitamin levels measured between January 2009 and December 2011.
Serum laboratory parameters of inflammatory status were also collected, including C-reactive protein (CRP), IgG, and IgE if they were available from the same date as the serum 25(OH)D concentration. The date of the laboratory values was recorded and categorized by season: January to March as winter, April to June as spring, July to September as summer, and October to December as fall. In addition, information was collected regarding CFTR genotype if known, medications at the time of the laboratory measures, microbiology, and presence of CF-related comorbidities. Microbiology results were obtained from the three most recent cultures; colonization was defined as having two out of the three cultures positive for the same organism. However, if subjects had ever had a positive culture for Pseudomonas aeruginosa, that data was also recorded. Information on the brand and dose of vitamin D was obtained as well as any additional supplements that were being used. A total daily supplemental vitamin D dose was calculated by combining the dose of vitamin D in the ADEK vitamin with any additional vitamin D supplementation in the medical record. Vitamin D deficiency was defined as a serum 25(OH)D concentration less than 20 ng/ml, insufficiency as serum 25(OH)D concentration 20 to 29.9 ng/ml, and sufficiency as serum 25(OH)D concentration greater than or equal to 30 ng/ml. In addition, all patients with a concentration less than 30 ng/ml were pooled for some of the analyses.
Methods
Statistical Analysis
A chart review was performed of the electronic medical record, collecting the most recent set of laboratory values within the time frame specified above, and using the visit from that date to obtain the remainder of the data. Data abstracted included: age, sex, exocrine pancreatic status, weight for length (w/l) percentile for those less than 2 years old or BMI percentile for those greater than 2 years old, and FEV1 expressed as percent predicted. Serum 25(OH)D concentration, the internationally accepted marker of vitamin D status, as well as serum vitamin A and E concentrations, were recorded. All serum 25(OH)D concentrations were performed by the BCH Clinical Laboratory using liquid chromatography–tandem mass spectrometry (AB Sciex, Foster City, CA).
Clinical and inflammatory markers were compared among the vitamin D groups using Chi-square (or analysis of variance) and Student t tests. Medians were used to compare continuous variables, and comparisons were performed using Mann-Whitney test and Kruskal-Wallis for multiple groups. In addition, we performed multivariate logistic regression analyses. For these models, subjects were divided into two age groups: those less than 6 years old and those who were 6 to 12 years old. This was done to include FEV1 as an independent variable, as only the older group of patients had these data available. Models were created to examine the relationship between vitamin D and Pseudomonas culture positivity, and levels of CRP, IgE, and IgG using the
Methods Study Cohort
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following independent variables: age, sex, genotype, BMI (or w/l), pancreatic insufficiency, and FEV1. Analysis was performed using IBM SPSS version 19 (Chicago, IL). Statistical significance was set as a P value less than 0.05, and all reported P values are two-sided.
Results Demographics and Prevalence of Vitamin D Insufficiency
Data were collected for 148 children. Subjects ranged in age from 10 months to 12 years (mean age, 7 yr), and 43% were girls. For some statistical analyses, patients were divided into two age groups: 0 to 5 years (n = 58) and 6 to 12 years (n = 90). The majority of subjects were pancreatic insufficient (81%). The mean serum 25 (OH)D concentration for the entire cohort was 32.4 ng/ml (SD, 9) (Table 1). Overall, 43% (63 of 148) were vitamin D insufficient or deficient. The distribution of serum 25(OH)D concentrations is illustrated in Figure 1A. The mean BMI or weight for length (w/l) percentile was at the 52nd percentile and did not differ between the vitamin D–sufficient, –insufficient, and –deficient groups (52.1 6 27, 50 6 28.3, and 62.4 6 32 percentile, respectively; P = 0.496). There was a significant difference in mean age between the vitamin D–sufficient, –insufficient, and –deficient groups (77.1 6 40.8, 94 6 37.9, and 69.5 6 46, respectively; P = 0.032). However, the greatest difference was between the vitamin D–insufficient and –deficient groups, with the oldest group being vitamin D–insufficient and the youngest group being vitamin D–deficient. Among the subjects with pancreatic sufficiency (n = 28), 50% (14 of 28) were vitamin D insufficient or deficient, whereas among pancreatic-insufficient patients (n = 120), 41% (49 of 120) were vitamin D insufficient or deficient (P = 0.377). There was no difference in the mean serum 25(OH)D concentration between the pancreatic-insufficient versus -sufficient groups (32.5 6 8.7 and 32.3 6 10.4 ng/ml, respectively; P = 0.93). The distribution of vitamin D concentrations by season is illustrated in Figure 1B. There was no significant difference in median vitamin D concentration by the season in which the test was obtained (P = 0.159).
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BRIEF COMMUNICATIONS Table 1. Demographic and clinical characteristics of sample compared by vitamin D status Variable
All Subjects
Overall N (%) BMI (weight/length) percentile, mean (SD) Age at time of visit, mean (SD), mo Female sex Delta F508 homozygous Pancreatic insufficient Most recent PFTs: FEV1% predicted (n = 96), mean (SD) Current proton pump inhibitor Recent oral or IV antibiotics 25(OH)D, ng/mL, mean (SD)
148 52.0 82.7 64 66 120 99
(100) (27.8) (40.8) (43) (45) (81) (18)
67 (45) 46 (31) 32.4 (9)
Vitamin D Sufficient 85 52.1 77.1 41 40 71 101
(57) (27) (40.8) (64) (61) (59) (19)
34 (51) 22 (48) 38.3 (6.7)
Vitamin D Insufficient 53 50 94 20 21 41 96
(36) (28.3) (37.9) (31) (32) (34) (17)
29 (43) 20 (43) 26.1 (2.4)
Vitamin D Deficient 10 61.4 69.5 3 5 8 94
(7) (32) (46) (5) (7) (7) (12)
4 (6) 4 (9) 16.2 (2.3)
P Value
0.496 0.032 0.327 0.651 0.664 0.301 0.226 0.281 ,0.0001
Definition of abbreviations: BMI = body mass index; IV = intravenous; PFTs = pulmonary function tests. Data are presented as N (%) unless otherwise noted. Variables with significant P value (,0.05) are shown in bold.
Comparison of Clinical/Inflammatory Markers between Vitamin D–Sufficient and –Insufficient Subjects
The median serum 25(OH)D concentration in subjects ever colonized with Pseudomonas was significantly lower than those without this infection (27.7; interquartile range [IQR], 25.3, 33.8; vs. 32.9; IQR, 26.5, 39.3; P = 0.021; Figure 2). This difference was not seen in subjects colonized with methicillin-resistant staphylococcus aureus and methicillinsensitive staphylococcus aureus (Figure 2). Table 2 shows serum inflammatory markers in the vitamin D–insufficient/ deficient versus –sufficient groups. P. aeruginosa was a more common pathogen in the patients who were vitamin D insufficient/deficient as compared with those who were vitamin D sufficient (18 of
63 vs. 11 of 85, respectively; P = 0.018). There was no difference in median CRP, mean IgG, or mean IgE. Multivariate logistic regression analysis of possible prognostic factors (age, sex, BMI percentile, genotype, pancreatic insufficiency, FEV1, CRP, IgG, IgE, and history of Pseudomonas) for vitamin D insufficiency was performed for subjects aged 6 to 12 years (Table 3). Subjects aged 6 to 12 years with a history of a positive Pseudomonas culture were significantly more likely to be vitamin D insufficient/ deficient, whereas CRP, IgG, and IgE were not found to be predictive of vitamin D status. In addition, BMI percentile and FEV1 did not correlate with vitamin D status. Supplemental vitamin D dose was available for 131 of the patients. Overall, the median dose was 800 IU with a range of 0 to 3,600 IU (IQR, 400, 1,000 IU). The
Figure 1. (A) Boxplot of serum 25(OH)D concentrations, grouped by vitamin D status: Deficient, Insufficient and Sufficient. (B) Boxplot of serum 25(OH)D concentration by season. There is no significant difference between the median serum 25(OH)D concentrations obtained in each season. Winter is defined as January to March, spring as April to June, summer as July to September, and fall as October to December. The top and bottom of the boxes are quartile boundaries; center belt is the median. Exterior points are outliers, falling above the 90th percentile or below the 10th percentile. Vertical lines extend to the position of the farthest nonoutlier above and below the box.
Simoneau, Bazzaz, Sawicki, et al.: Vitamin D Status in Pediatric Patients with CF
median dose was compared between the pancreatic-sufficient versus -insufficient groups and between the vitamin D– sufficient and –insufficient/deficient groups. In the pancreatic-sufficient group, 79% (22 of 28) subjects were not taking a vitamin D supplement, whereas 3% (3 of 103) pancreatic-insufficient patients were not taking any vitamin D supplementation (data not shown, P , 0.001). The median vitamin D dose in the pancreatic-sufficient group was significantly lower than that in the pancreatic-insufficient group (0 vs. 800, respectively; P , 0.0001; data not shown). However, there was no difference in the median vitamin D dose compared between the vitamin D–sufficient and –insufficient/deficient groups (Table 2).
Discussion In this study, we report that many young children with CF had a serum 25(OH)D concentration less than the current recommended optimal threshold for this patient population of 30 ng/ml. However, the prevalence of vitamin D insufficiency in our cohort was lower than what has been reported previously. In 2007, Rovner and colleagues found that 90% of pediatric patients with CF were vitamin D insufficient (3). Similarly, Brodlie and colleagues found that 90% of their pediatric CF population was vitamin D insufficient, and after increasing the supplementation dose, 49% remained insufficient (13). Our finding may indicate a greater awareness about vitamin D resulting in additional supplementation. The CF Foundation published new guidelines for the management of vitamin D 207
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Figure 2. Boxplots of serum 25(OH)D concentration compared by bacterial colonization. There is no significant difference in median serum 25(OH)D concentration between subjects colonized with methicillin-resistant staphylococcus aureus (MRSA) (Yes) or not colonized with MRSA (No). The same is true for methicillin-sensitive staphylococcus aureus (MSSA). However, the subjects with a history of a prior throat or sputum culture positive for Pseudomonas had a significantly lower median serum 25(OH)D concentration compared with those with no Pseudomonas. The top and bottom of the box are quartile boundaries; center belt is the median. Exterior points are outliers, falling above the 90th percentile or below the 10th percentile. Vertical lines extend to the position of the farthest nonoutlier above and below the box.
insufficiency and deficiency in the spring of 2012 (14). Although the data described in this paper were obtained before the new guidelines, there was likely greater awareness of and attention paid to vitamin D replacement during the time frame of the study. Patients in our center were aggressively supplemented when they were found to have serum 25(OH)D
concentrations less than 30 ng/ml. In addition, this finding of improved serum 25 (OH)D concentrations may indicate that children with CF under 12 years of age are less likely to be vitamin D insufficient when compared with older cohorts of children. Interestingly, in our sample, the individuals with normal pancreatic function had a higher rate of vitamin D insufficiency
than those with pancreatic insufficiency (50 vs. 41%). This finding is likely explained by the lack of routine vitamin D supplementation in the pancreaticsufficient patients, with only 21% of the pancreatic-sufficient patients being on any vitamin supplementation. However, these data suggest that perhaps these patients also require some degree of vitamin D supplementation. These findings are similar to what has been found in studies examining vitamin D insufficiency in the general pediatric population. Gordon and colleagues in 2008 found that 40% of healthy toddlers and infants had vitamin D insufficiency (15). Although our study found lower rates of vitamin D insufficiency than what had previously been described, the rates are still quite high. There are likely several reasons for this, including decreased sun exposure in chronically ill children, low dietary intake, or poor absorption. Despite receiving pancreatic enzymes, patients with CF have been shown to have decreased absorption of ergocalciferol and decreased hepatic 25-hydroxylation of vitamin D compared with the non-CF population (16). It is interesting, however, that the vitamin D levels did not significantly differ by season. However, there was a trend toward higher levels in the summer and fall. The current recommendation by the CF Foundation is to check serum 25(OH)D concentrations at the end of winter, when
Table 2. Clinical variables and markers of disease severity compared by vitamin D status Variable
IgE, mean (SD) IgG, mean (SD) CRP, median (IQR) Vitamin E level, mean (SD) Vitamin A level, mean (SD) Supplemental Vitamin D dose, median (IQR) Any bacterial colonization MRSA colonization MSSA colonization History of Pseudomonas Labs collected during acute illness Current or recent antibiotic treatment* Current proton pump inhibitor
N (%)
Mean (SD)
Vitamin D Insufficient/Deficient (N = 63)
Vitamin D Sufficient (N = 85)
128 101.6 (206) 86.3 (178.5) 58 921.5 (336) 935.6 (390.3) 87 (59) 0.099 (0.099, 0.11) 0.24 (0.56) 143 9.69 (3.9) 10.7 (3.9) 144 31.7 (8) 32.5 (7.9) 131 800 (400, 1,000) 800 (400, 1,000) 128 14 95 29 18 46
(86) (9.5) (64) (20) (12) (31)
67 (45)
74 8 53 11 10 22
(87) (9) (62) (13) (12) (26)
34 (40)
122.6 905.3 0.45 8.2 30.0 800 54 6 42 18 7 24
(238.6) (266.3) (1.6) (3.4) (8.5) (400, 1,000)
P Value
0.326 0.735 0.388 ,0.0001 0.034 0.575
(86) (9) (67) (29) (11) (38)
0.813 0.982 0.588 0.018 0.902 0.112
33 (52)
0.135
Definition of abbreviations: CRP = C-reactive protein; IQR = interquartile range, Q1, Q3; MRSA = methicillin-resistant staphylococcus aureus; MSSA = methicillin-sensitive staphylococcus aureus. Values reported as N (%) unless otherwise indicated. *Within the previous 4 weeks. Variables with a significant P value (,0.05) are shown in bold.
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BRIEF COMMUNICATIONS Table 3. Multivariate odds ratios of vitamin D insufficiency according to markers of inflammation and bacterial culture in children aged 6 to 12 years (N = 90) Variable CRP IgE IgG History of Pseudomonas
N
OR* (95% CI)
53 73 35 86
0 (0–975) 1.0 (0.998–1.00) 1.0 (1.00–1.01) 3.2 (1.1–9.4)
P Value 0.285 0.892 0.051 0.033
Definition of abbreviations: BMI = body mass index; CI = confidence interval; CRP = C-reactive protein; OR = odds ratio. *OR adjusted for age, sex, BMI percentile, genotype, pancreatic insufficiency, and FEV1 from logistic regression analyses. Variables with significant P value (,0.05) are shown in bold.
they are most likely at their lowest level (14), and this recommendation is based on evidence from adult literature demonstrating that vitamin D status fluctuates by season (17, 18). It may be that in such a young pediatric population in New England, there is less seasonal variability in sun exposure. The patients with vitamin D insufficiency also had significantly lower levels of vitamin A and E, suggesting that the vitamin D insufficiency may be related to poor medication adherence. This is further supported by the finding that there is no difference in median supplemental vitamin D dose between the vitamin D– sufficient versus –insufficient/deficient groups. Although the prescribed dose may be the same, the actual dose taken by the patient was not measured by this study. In our study, common clinical indicators of disease severity, lung function and nutritional status, were not associated with vitamin D status. The mean BMI percentile was similar in the vitamin D–sufficient and –insufficient groups, suggesting that nutritional status may not be a significant factor in determining vitamin D status in this young population. Similarly, there was no significant difference in FEV1 between the vitamin D–sufficient and –insufficient groups. However, in a cohort of young patients, one would not expect to see abnormal lung function. A prospective study evaluating how lung function may decline over time
would be necessary to further assess whether vitamin D status has an impact on lung function. However, we did find that the patients who were vitamin D– insufficient or –deficient were more likely to be colonized with P. aeruginosa (29% prevalence compared with 13% prevalence in the vitamin D–sufficient group). P. aeruginosa colonization has been associated with a more rapid decline in lung function in patients with CF older than 7 years (19). Our finding that children with vitamin D insufficiency were more likely to be colonized with P. aeruginosa is interesting and suggests a possible mediating role of vitamin D with respect to airway infection and long-term pulmonary function in CF. This association is similar to a recent study of vitamin D status in patients with non-CF bronchiectasis in which patients with vitamin D deficiency (25[OH]D less than 25 nmol/L) were more likely to exhibit bacterial colonization, including P. aeruginosa (20). One possible explanation for this association is the finding that patients with low serum 25 (OH)D levels had higher levels of airway vitamin D–binding protein (20). Vitamin D–binding protein is expressed by inflammatory cells, particularly neutrophils and macrophages, both of which play an important role in CF-related inflammation. Although the mean serum 25(OH)D concentration was significantly different between the Pseudomonas-positive and -negative groups, the levels are actually quite close
References 1 Hall WB, Sparks AA, Aris RM. Vitamin D deficiency in cystic fibrosis. Int J Endocrinol 2010;2010:218691.
(29.6 vs. 33.2 ng/ml, P = 0.047), and it is difficult to determine what is a clinically relevant difference and where the optimal concentration lies. Furthermore, due to limitations of the study, we were unable to determine the serum 25(OH)D concentration closest to the time of Pseudomonas acquisition, which should be assessed in future studies. Interestingly, we did not find a significant difference in any of the inflammatory markers (IgG, IgE, or CRP) in the patients who had vitamin D insufficiency versus those who did not. It is possible that our sample was underpowered to detect such an association, given that many children in our cohort did not have these laboratory values available. The limitations of this study include small sample size and cross-sectional design. In addition, the nature of chart review inherently limits what data are available. Further prospective studies are necessary to verify and understand the potential connection between vitamin D and inflammation and bacterial colonization. To our knowledge, this is the first study to assess vitamin D status and clinical markers of disease severity in very young children with CF. Our study suggests that vitamin D insufficiency is prevalent in young children with CF, even those with pancreatic sufficiency. These findings support the current recommendation for annual screening of fat-soluble vitamin levels in all patients with CF. Furthermore, the connection between vitamin D insufficiency and P. aeruginosa colonization warrants further investigation. To determine more definitively the impact of vitamin D insufficiency on inflammation and clinical outcomes, larger prospective longitudinal studies will be needed. n Author disclosures are available with the text of this article at www.atsjournals.org. Acknowledgment: The authors thank the Cystic Fibrosis Foundation for providing fellowship funding and the patients and their families who made this work possible. They also thank Dr. Craig Schramm for statistical assistance.
2 Boyle MP, Noschese ML, Watts SL, Davis ME, Stenner SE, Lechtzin N. Failure of high-dose ergocalciferol to correct vitamin D deficiency in adults with cystic fibrosis. Am J Respir Crit Care Med 2005;172: 212–217.
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BRIEF COMMUNICATIONS 3 Rovner AJ, Stallings VA, Schall JI, Leonard MB, Zemel BS. Vitamin D insufficiency in children, adolescents, and young adults with cystic fibrosis despite routine oral supplementation. Am J Clin Nutr 2007;86:1694–1699. 4 Feranchak AP, Sontag MK, Wagener JS, Hammond KB, Accurso FJ, Sokol RJ. Prospective, long-term study of fat-soluble vitamin status in children with cystic fibrosis identified by newborn screen. J Pediatr 1999;135:601–610. 5 Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–281. 6 Haworth CS. Impact of cystic fibrosis on bone health. Curr Opin Pulm Med 2010;16:616–622. 7 Khazai N, Judd SE, Tangpricha V. Calcium and vitamin D: skeletal and extraskeletal health. Curr Rheumatol Rep 2008;10:110–117. 8 Tangpricha V, Spina C, Yao M, Chen TC, Wolfe MM, Holick MF. Vitamin D deficiency enhances the growth of MC-26 colon cancer xenografts in Balb/c mice. J Nutr 2005;135:2350–2354. 9 Mathieu C, Gysemans C, Giulietti A, Bouillon R. Vitamin D and diabetes. Diabetologia 2005;48:1247–1257. 10 Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006; 311:1770–1773. 11 Pincikova T, Nilsson K, Moen IE, Karpati F, Fluge G, Hollsing A, Knudsen PK, Lindblad A, Mared L, Pressler T, et al.; Scandinavian Cystic Fibrosis Study Consortium. Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study. Eur J Clin Nutr 2011;65:102–109. 12 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;66:1072–1074.
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13 Brodlie M, Orchard WA, Reeks GA, Pattman S, McCabe H, O’Brien CJ, Thomas MF, Spencer DA. Vitamin D in children with cystic fibrosis. Arch Dis Child 2012;97:982–984. 14 Tangpricha V, Kelly A, Stephenson A, Maguiness K, Enders J, Robinson KA, Marshall BC, Borowitz D; Cystic Fibrosis Foundation Vitamin D Evidence-Based Review Committee. 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;97:1082–1093. 15 Gordon CM, Feldman HA, Sinclair L, Williams AL, Kleinman PK, PerezRossello J, Cox JE. Prevalence of vitamin D deficiency among healthy infants and toddlers. Arch Pediatr Adolesc Med 2008;162: 505–512. 16 Lark RK, Lester GE, Ontjes DA, Blackwood AD, Hollis BW, Hensler MM, Aris RM. Diminished and erratic absorption of ergocalciferol in adult cystic fibrosis patients. Am J Clin Nutr 2001;73:602–606. 17 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;69:374–381. 18 Stephenson A, Brotherwood M, Robert R, Atenafu E, Corey M, Tullis E. Cholecalciferol significantly increases 25-hydroxyvitamin D concentrations in adults with cystic fibrosis. Am J Clin Nutr 2007;85: 1307–1311. 19 Schaedel C, de Monestrol I, Hjelte L, Johannesson M, Kornfalt ¨ R, Lindblad A, Strandvik B, Wahlgren L, Holmberg L. Predictors of deterioration of lung function in cystic fibrosis. Pediatr Pulmonol 2002;33:483–491. 20 Chalmers JD, McHugh BJ, Docherty C, Govan JR, Hill AT. Vitamin-D deficiency is associated with chronic bacterial colonisation and disease severity in bronchiectasis. Thorax 2013;68:39–47.
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Abstract Rationale: Patients with cystic fibrosis (CF) have high rates of vitamin D insufficiency. The relation between vitamin D status and inflammation in patients with CF is poorly understood. Objectives: To determine the prevalence of vitamin D deficiency and insufficiency in a young CF population and to examine correlations between vitamin D status, disease severity, and inflammatory markers. Methods: This was a retrospective chart review of patients with CF under the age of 12 years. Serum laboratory parameters, growth indices, pancreatic status, CFTR genetics, medications, microbiology, and presence of CF-related comorbidities were collected for patients who had fat-soluble vitamin levels measured between January 1, 2009 and December 31, 2011. Vitamin D deficiency was defined as a serum 25(OH)D less than 20 ng/ml and insufficiency as serum 25(OH)D 20 to 29.9 ng/ml. Associations between serum vitamin D concentration and clinical/inflammatory markers were assessed using Chi-square and t tests.
Measurements and Main Results: Data were collected for 148 children. The mean serum 25(OH)D concentration was 32.4 ng/ml (SD, 8.9). Seven percent (10 of 148) were vitamin D deficient, and 36% (53 of 148) were vitamin D insufficient. Among the pancreatic-sufficient patients, 50% (14 of 28) were vitamin D insufficient/deficient, whereas among pancreatic-insufficient patients, 41% (49 of 120) were vitamin D insufficient/deficient. Pseudomonas aeruginosa was a more common pathogen in the patients who were vitamin D insufficient/deficient (18 of 63 vs. 11 of 85, P = 0.018). There was no difference between vitamin D–sufficient versus –insufficient groups in terms of other bacterial colonization or inflammatory markers. Conclusions: Overall, vitamin D insufficiency is common among young children with CF. Vitamin D insufficiency is prevalent even in children who are pancreatic sufficient. In this population, vitamin D insufficiency is associated with a history of Pseudomonas colonization but not with classic markers of systemic inflammation. Keywords: cystic fibrosis; vitamin D; inflammation
(Received in original form June 14, 2013; accepted in final form December 28, 2013 ) Supported by Cystic Fibrosis Foundation Training Grant SIMONEA120 (T.S.). Author Contributions: All authors contributed to design and data collection of the study, and writing and critically editing the manuscript. Correspondence and requests for reprints should be addressed to Tregony Simoneau, M.D., Boston Children’s Hospital, Division of Respiratory Diseases, 300 Longwood Avenue, Boston, MA 02115. E-mail: [email protected] Ann Am Thorac Soc Vol 11, No 2, pp 205–210, Feb 2014 Copyright © 2014 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201306-171BC Internet address: www.atsjournals.org
Individuals with cystic fibrosis (CF) are known to be at increased risk of developing vitamin D insufficiency (1). Prior research has identified extremely high rates of insufficient vitamin D levels in CF populations, with rates higher than 80% in both adults and children (2, 3). Since many countries have adopted newborn screening programs for CF, the overall nutritional status of young children with CF
has improved, but vitamin D insufficiency remains a significant problem (4). Vitamin D insufficiency results in decreased intestinal absorption of calcium, resulting in secondary hyperparathyroidism. The elevated parathyroid hormone causes calcium resorption from bone, resulting in bone weakness, skeletal losses, and early osteoporosis (5). Perhaps related to the high
Simoneau, Bazzaz, Sawicki, et al.: Vitamin D Status in Pediatric Patients with CF
rates of vitamin D insufficiency, individuals with CF have also been shown to have low bone mineral density and a relatively high fracture prevalence rate of 20% (6). In addition to effects on bone health, vitamin D deficiency is correlated with an increased risk for the development of cancer, autoimmune diseases, infections, and cardiovascular disease among individuals without CF (5, 7–9). There is
205
BRIEF COMMUNICATIONS also evidence to suggest that vitamin D plays a role in modulating the innate immune system, and vitamin D receptors have been found on Th1 cells and macrophages (5, 10). Few studies have assessed whether vitamin D status has an impact on inflammation or clinical outcomes in CF. The Scandinavian Cystic Fibrosis Nutritional Study found an inverse relationship between vitamin D and serum IgG levels (11), and a recent trial testing the effects of high-dose vitamin D supplementation on inflammation found a significant reduction in IL-6 and tumor necrosis factor-a, two inflammatory markers (12). We performed a retrospective analysis examining the associations between vitamin D status, inflammation, and disease severity in children with CF, specifically focusing on those younger than 12 years of age. We hypothesized that vitamin D insufficiency would correlate with markers of disease severity such as pulmonary function (FEV1), body mass index (BMI), and bacterial colonization.
This study was approved by the Boston Children’s Hospital (BCH) Institutional Review Board. A retrospective chart review was performed for children less than 12 years old who presented to the BCH Pediatric CF Center who had fat-soluble vitamin levels measured between January 2009 and December 2011.
Serum laboratory parameters of inflammatory status were also collected, including C-reactive protein (CRP), IgG, and IgE if they were available from the same date as the serum 25(OH)D concentration. The date of the laboratory values was recorded and categorized by season: January to March as winter, April to June as spring, July to September as summer, and October to December as fall. In addition, information was collected regarding CFTR genotype if known, medications at the time of the laboratory measures, microbiology, and presence of CF-related comorbidities. Microbiology results were obtained from the three most recent cultures; colonization was defined as having two out of the three cultures positive for the same organism. However, if subjects had ever had a positive culture for Pseudomonas aeruginosa, that data was also recorded. Information on the brand and dose of vitamin D was obtained as well as any additional supplements that were being used. A total daily supplemental vitamin D dose was calculated by combining the dose of vitamin D in the ADEK vitamin with any additional vitamin D supplementation in the medical record. Vitamin D deficiency was defined as a serum 25(OH)D concentration less than 20 ng/ml, insufficiency as serum 25(OH)D concentration 20 to 29.9 ng/ml, and sufficiency as serum 25(OH)D concentration greater than or equal to 30 ng/ml. In addition, all patients with a concentration less than 30 ng/ml were pooled for some of the analyses.
Methods
Statistical Analysis
A chart review was performed of the electronic medical record, collecting the most recent set of laboratory values within the time frame specified above, and using the visit from that date to obtain the remainder of the data. Data abstracted included: age, sex, exocrine pancreatic status, weight for length (w/l) percentile for those less than 2 years old or BMI percentile for those greater than 2 years old, and FEV1 expressed as percent predicted. Serum 25(OH)D concentration, the internationally accepted marker of vitamin D status, as well as serum vitamin A and E concentrations, were recorded. All serum 25(OH)D concentrations were performed by the BCH Clinical Laboratory using liquid chromatography–tandem mass spectrometry (AB Sciex, Foster City, CA).
Clinical and inflammatory markers were compared among the vitamin D groups using Chi-square (or analysis of variance) and Student t tests. Medians were used to compare continuous variables, and comparisons were performed using Mann-Whitney test and Kruskal-Wallis for multiple groups. In addition, we performed multivariate logistic regression analyses. For these models, subjects were divided into two age groups: those less than 6 years old and those who were 6 to 12 years old. This was done to include FEV1 as an independent variable, as only the older group of patients had these data available. Models were created to examine the relationship between vitamin D and Pseudomonas culture positivity, and levels of CRP, IgE, and IgG using the
Methods Study Cohort
206
following independent variables: age, sex, genotype, BMI (or w/l), pancreatic insufficiency, and FEV1. Analysis was performed using IBM SPSS version 19 (Chicago, IL). Statistical significance was set as a P value less than 0.05, and all reported P values are two-sided.
Results Demographics and Prevalence of Vitamin D Insufficiency
Data were collected for 148 children. Subjects ranged in age from 10 months to 12 years (mean age, 7 yr), and 43% were girls. For some statistical analyses, patients were divided into two age groups: 0 to 5 years (n = 58) and 6 to 12 years (n = 90). The majority of subjects were pancreatic insufficient (81%). The mean serum 25 (OH)D concentration for the entire cohort was 32.4 ng/ml (SD, 9) (Table 1). Overall, 43% (63 of 148) were vitamin D insufficient or deficient. The distribution of serum 25(OH)D concentrations is illustrated in Figure 1A. The mean BMI or weight for length (w/l) percentile was at the 52nd percentile and did not differ between the vitamin D–sufficient, –insufficient, and –deficient groups (52.1 6 27, 50 6 28.3, and 62.4 6 32 percentile, respectively; P = 0.496). There was a significant difference in mean age between the vitamin D–sufficient, –insufficient, and –deficient groups (77.1 6 40.8, 94 6 37.9, and 69.5 6 46, respectively; P = 0.032). However, the greatest difference was between the vitamin D–insufficient and –deficient groups, with the oldest group being vitamin D–insufficient and the youngest group being vitamin D–deficient. Among the subjects with pancreatic sufficiency (n = 28), 50% (14 of 28) were vitamin D insufficient or deficient, whereas among pancreatic-insufficient patients (n = 120), 41% (49 of 120) were vitamin D insufficient or deficient (P = 0.377). There was no difference in the mean serum 25(OH)D concentration between the pancreatic-insufficient versus -sufficient groups (32.5 6 8.7 and 32.3 6 10.4 ng/ml, respectively; P = 0.93). The distribution of vitamin D concentrations by season is illustrated in Figure 1B. There was no significant difference in median vitamin D concentration by the season in which the test was obtained (P = 0.159).
AnnalsATS Volume 11 Number 2 | February 2014
BRIEF COMMUNICATIONS Table 1. Demographic and clinical characteristics of sample compared by vitamin D status Variable
All Subjects
Overall N (%) BMI (weight/length) percentile, mean (SD) Age at time of visit, mean (SD), mo Female sex Delta F508 homozygous Pancreatic insufficient Most recent PFTs: FEV1% predicted (n = 96), mean (SD) Current proton pump inhibitor Recent oral or IV antibiotics 25(OH)D, ng/mL, mean (SD)
148 52.0 82.7 64 66 120 99
(100) (27.8) (40.8) (43) (45) (81) (18)
67 (45) 46 (31) 32.4 (9)
Vitamin D Sufficient 85 52.1 77.1 41 40 71 101
(57) (27) (40.8) (64) (61) (59) (19)
34 (51) 22 (48) 38.3 (6.7)
Vitamin D Insufficient 53 50 94 20 21 41 96
(36) (28.3) (37.9) (31) (32) (34) (17)
29 (43) 20 (43) 26.1 (2.4)
Vitamin D Deficient 10 61.4 69.5 3 5 8 94
(7) (32) (46) (5) (7) (7) (12)
4 (6) 4 (9) 16.2 (2.3)
P Value
0.496 0.032 0.327 0.651 0.664 0.301 0.226 0.281 ,0.0001
Definition of abbreviations: BMI = body mass index; IV = intravenous; PFTs = pulmonary function tests. Data are presented as N (%) unless otherwise noted. Variables with significant P value (,0.05) are shown in bold.
Comparison of Clinical/Inflammatory Markers between Vitamin D–Sufficient and –Insufficient Subjects
The median serum 25(OH)D concentration in subjects ever colonized with Pseudomonas was significantly lower than those without this infection (27.7; interquartile range [IQR], 25.3, 33.8; vs. 32.9; IQR, 26.5, 39.3; P = 0.021; Figure 2). This difference was not seen in subjects colonized with methicillin-resistant staphylococcus aureus and methicillinsensitive staphylococcus aureus (Figure 2). Table 2 shows serum inflammatory markers in the vitamin D–insufficient/ deficient versus –sufficient groups. P. aeruginosa was a more common pathogen in the patients who were vitamin D insufficient/deficient as compared with those who were vitamin D sufficient (18 of
63 vs. 11 of 85, respectively; P = 0.018). There was no difference in median CRP, mean IgG, or mean IgE. Multivariate logistic regression analysis of possible prognostic factors (age, sex, BMI percentile, genotype, pancreatic insufficiency, FEV1, CRP, IgG, IgE, and history of Pseudomonas) for vitamin D insufficiency was performed for subjects aged 6 to 12 years (Table 3). Subjects aged 6 to 12 years with a history of a positive Pseudomonas culture were significantly more likely to be vitamin D insufficient/ deficient, whereas CRP, IgG, and IgE were not found to be predictive of vitamin D status. In addition, BMI percentile and FEV1 did not correlate with vitamin D status. Supplemental vitamin D dose was available for 131 of the patients. Overall, the median dose was 800 IU with a range of 0 to 3,600 IU (IQR, 400, 1,000 IU). The
Figure 1. (A) Boxplot of serum 25(OH)D concentrations, grouped by vitamin D status: Deficient, Insufficient and Sufficient. (B) Boxplot of serum 25(OH)D concentration by season. There is no significant difference between the median serum 25(OH)D concentrations obtained in each season. Winter is defined as January to March, spring as April to June, summer as July to September, and fall as October to December. The top and bottom of the boxes are quartile boundaries; center belt is the median. Exterior points are outliers, falling above the 90th percentile or below the 10th percentile. Vertical lines extend to the position of the farthest nonoutlier above and below the box.
Simoneau, Bazzaz, Sawicki, et al.: Vitamin D Status in Pediatric Patients with CF
median dose was compared between the pancreatic-sufficient versus -insufficient groups and between the vitamin D– sufficient and –insufficient/deficient groups. In the pancreatic-sufficient group, 79% (22 of 28) subjects were not taking a vitamin D supplement, whereas 3% (3 of 103) pancreatic-insufficient patients were not taking any vitamin D supplementation (data not shown, P , 0.001). The median vitamin D dose in the pancreatic-sufficient group was significantly lower than that in the pancreatic-insufficient group (0 vs. 800, respectively; P , 0.0001; data not shown). However, there was no difference in the median vitamin D dose compared between the vitamin D–sufficient and –insufficient/deficient groups (Table 2).
Discussion In this study, we report that many young children with CF had a serum 25(OH)D concentration less than the current recommended optimal threshold for this patient population of 30 ng/ml. However, the prevalence of vitamin D insufficiency in our cohort was lower than what has been reported previously. In 2007, Rovner and colleagues found that 90% of pediatric patients with CF were vitamin D insufficient (3). Similarly, Brodlie and colleagues found that 90% of their pediatric CF population was vitamin D insufficient, and after increasing the supplementation dose, 49% remained insufficient (13). Our finding may indicate a greater awareness about vitamin D resulting in additional supplementation. The CF Foundation published new guidelines for the management of vitamin D 207
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Figure 2. Boxplots of serum 25(OH)D concentration compared by bacterial colonization. There is no significant difference in median serum 25(OH)D concentration between subjects colonized with methicillin-resistant staphylococcus aureus (MRSA) (Yes) or not colonized with MRSA (No). The same is true for methicillin-sensitive staphylococcus aureus (MSSA). However, the subjects with a history of a prior throat or sputum culture positive for Pseudomonas had a significantly lower median serum 25(OH)D concentration compared with those with no Pseudomonas. The top and bottom of the box are quartile boundaries; center belt is the median. Exterior points are outliers, falling above the 90th percentile or below the 10th percentile. Vertical lines extend to the position of the farthest nonoutlier above and below the box.
insufficiency and deficiency in the spring of 2012 (14). Although the data described in this paper were obtained before the new guidelines, there was likely greater awareness of and attention paid to vitamin D replacement during the time frame of the study. Patients in our center were aggressively supplemented when they were found to have serum 25(OH)D
concentrations less than 30 ng/ml. In addition, this finding of improved serum 25 (OH)D concentrations may indicate that children with CF under 12 years of age are less likely to be vitamin D insufficient when compared with older cohorts of children. Interestingly, in our sample, the individuals with normal pancreatic function had a higher rate of vitamin D insufficiency
than those with pancreatic insufficiency (50 vs. 41%). This finding is likely explained by the lack of routine vitamin D supplementation in the pancreaticsufficient patients, with only 21% of the pancreatic-sufficient patients being on any vitamin supplementation. However, these data suggest that perhaps these patients also require some degree of vitamin D supplementation. These findings are similar to what has been found in studies examining vitamin D insufficiency in the general pediatric population. Gordon and colleagues in 2008 found that 40% of healthy toddlers and infants had vitamin D insufficiency (15). Although our study found lower rates of vitamin D insufficiency than what had previously been described, the rates are still quite high. There are likely several reasons for this, including decreased sun exposure in chronically ill children, low dietary intake, or poor absorption. Despite receiving pancreatic enzymes, patients with CF have been shown to have decreased absorption of ergocalciferol and decreased hepatic 25-hydroxylation of vitamin D compared with the non-CF population (16). It is interesting, however, that the vitamin D levels did not significantly differ by season. However, there was a trend toward higher levels in the summer and fall. The current recommendation by the CF Foundation is to check serum 25(OH)D concentrations at the end of winter, when
Table 2. Clinical variables and markers of disease severity compared by vitamin D status Variable
IgE, mean (SD) IgG, mean (SD) CRP, median (IQR) Vitamin E level, mean (SD) Vitamin A level, mean (SD) Supplemental Vitamin D dose, median (IQR) Any bacterial colonization MRSA colonization MSSA colonization History of Pseudomonas Labs collected during acute illness Current or recent antibiotic treatment* Current proton pump inhibitor
N (%)
Mean (SD)
Vitamin D Insufficient/Deficient (N = 63)
Vitamin D Sufficient (N = 85)
128 101.6 (206) 86.3 (178.5) 58 921.5 (336) 935.6 (390.3) 87 (59) 0.099 (0.099, 0.11) 0.24 (0.56) 143 9.69 (3.9) 10.7 (3.9) 144 31.7 (8) 32.5 (7.9) 131 800 (400, 1,000) 800 (400, 1,000) 128 14 95 29 18 46
(86) (9.5) (64) (20) (12) (31)
67 (45)
74 8 53 11 10 22
(87) (9) (62) (13) (12) (26)
34 (40)
122.6 905.3 0.45 8.2 30.0 800 54 6 42 18 7 24
(238.6) (266.3) (1.6) (3.4) (8.5) (400, 1,000)
P Value
0.326 0.735 0.388 ,0.0001 0.034 0.575
(86) (9) (67) (29) (11) (38)
0.813 0.982 0.588 0.018 0.902 0.112
33 (52)
0.135
Definition of abbreviations: CRP = C-reactive protein; IQR = interquartile range, Q1, Q3; MRSA = methicillin-resistant staphylococcus aureus; MSSA = methicillin-sensitive staphylococcus aureus. Values reported as N (%) unless otherwise indicated. *Within the previous 4 weeks. Variables with a significant P value (,0.05) are shown in bold.
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AnnalsATS Volume 11 Number 2 | February 2014
BRIEF COMMUNICATIONS Table 3. Multivariate odds ratios of vitamin D insufficiency according to markers of inflammation and bacterial culture in children aged 6 to 12 years (N = 90) Variable CRP IgE IgG History of Pseudomonas
N
OR* (95% CI)
53 73 35 86
0 (0–975) 1.0 (0.998–1.00) 1.0 (1.00–1.01) 3.2 (1.1–9.4)
P Value 0.285 0.892 0.051 0.033
Definition of abbreviations: BMI = body mass index; CI = confidence interval; CRP = C-reactive protein; OR = odds ratio. *OR adjusted for age, sex, BMI percentile, genotype, pancreatic insufficiency, and FEV1 from logistic regression analyses. Variables with significant P value (,0.05) are shown in bold.
they are most likely at their lowest level (14), and this recommendation is based on evidence from adult literature demonstrating that vitamin D status fluctuates by season (17, 18). It may be that in such a young pediatric population in New England, there is less seasonal variability in sun exposure. The patients with vitamin D insufficiency also had significantly lower levels of vitamin A and E, suggesting that the vitamin D insufficiency may be related to poor medication adherence. This is further supported by the finding that there is no difference in median supplemental vitamin D dose between the vitamin D– sufficient versus –insufficient/deficient groups. Although the prescribed dose may be the same, the actual dose taken by the patient was not measured by this study. In our study, common clinical indicators of disease severity, lung function and nutritional status, were not associated with vitamin D status. The mean BMI percentile was similar in the vitamin D–sufficient and –insufficient groups, suggesting that nutritional status may not be a significant factor in determining vitamin D status in this young population. Similarly, there was no significant difference in FEV1 between the vitamin D–sufficient and –insufficient groups. However, in a cohort of young patients, one would not expect to see abnormal lung function. A prospective study evaluating how lung function may decline over time
would be necessary to further assess whether vitamin D status has an impact on lung function. However, we did find that the patients who were vitamin D– insufficient or –deficient were more likely to be colonized with P. aeruginosa (29% prevalence compared with 13% prevalence in the vitamin D–sufficient group). P. aeruginosa colonization has been associated with a more rapid decline in lung function in patients with CF older than 7 years (19). Our finding that children with vitamin D insufficiency were more likely to be colonized with P. aeruginosa is interesting and suggests a possible mediating role of vitamin D with respect to airway infection and long-term pulmonary function in CF. This association is similar to a recent study of vitamin D status in patients with non-CF bronchiectasis in which patients with vitamin D deficiency (25[OH]D less than 25 nmol/L) were more likely to exhibit bacterial colonization, including P. aeruginosa (20). One possible explanation for this association is the finding that patients with low serum 25 (OH)D levels had higher levels of airway vitamin D–binding protein (20). Vitamin D–binding protein is expressed by inflammatory cells, particularly neutrophils and macrophages, both of which play an important role in CF-related inflammation. Although the mean serum 25(OH)D concentration was significantly different between the Pseudomonas-positive and -negative groups, the levels are actually quite close
References 1 Hall WB, Sparks AA, Aris RM. Vitamin D deficiency in cystic fibrosis. Int J Endocrinol 2010;2010:218691.
(29.6 vs. 33.2 ng/ml, P = 0.047), and it is difficult to determine what is a clinically relevant difference and where the optimal concentration lies. Furthermore, due to limitations of the study, we were unable to determine the serum 25(OH)D concentration closest to the time of Pseudomonas acquisition, which should be assessed in future studies. Interestingly, we did not find a significant difference in any of the inflammatory markers (IgG, IgE, or CRP) in the patients who had vitamin D insufficiency versus those who did not. It is possible that our sample was underpowered to detect such an association, given that many children in our cohort did not have these laboratory values available. The limitations of this study include small sample size and cross-sectional design. In addition, the nature of chart review inherently limits what data are available. Further prospective studies are necessary to verify and understand the potential connection between vitamin D and inflammation and bacterial colonization. To our knowledge, this is the first study to assess vitamin D status and clinical markers of disease severity in very young children with CF. Our study suggests that vitamin D insufficiency is prevalent in young children with CF, even those with pancreatic sufficiency. These findings support the current recommendation for annual screening of fat-soluble vitamin levels in all patients with CF. Furthermore, the connection between vitamin D insufficiency and P. aeruginosa colonization warrants further investigation. To determine more definitively the impact of vitamin D insufficiency on inflammation and clinical outcomes, larger prospective longitudinal studies will be needed. n Author disclosures are available with the text of this article at www.atsjournals.org. Acknowledgment: The authors thank the Cystic Fibrosis Foundation for providing fellowship funding and the patients and their families who made this work possible. They also thank Dr. Craig Schramm for statistical assistance.
2 Boyle MP, Noschese ML, Watts SL, Davis ME, Stenner SE, Lechtzin N. Failure of high-dose ergocalciferol to correct vitamin D deficiency in adults with cystic fibrosis. Am J Respir Crit Care Med 2005;172: 212–217.
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13 Brodlie M, Orchard WA, Reeks GA, Pattman S, McCabe H, O’Brien CJ, Thomas MF, Spencer DA. Vitamin D in children with cystic fibrosis. Arch Dis Child 2012;97:982–984. 14 Tangpricha V, Kelly A, Stephenson A, Maguiness K, Enders J, Robinson KA, Marshall BC, Borowitz D; Cystic Fibrosis Foundation Vitamin D Evidence-Based Review Committee. 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;97:1082–1093. 15 Gordon CM, Feldman HA, Sinclair L, Williams AL, Kleinman PK, PerezRossello J, Cox JE. Prevalence of vitamin D deficiency among healthy infants and toddlers. Arch Pediatr Adolesc Med 2008;162: 505–512. 16 Lark RK, Lester GE, Ontjes DA, Blackwood AD, Hollis BW, Hensler MM, Aris RM. Diminished and erratic absorption of ergocalciferol in adult cystic fibrosis patients. Am J Clin Nutr 2001;73:602–606. 17 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;69:374–381. 18 Stephenson A, Brotherwood M, Robert R, Atenafu E, Corey M, Tullis E. Cholecalciferol significantly increases 25-hydroxyvitamin D concentrations in adults with cystic fibrosis. Am J Clin Nutr 2007;85: 1307–1311. 19 Schaedel C, de Monestrol I, Hjelte L, Johannesson M, Kornfalt ¨ R, Lindblad A, Strandvik B, Wahlgren L, Holmberg L. Predictors of deterioration of lung function in cystic fibrosis. Pediatr Pulmonol 2002;33:483–491. 20 Chalmers JD, McHugh BJ, Docherty C, Govan JR, Hill AT. Vitamin-D deficiency is associated with chronic bacterial colonisation and disease severity in bronchiectasis. Thorax 2013;68:39–47.
AnnalsATS Volume 11 Number 2 | February 2014
