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Vitamin D3 therapy in patients with asthma complicated by sinonasal disease: Secondary analysis of the Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma trial
Letter to the Editor Vitamin D3 therapy in patients with asthma complicated by sinonasal disease: Secondary analysis of the Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma trial To the Editor: Our recent Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma (VIDA) clinical trial (NCT01248065) revealed that vitamin D3 supplementation in adults with persistent asthma and vitamin D insufficiency (serum 25-hydroxyvitamin D, <30 ng/mL) did not reduce the rate of asthma treatment failures.1 Inadequate vitamin D status has been implicated in the pathogenesis of chronic sinonasal disease, which frequently coexists with asthma.2,3 In this prespecified secondary analysis of the VIDA trial, we aimed to investigate the effects of vitamin D3 supplementation on sinonasal disease and asthma control in patients with symptomatic asthma and vitamin D insufficiency. For a complete description of the study methods, see the Methods section in this article’s Online Repository at www. jacionline.org. Briefly, 408 adults with symptomatic asthma and vitamin D insufficiency were randomized to receive placebo (n 5 207) or oral vitamin D3 (n 5 201) in addition to a stable dose of inhaled corticosteroid (ICS) for 12 weeks. A sinonasal questionnaire (SNQ) was used at baseline to indicate the presence _1.0).4 of sinonasal disease (defined as a score > Of the 408 subjects, 242 (59.3%) had chronic sinonasal disease at baseline. Baseline clinical characteristics were similar across the groups (see Table E1 in this article’s Online Repository at www.jacionline.org). Vitamin D3 treatment led to substantial improvements in 25(OH)vitamin D levels in subjects with (42.0 ng/ mL; 95% CI, 40.2-43.7 ng/mL) and without (40.8 ng/mL; 95% CI, 38.7-43.0 ng/mL) sinonasal disease (both P < .001 compared with baseline; Fig 1, A). Black and nonblack subjects responded similarly to vitamin D3 supplementation (Fig 1, B). There was no difference in the proportion of subjects with _ 1.0) between those randombaseline sinonasal disease (SNQ > ized to receive vitamin D3 and those randomized to placebo (Fig 1, A). Although vitamin D3 supplementation for 12 weeks was associated with a significant decrease (8.4%) in the percentage of subjects with sinonasal disease (P 5 .03), a similar reduction (8.2%) was also observed in the placebo group (P 5 .02). The magnitude of decrease was comparable between groups (P 5 .56), suggesting that vitamin D3 was no better than placebo in relieving sinonasal symptoms (Fig 1, C). This finding was corroborated by the lack of change in SNQ scores after 12 weeks in the vitamin D3 (20.14; 95% CI, 20.23 to 20.06) and placebo (20.14; 95% CI, 20.21 to 20.07) groups (P 5 .97; Fig 1, D). In an exploratory analysis, of 59 black subjects assigned to the vitamin D3 group, 28 (47.5%) had SNQ scores of 1.0 or greater after 12 weeks compared with 16 (25.4%) of 63 in the placebo group, which is lower than baseline (Fig 1, E). The rate of sinonasal disease in those receiving vitamin D3 was not improved when compared with those receiving placebo (P 5 .01). By contrast, the rates of sinonasal disease in nonblack subjects after
12 weeks were similar between the vitamin D3 and placebo groups (P 5 .17). A multivariate analysis was performed to determine the rates of asthma treatment failures and exacerbations in those with and those without sinonasal disease (Table I). Among those receiving vitamin D3, asthma exacerbations occurred in 23 (18.7%) of 123 subjects with sinonasal disease in comparison with 5 (6.4%) of 78 subjects without the disease (adjusted rate ratio [RR], 2.9; 95% CI, 1.1-7.7; P 5 .03). By contrast, the rate of asthma exacerbations was not significantly different among subjects with or without sinonasal disease after receiving placebo (adjusted RR, 0.9; 95% CI, 0.5-1.6; P 5 .68). In black subjects with sinonasal disease who received vitamin D3, 13 (36.1%) of 36 experienced asthma exacerbations, whereas only 2 (7.4%) of 27 exacerbations occurred in black subjects without the disease (adjusted RR, 5.3; 95% CI, 1.1-25.1; P 5 .04). No such association was observed in nonblack subjects receiving vitamin D3 (adjusted RR, 1.8; 95% CI, 0.5-6.6; P 5 .41) or in those in the placebo group. We further measured the rates of asthma treatment failure and exacerbation between subjects receiving vitamin D3 and those receiving placebo stratified by the presence or absence of sinonasal disease (Table II). Rates of asthma exacerbations were significantly lower in subjects treated with vitamin D3 with no sinonasal disease (adjusted RR, 0.3; 95% CI, 0.1-0.7; P 5 .01) but not in those with sinonasal disease (adjusted RR, 0.9; 95% CI, 0.51.7; P 5.80). A reduced risk of exacerbation in nonblack subjects without sinonasal disease receiving vitamin D3 was observed (adjusted RR, 0.2; 95% CI, 0.1-0.9; P 5 .03). Black subjects without sinonasal disease receiving vitamin D3 appeared to have a similar trend toward lower risk for exacerbation (adjusted RR, 0.2; 95% CI, 0.05-1.1; P 5 .06). There was no effect on asthma treatment failures stratified by the presence or absence of sinonasal disease. Our data show that vitamin D3 repletion does not positively influence the course of sinonasal disease in asthmatic patients. Decreased risk of asthma exacerbation associated with vitamin D3 was only seen in those without sinonasal disease. On the other hand, sinonasal disease was associated with a significantly greater rate of asthma exacerbation in black subjects taking vitamin D3, whereas no such relationship was seen in nonblack subjects. These findings imply interplay of race and genetic variance in the response to vitamin D3.5,6 There are several notable limitations to this study. Caution is needed in interpreting the present data given the small sample size of black subjects and the nature of subgroup analysis with limited power. Furthermore, the SNQ may not have adequate sensitivity to detect a response to vitamin D3 therapy, and the score of 1.0 might not represent the optimal cut point. Lastly, it remains unknown whether a 12-week course of treatment with vitamin D3 is sufficient to affect chronic sinonasal disease. In summary, correction of vitamin D insufficiency in patients with symptomatic asthma and sinonasal disease did not lead to improved clinical outcomes. In fact, we observed a higher risk of asthma exacerbations in those with sinonasal disease, especially in black subjects, suggesting potential deleterious effects of highdose vitamin D in some populations. Clinicians should keep this in mind when using supplements in these populations, but we must be cautious with this interpretation given the relatively small 1
2 LETTER TO THE EDITOR
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FIG 1. Responses to vitamin D3 supplementation in asthmatic patients with and without sinonasal disease. A, Baseline 25-hydroxyvitamin D levels were compared with levels 12 weeks after randomization to placebo or vitamin D3 in those with and without sinonasal disease. B, Similar comparison between black and nonblack subjects. Data are represented as means 6 SDs. C, Changes in percentage of sinonasal disease in the placebo and vitamin D3 groups. D, Changes in SNQ scores in response to vitamin D3 and placebo. E, Response to vitamin D3 and placebo in black and nonblack subjects with sinonasal disease.
TABLE I. Multivariate adjusted risks of asthma treatment failure and exacerbation: Relative RRs between subjects with sinonasal disease and those without Vitamin D3 (n 5 201)
Placebo (n 5 207)
Event rate (per person-year) Outcome
Asthma treatment failure Overall Nonblack subjects Black subjects Asthma exacerbation Overall Nonblack subjects Black subjects
Event rate (per person-year)
Sinonasal disease
No sinonasal disease
Adjusted* RR (95% CI)
P value
Sinonasal disease
No sinonasal disease
Adjusted* RR (95% CI)
P value
0.59 0.45 0.93
0.57 0.47 0.75
1.1 (0.7-1.8) 1.0 (0.5-2.1) 1.2 (0.6-2.7)
.74 .98 .61
0.70 0.62 0.96
0.80 0.64 1.00
0.9 (0.6-1.5) 1.0 (0.5-1.8) 0.9 (0.5-1.9)
.82 .89 .85
0.35 0.21 0.67
0.12 0.11 0.14
2.9 (1.1-7.7) 1.8 (0.5-6.6) 5.3 (1.1-25.1)
.03 .41 .04
0.36 0.35 0.38
0.46 0.42 0.52
0.9 (0.5-1.6) 1.0 (0.4-2.3) 0.6 (0.2-1.7)
.68 .97 .33
*Poisson regression models adjusted for partnership, body mass index, black race, baseline percent predicted FEV1, baseline asthma symptoms, and baseline 25-hydroxyvitamin D levels. See the Methods section in this article’s Online Repository for definitions of asthma treatment failure and asthma exacerbation.
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TABLE II. Multivariate adjusted risks of asthma treatment failure and exacerbation: Relative RRs between subjects assigned to receive vitamin D3 and placebo No sinonasal disease (n 5 166) Event rate (per person-year) Outcome
Asthma treatment failure Overall Nonblack subjects Black subjects Asthma exacerbation Overall Nonblack subjects Black subjects
Sinonasal disease (n 5 242) Event rate (per person-year) P value
Vitamin D3
Placebo
Adjusted* RR (95% CI)
P value
Vitamin D3
Placebo
Adjusted* RR (95% CI)
0.57 0.47 0.75
0.80 0.64 1.00
0.7 (0.4-1.2) 0.6 (0.3-1.3) 0.7 (0.3-1.6)
.24 .19 .43
0.59 0.45 0.93
0.70 0.62 0.96
0.8 (0.5-1.3) 0.8 (0.4-1.3) 1.0 (0.5-2.0)
.43 .33 .95
0.12 0.11 0.14
0.46 0.42 0.52
0.3 (0.1-0.7) 0.2 (0.1-0.9) 0.2 (0.05-1.1)
.01 .03 .06
0.35 0.21 0.67
0.36 0.35 0.38
0.9 (0.5-1.7) 0.6 (0.2-1.2) 2.0 (0.7-5.5)
.80 .14 .17
*Poisson regression models adjusted for partnership, body mass index, black race, baseline percent predicted FEV1, baseline asthma symptoms, and baseline 25-hydroxyvitamin D levels. See the Methods section in this article’s Online Repository for definitions of asthma treatment failure and asthma exacerbation.
number of black subjects in this study. Conversely, vitamin D3 was associated with a lower risk of asthma exacerbation in asthmatic patients without sinonasal disease. Overall, vitamin D3 supplementation in the setting of patients with symptomatic asthma needs to take into account the underlying phenotype of sinonasal disease. Junfang Jiao, MD, PhDa Tonya S. King, PhDb Matthew McKenziec Leonard B. Bacharier, MDd Anne E. Dixon, MDe Christopher D. Codispoti, MD, PhDf Ryan M. Dunn, MDg Nicole L. Grossman, MDh Njira L. Lugogo, MDi Sima K. Ramratnam, MD, MPHj Russell S. Traister, MDk Michael E. Wechsler, MD, MMScl Mario Castro, MD, MPHm for the National Heart, Lung, and Blood Institute’s AsthmaNet From athe Division of Allergy and Immunology, Department of Internal Medicine, Washington University School of Medicine, St Louis, Mo; bthe Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pa; cSt Louis College of Pharmacy, St Louis, Mo; dthe Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, St Louis Children’s Hospital, Washington University School of Medicine, St Louis, Mo; ethe University of Vermont College of Medicine, Burlington, Vt; fRush University Medical Center, Chicago, Ill; gNational Jewish Health, Denver, Colo; hBrigham and Women’s Hospital, Boston, Mass; iDuke University School of Medicine, Durham, NC; jthe University of Wisconsin School of Medicine, Madison, Wis; kthe Division of Pulmonary, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa; lthe Department of Medicine, National Jewish Health, Denver, Colo; and mthe Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St Louis, Mo. E-mail: [email protected]. Supported by the National Heart, Lung, and Blood Institute/National Institutes of Health grants HL098102, U10HL098096, UL1TR000150, UL1TR000430, UL1TR000050, HL098075, UL1TR001082, HL098090, HL098177, UL1TR000439, HL098098, UL1TR000448, HL098107, HL098112, HL098103, UL1TR000454, and HL098115. Trial Registration: ClinicalTrials.gov NCT01248065.
Disclosure of potential conflict of interest: T. S. King receives research funding from the National Institutes of Health (NIH) and serves as a consultant for Pearl Therapeutics and KaloBios. L. B. Bacharier serves as a consultant for Aerocrine, GlaxoSmithKline, Genentech/Novartis, Merck, Schering, Cephalon, DBV Technologies, Teva, and Meda; receives grant funding from the NIH; and receives payment for lectures from Aerocrine, AstraZeneca, Genentech/Novartis, GlaxoSmithKline, Merck, Schering, and Teva. A. E. Dixon serves as a consultant for Roche and receives grant funding from Pfizer and royalties from Springer. N. L. Lugogo receives research funding from the NIH, serves as an advisory board member for Teva and a consultant for GlaxoSmithKline and received research funding from the NIH, AstraZeneca, GlaxoSmithKline, Sanofi, and Genentech. M. E. Wechsler personal fees from Novartis, Sepracor/Sunovion, NKT Therapeutics, Asthmatx/BSCI, Merck, Regeneron, MedImmune, Novartis, Ambitbio, Vectura, Sanofi, Teva, Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca, outside the submitted work. M. Castro reports research funding from the National Institutes of Health during the conduct of the study; personal fees from Asthmatx/Boston Scientific, IPS/Holaria, Genentech, Merck, GlaxoSmithKline, Genentech, Boehringer Ingelheim, and Elsevier; grants from Boston Scientific, Amgen, Ception/Cephalon/Teva, Genetech, MedImmune, Merck, Novartis, GlaxoSmithKline, Sanofi Aventis, Vectura, NextBio, and KalaBios; and stock options from Sparo, all outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest. REFERENCES 1. Castro M, King TS, Kunselman SJ, Cabana MD, Denlinger L, Holguin F, et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. JAMA 2014;311:2083-91. 2. Mulligan JK, Bleier BS, O’Connell B, Mulligan RM, Wagner C, Schlosser RJ. Vitamin D3 correlates inversely with systemic dendritic cell numbers and bone erosion in chronic rhinosinusitis with nasal polyps and allergic fungal rhinosinusitis. Clin Exp Immunol 2011;164:312-20. 3. Mulligan JK, Nagel W, O’Connell BP, Wentzel J, Atkinson C, Schlosser RJ. Cigarette smoke exposure is associated with vitamin D3 deficiencies in patients with chronic rhinosinusitis. J Allergy Clin Immunol 2014;134:342-9. 4. Dixon AE, Sugar EA, Zinreich SJ, Slavin RG, Corren J, Naclerio RM, et al. Criteria to screen for chronic sinonasal disease. Chest 2009;136:1324-32. 5. Pinto JM, Schneider J, Perez R, DeTineo M, Baroody FM, Naclerio RM. Serum 25-hydroxyvitamin D levels are lower in urban African American subjects with chronic rhinosinusitis. J Allergy Clin Immunol 2008;122:415-7. 6. Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 2013;369:1991-2000. http://dx.doi.org/10.1016/j.jaci.2015.12.1329
3.e1 LETTER TO THE EDITOR
METHODS Study design and subjects The present study is a preplanned secondary analysis of a multicenter, randomized, double-blinded, placebo-controlled clinical trial (VIDA). The subjects, study design, and primary end points have been previously described.E1 In brief, 408 adult patients with serum 25-hydroxyvitamin D levels of less than 30 ng/mL and persistent asthma symptoms despite the use of low-dose ICSs were randomized to receive add-on therapy with placebo or high-dose vitamin D3 (100,000 IU loading dose followed by 4,000 IU/d) for 28 weeks. During the ICS stable phase (phase I, weeks 5-17), study subjects were maintained on inhaled ciclesonide (80 mg per puff), 2 puffs twice daily (320 mg/d), for 12 weeks after randomization. Thereafter, those who met the asthma stability criteria underwent ciclesonide dose reduction by 50% for 8 weeks (phase IIa, weeks 18-25) and then by 75% for 8 weeks (phase IIb, weeks 26-33). Asthma treatment failures; lung function; allergic sensitization, asthma symptoms, control, exacerbations requiring systemic corticosteroids; and serum 25-hydroxyvitamin D levels were assessed. Asthma treatment failure was defined as the occurrence of 1 or more of the following: (1) prebronchodilator peak expiratory flow of 65% or less of baseline on any 2 of 3 consecutive scheduled measurements; (2) increase in as-needed levalbuterol use of 8 or more puffs per 24 hours over baseline use for 48 hours; (3) prebronchodilator FEV1 of 80% or less of baseline on 2 consecutive measurements; (4) additional ICS or oral/parenteral corticosteroids because of asthma; (5) need for emergency treatment at a medical facility that was related to or complicated by the participant’s asthma and that resulted in systemic corticosteroid treatment or hospitalization for an acute asthma exacerbation; (6) participant’s refusal to continue study drugs because of lack of satisfaction with treatment; or (7) physician’s clinical judgment for safety reasons. Asthma exacerbation was defined by meeting the criteria for treatment failure and 1 or more of the following 6 criteria: (1) failure to respond within 48 hours to the treatment failure rescue algorithm; (2) FEV1 of less than 50% of baseline on 2 consecutive measurements; (3) FEV1 of less than 40% of predicted value on 2 consecutive measurements; (4) use of 16 or more puffs of as-needed bagonist (levalbuterol) per 24 hours for a period of 48 hours; (5) experiencing an exacerbation of asthma in the opinion of the study investigator or personal physician; or (6) use of oral/parenteral corticosteroids because of asthma.
SNQ The presence of sinonasal disease in subjects was determined by using a validated SNQ. The SNQ is a 5-item, symptom-based instrument developed to screen for chronic rhinitis and sinusitis.E2 The questionnaire queries the presence of sinonasal symptoms (runny nose, postnasal drip, need to blow the nose, facial pain or pressure, and nasal obstruction) over the preceding 3 months. Scoring for each item is based on the frequency of symptoms: never (0), 1 to 4 times per month (1), 2 to 6 times per week (2), and daily (3). The final score is reported as the average of 5 items, with a range of between 0 and 3. In asthmatic patients an SNQ score of 1 or greater is highly sensitive
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(0.94; 95% CI, 0.81-1.00) and specific (1.00; 95% CI, 0.47-1.00) in determining the presence of sinonasal disease. Decrease in sensitivity and increase in specificity have been noted with higher cut points. Subjects were instructed to complete the SNQ at week 4 (before randomization) and week 17 (end of ICS stable phase I) during their study visits. The outcome analyses were performed by using SNQ score cut points of 1 or more and 1.5 or more.
Statistical analysis Baseline characteristics were compared between those with and without sinonasal disease by using x2 tests for categorical factors and t tests or Wilcoxon rank sum tests for those factors measured on a continuous scale. All analyses were prespecified, except the confirmatory analysis, by using a higher SNQ score cut point of 1.5 for defining sinonasal disease. Within-group changes in 25-hydroxyvitamin D levels from baseline to the follow-up visit were evaluated by using paired t tests, and average follow-up visit levels were compared between groups by using independent t tests. Change in the proportion of participants with sinonasal disease from baseline to follow-up was analyzed by using the McNemar test for paired proportions, whereas the proportion of participants with sinonasal disease at a given time point was compared between groups with x2 tests. The overall rates of treatment failure and exacerbation were compared between those with and without sinonasal disease in each treatment group by fitting Poisson regression models containing an effect for sinonasal disease with additional adjustment for partnership, body mass index, race, baseline percent predicted FEV1, baseline 25-hydroxyvitamin D level, and baseline asthma symptoms. Results from these models are reported in terms of adjusted RRs and corresponding 95% CIs. Multivariable logistic regression was applied to investigate potential predictors of persistent sinonasal disease, which was defined as sinonasal _ 1) present at baseline and 12 weeks. Baseline disease (SNQ score > characteristics were evaluated in the model, and a manual backward selection procedure was applied to determine the most parsimonious model. Variables considered in the full model included regimen, partnership, age, body mass index, race, sex, baseline percent predicted FEV1, baseline sun exposure, skin pigmentation, baseline skin pigmentation level, baseline 25-hydroxyvitamin D level, oral corticosteroid responsiveness, bronchodilator reversibility, number of positive allergen skin test results, and season. Variables remaining in the model after backward selection included partnership, race, sex, age, baseline percent predicted FEV1, and season. Results are reported in terms of adjusted odds ratios, 95% CIs, and P values.
REFERENCES E1. Castro M, King TS, Kunselman SJ, Cabana MD, Denlinger L, Holguin F, et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. JAMA 2014;311:2083-91. E2. Dixon AE, Sugar EA, Zinreich SJ, Slavin RG, Corren J, Naclerio RM, et al. Criteria to screen for chronic sinonasal disease. Chest 2009;136:1324-32.
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TABLE E1. Baseline characteristics of study subjects Variable
Demographics Male sex Race/ethnicity Black White Hispanic Other* BMI (kg/m2) Age at asthma diagnosis (y) Pulmonary function tests Prebronchodilator FEV1 (L) Prebronchodilator FEV1 (% predicted) Prebronchodilator FVC (L) Prebronchodilator FEV1/FVC ratio Maximum albuterol reversibility (% change [n 5 406]) Methacholine PC20 (n 5 391) Asthma characteristics ACT score AM symptom score (2-wk average) PM symptom score (2-wk average) AM PEF (2-wk average [L/min]) PM PEF (2-wk average [L/min]) Sputum eosinophils (%), median (IQR [n 5 338]) Positive skin test results, median (IQR [n 5 390]) Oral steroid used during the past 12 mo ICS used during the past 12 mo 25-Hydroxyvitamin D (ng/mL)
No sinonasal disease, SNQ score < 1 (n 5 166), no. (%)
Sinonasal disease, _ 1 (n 5 242), no. (%) SNQ score >
61 (36.8)
69 (28.5)
P value
.08 .02
66 74 20 6 32.4 13.7
(39.8) (44.6) (12.1) (3.6) (9.8) (13.6)
65 142 19 16 31.3 15.5
(26.9) (58.7) (7.9) (6.6) (8.2) (14.6)
.21 .20
2.6 78.8 3.6 0.7 16.6 0.6
(0.8) (13.6) (1.0) (0.1) (11.0) (1.6)
2.7 81.9 3.7 0.7 18.2 0.7
(0.8) (14.2) (1.2) (0.1) (12.2) (1.7)
.20 .03 .19 .86 .19 .56
(3.3) (0.4) (0.4) (104.3) (105.8) (0.0-1.3) (2-6) (31.8) (44.6) (6.6)
.48 .007 .006 .06 .08 .33 .39 .62 .54 .02
19.2 0.4 0.4 382.1 388.3 0.3 3 49 69 17.9
(3.2) (0.3) (0.4) (105.2) (106.8) (0.0-1.4) (2-5) (29.5) (41.6) (6.9)
19.0 0.5 0.5 402.0 407.0 0.4 3 77 108 19.5
ACT, Asthma Control Test; BMI, body mass index, FVC, forced vital capacity; IQR, interquartile range; PEF, peak expiratory flow. *Included Asian/Pacific Islanders, American Indians, Alaskan Natives, or participant-selected ‘‘other’’ category. The average score for shortness of breath, chest tightness, wheezing, cough, and phlegm or mucus (0 5 absent, 1 5 mild, 2 5 moderate, 3 5 severe).
12 weeks were similar between the vitamin D3 and placebo groups (P 5 .17). A multivariate analysis was performed to determine the rates of asthma treatment failures and exacerbations in those with and those without sinonasal disease (Table I). Among those receiving vitamin D3, asthma exacerbations occurred in 23 (18.7%) of 123 subjects with sinonasal disease in comparison with 5 (6.4%) of 78 subjects without the disease (adjusted rate ratio [RR], 2.9; 95% CI, 1.1-7.7; P 5 .03). By contrast, the rate of asthma exacerbations was not significantly different among subjects with or without sinonasal disease after receiving placebo (adjusted RR, 0.9; 95% CI, 0.5-1.6; P 5 .68). In black subjects with sinonasal disease who received vitamin D3, 13 (36.1%) of 36 experienced asthma exacerbations, whereas only 2 (7.4%) of 27 exacerbations occurred in black subjects without the disease (adjusted RR, 5.3; 95% CI, 1.1-25.1; P 5 .04). No such association was observed in nonblack subjects receiving vitamin D3 (adjusted RR, 1.8; 95% CI, 0.5-6.6; P 5 .41) or in those in the placebo group. We further measured the rates of asthma treatment failure and exacerbation between subjects receiving vitamin D3 and those receiving placebo stratified by the presence or absence of sinonasal disease (Table II). Rates of asthma exacerbations were significantly lower in subjects treated with vitamin D3 with no sinonasal disease (adjusted RR, 0.3; 95% CI, 0.1-0.7; P 5 .01) but not in those with sinonasal disease (adjusted RR, 0.9; 95% CI, 0.51.7; P 5.80). A reduced risk of exacerbation in nonblack subjects without sinonasal disease receiving vitamin D3 was observed (adjusted RR, 0.2; 95% CI, 0.1-0.9; P 5 .03). Black subjects without sinonasal disease receiving vitamin D3 appeared to have a similar trend toward lower risk for exacerbation (adjusted RR, 0.2; 95% CI, 0.05-1.1; P 5 .06). There was no effect on asthma treatment failures stratified by the presence or absence of sinonasal disease. Our data show that vitamin D3 repletion does not positively influence the course of sinonasal disease in asthmatic patients. Decreased risk of asthma exacerbation associated with vitamin D3 was only seen in those without sinonasal disease. On the other hand, sinonasal disease was associated with a significantly greater rate of asthma exacerbation in black subjects taking vitamin D3, whereas no such relationship was seen in nonblack subjects. These findings imply interplay of race and genetic variance in the response to vitamin D3.5,6 There are several notable limitations to this study. Caution is needed in interpreting the present data given the small sample size of black subjects and the nature of subgroup analysis with limited power. Furthermore, the SNQ may not have adequate sensitivity to detect a response to vitamin D3 therapy, and the score of 1.0 might not represent the optimal cut point. Lastly, it remains unknown whether a 12-week course of treatment with vitamin D3 is sufficient to affect chronic sinonasal disease. In summary, correction of vitamin D insufficiency in patients with symptomatic asthma and sinonasal disease did not lead to improved clinical outcomes. In fact, we observed a higher risk of asthma exacerbations in those with sinonasal disease, especially in black subjects, suggesting potential deleterious effects of highdose vitamin D in some populations. Clinicians should keep this in mind when using supplements in these populations, but we must be cautious with this interpretation given the relatively small 1
2 LETTER TO THE EDITOR
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FIG 1. Responses to vitamin D3 supplementation in asthmatic patients with and without sinonasal disease. A, Baseline 25-hydroxyvitamin D levels were compared with levels 12 weeks after randomization to placebo or vitamin D3 in those with and without sinonasal disease. B, Similar comparison between black and nonblack subjects. Data are represented as means 6 SDs. C, Changes in percentage of sinonasal disease in the placebo and vitamin D3 groups. D, Changes in SNQ scores in response to vitamin D3 and placebo. E, Response to vitamin D3 and placebo in black and nonblack subjects with sinonasal disease.
TABLE I. Multivariate adjusted risks of asthma treatment failure and exacerbation: Relative RRs between subjects with sinonasal disease and those without Vitamin D3 (n 5 201)
Placebo (n 5 207)
Event rate (per person-year) Outcome
Asthma treatment failure Overall Nonblack subjects Black subjects Asthma exacerbation Overall Nonblack subjects Black subjects
Event rate (per person-year)
Sinonasal disease
No sinonasal disease
Adjusted* RR (95% CI)
P value
Sinonasal disease
No sinonasal disease
Adjusted* RR (95% CI)
P value
0.59 0.45 0.93
0.57 0.47 0.75
1.1 (0.7-1.8) 1.0 (0.5-2.1) 1.2 (0.6-2.7)
.74 .98 .61
0.70 0.62 0.96
0.80 0.64 1.00
0.9 (0.6-1.5) 1.0 (0.5-1.8) 0.9 (0.5-1.9)
.82 .89 .85
0.35 0.21 0.67
0.12 0.11 0.14
2.9 (1.1-7.7) 1.8 (0.5-6.6) 5.3 (1.1-25.1)
.03 .41 .04
0.36 0.35 0.38
0.46 0.42 0.52
0.9 (0.5-1.6) 1.0 (0.4-2.3) 0.6 (0.2-1.7)
.68 .97 .33
*Poisson regression models adjusted for partnership, body mass index, black race, baseline percent predicted FEV1, baseline asthma symptoms, and baseline 25-hydroxyvitamin D levels. See the Methods section in this article’s Online Repository for definitions of asthma treatment failure and asthma exacerbation.
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TABLE II. Multivariate adjusted risks of asthma treatment failure and exacerbation: Relative RRs between subjects assigned to receive vitamin D3 and placebo No sinonasal disease (n 5 166) Event rate (per person-year) Outcome
Asthma treatment failure Overall Nonblack subjects Black subjects Asthma exacerbation Overall Nonblack subjects Black subjects
Sinonasal disease (n 5 242) Event rate (per person-year) P value
Vitamin D3
Placebo
Adjusted* RR (95% CI)
P value
Vitamin D3
Placebo
Adjusted* RR (95% CI)
0.57 0.47 0.75
0.80 0.64 1.00
0.7 (0.4-1.2) 0.6 (0.3-1.3) 0.7 (0.3-1.6)
.24 .19 .43
0.59 0.45 0.93
0.70 0.62 0.96
0.8 (0.5-1.3) 0.8 (0.4-1.3) 1.0 (0.5-2.0)
.43 .33 .95
0.12 0.11 0.14
0.46 0.42 0.52
0.3 (0.1-0.7) 0.2 (0.1-0.9) 0.2 (0.05-1.1)
.01 .03 .06
0.35 0.21 0.67
0.36 0.35 0.38
0.9 (0.5-1.7) 0.6 (0.2-1.2) 2.0 (0.7-5.5)
.80 .14 .17
*Poisson regression models adjusted for partnership, body mass index, black race, baseline percent predicted FEV1, baseline asthma symptoms, and baseline 25-hydroxyvitamin D levels. See the Methods section in this article’s Online Repository for definitions of asthma treatment failure and asthma exacerbation.
number of black subjects in this study. Conversely, vitamin D3 was associated with a lower risk of asthma exacerbation in asthmatic patients without sinonasal disease. Overall, vitamin D3 supplementation in the setting of patients with symptomatic asthma needs to take into account the underlying phenotype of sinonasal disease. Junfang Jiao, MD, PhDa Tonya S. King, PhDb Matthew McKenziec Leonard B. Bacharier, MDd Anne E. Dixon, MDe Christopher D. Codispoti, MD, PhDf Ryan M. Dunn, MDg Nicole L. Grossman, MDh Njira L. Lugogo, MDi Sima K. Ramratnam, MD, MPHj Russell S. Traister, MDk Michael E. Wechsler, MD, MMScl Mario Castro, MD, MPHm for the National Heart, Lung, and Blood Institute’s AsthmaNet From athe Division of Allergy and Immunology, Department of Internal Medicine, Washington University School of Medicine, St Louis, Mo; bthe Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pa; cSt Louis College of Pharmacy, St Louis, Mo; dthe Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, St Louis Children’s Hospital, Washington University School of Medicine, St Louis, Mo; ethe University of Vermont College of Medicine, Burlington, Vt; fRush University Medical Center, Chicago, Ill; gNational Jewish Health, Denver, Colo; hBrigham and Women’s Hospital, Boston, Mass; iDuke University School of Medicine, Durham, NC; jthe University of Wisconsin School of Medicine, Madison, Wis; kthe Division of Pulmonary, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa; lthe Department of Medicine, National Jewish Health, Denver, Colo; and mthe Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St Louis, Mo. E-mail: [email protected]. Supported by the National Heart, Lung, and Blood Institute/National Institutes of Health grants HL098102, U10HL098096, UL1TR000150, UL1TR000430, UL1TR000050, HL098075, UL1TR001082, HL098090, HL098177, UL1TR000439, HL098098, UL1TR000448, HL098107, HL098112, HL098103, UL1TR000454, and HL098115. Trial Registration: ClinicalTrials.gov NCT01248065.
Disclosure of potential conflict of interest: T. S. King receives research funding from the National Institutes of Health (NIH) and serves as a consultant for Pearl Therapeutics and KaloBios. L. B. Bacharier serves as a consultant for Aerocrine, GlaxoSmithKline, Genentech/Novartis, Merck, Schering, Cephalon, DBV Technologies, Teva, and Meda; receives grant funding from the NIH; and receives payment for lectures from Aerocrine, AstraZeneca, Genentech/Novartis, GlaxoSmithKline, Merck, Schering, and Teva. A. E. Dixon serves as a consultant for Roche and receives grant funding from Pfizer and royalties from Springer. N. L. Lugogo receives research funding from the NIH, serves as an advisory board member for Teva and a consultant for GlaxoSmithKline and received research funding from the NIH, AstraZeneca, GlaxoSmithKline, Sanofi, and Genentech. M. E. Wechsler personal fees from Novartis, Sepracor/Sunovion, NKT Therapeutics, Asthmatx/BSCI, Merck, Regeneron, MedImmune, Novartis, Ambitbio, Vectura, Sanofi, Teva, Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca, outside the submitted work. M. Castro reports research funding from the National Institutes of Health during the conduct of the study; personal fees from Asthmatx/Boston Scientific, IPS/Holaria, Genentech, Merck, GlaxoSmithKline, Genentech, Boehringer Ingelheim, and Elsevier; grants from Boston Scientific, Amgen, Ception/Cephalon/Teva, Genetech, MedImmune, Merck, Novartis, GlaxoSmithKline, Sanofi Aventis, Vectura, NextBio, and KalaBios; and stock options from Sparo, all outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest. REFERENCES 1. Castro M, King TS, Kunselman SJ, Cabana MD, Denlinger L, Holguin F, et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. JAMA 2014;311:2083-91. 2. Mulligan JK, Bleier BS, O’Connell B, Mulligan RM, Wagner C, Schlosser RJ. Vitamin D3 correlates inversely with systemic dendritic cell numbers and bone erosion in chronic rhinosinusitis with nasal polyps and allergic fungal rhinosinusitis. Clin Exp Immunol 2011;164:312-20. 3. Mulligan JK, Nagel W, O’Connell BP, Wentzel J, Atkinson C, Schlosser RJ. Cigarette smoke exposure is associated with vitamin D3 deficiencies in patients with chronic rhinosinusitis. J Allergy Clin Immunol 2014;134:342-9. 4. Dixon AE, Sugar EA, Zinreich SJ, Slavin RG, Corren J, Naclerio RM, et al. Criteria to screen for chronic sinonasal disease. Chest 2009;136:1324-32. 5. Pinto JM, Schneider J, Perez R, DeTineo M, Baroody FM, Naclerio RM. Serum 25-hydroxyvitamin D levels are lower in urban African American subjects with chronic rhinosinusitis. J Allergy Clin Immunol 2008;122:415-7. 6. Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 2013;369:1991-2000. http://dx.doi.org/10.1016/j.jaci.2015.12.1329
3.e1 LETTER TO THE EDITOR
METHODS Study design and subjects The present study is a preplanned secondary analysis of a multicenter, randomized, double-blinded, placebo-controlled clinical trial (VIDA). The subjects, study design, and primary end points have been previously described.E1 In brief, 408 adult patients with serum 25-hydroxyvitamin D levels of less than 30 ng/mL and persistent asthma symptoms despite the use of low-dose ICSs were randomized to receive add-on therapy with placebo or high-dose vitamin D3 (100,000 IU loading dose followed by 4,000 IU/d) for 28 weeks. During the ICS stable phase (phase I, weeks 5-17), study subjects were maintained on inhaled ciclesonide (80 mg per puff), 2 puffs twice daily (320 mg/d), for 12 weeks after randomization. Thereafter, those who met the asthma stability criteria underwent ciclesonide dose reduction by 50% for 8 weeks (phase IIa, weeks 18-25) and then by 75% for 8 weeks (phase IIb, weeks 26-33). Asthma treatment failures; lung function; allergic sensitization, asthma symptoms, control, exacerbations requiring systemic corticosteroids; and serum 25-hydroxyvitamin D levels were assessed. Asthma treatment failure was defined as the occurrence of 1 or more of the following: (1) prebronchodilator peak expiratory flow of 65% or less of baseline on any 2 of 3 consecutive scheduled measurements; (2) increase in as-needed levalbuterol use of 8 or more puffs per 24 hours over baseline use for 48 hours; (3) prebronchodilator FEV1 of 80% or less of baseline on 2 consecutive measurements; (4) additional ICS or oral/parenteral corticosteroids because of asthma; (5) need for emergency treatment at a medical facility that was related to or complicated by the participant’s asthma and that resulted in systemic corticosteroid treatment or hospitalization for an acute asthma exacerbation; (6) participant’s refusal to continue study drugs because of lack of satisfaction with treatment; or (7) physician’s clinical judgment for safety reasons. Asthma exacerbation was defined by meeting the criteria for treatment failure and 1 or more of the following 6 criteria: (1) failure to respond within 48 hours to the treatment failure rescue algorithm; (2) FEV1 of less than 50% of baseline on 2 consecutive measurements; (3) FEV1 of less than 40% of predicted value on 2 consecutive measurements; (4) use of 16 or more puffs of as-needed bagonist (levalbuterol) per 24 hours for a period of 48 hours; (5) experiencing an exacerbation of asthma in the opinion of the study investigator or personal physician; or (6) use of oral/parenteral corticosteroids because of asthma.
SNQ The presence of sinonasal disease in subjects was determined by using a validated SNQ. The SNQ is a 5-item, symptom-based instrument developed to screen for chronic rhinitis and sinusitis.E2 The questionnaire queries the presence of sinonasal symptoms (runny nose, postnasal drip, need to blow the nose, facial pain or pressure, and nasal obstruction) over the preceding 3 months. Scoring for each item is based on the frequency of symptoms: never (0), 1 to 4 times per month (1), 2 to 6 times per week (2), and daily (3). The final score is reported as the average of 5 items, with a range of between 0 and 3. In asthmatic patients an SNQ score of 1 or greater is highly sensitive
J ALLERGY CLIN IMMUNOL nnn 2016
(0.94; 95% CI, 0.81-1.00) and specific (1.00; 95% CI, 0.47-1.00) in determining the presence of sinonasal disease. Decrease in sensitivity and increase in specificity have been noted with higher cut points. Subjects were instructed to complete the SNQ at week 4 (before randomization) and week 17 (end of ICS stable phase I) during their study visits. The outcome analyses were performed by using SNQ score cut points of 1 or more and 1.5 or more.
Statistical analysis Baseline characteristics were compared between those with and without sinonasal disease by using x2 tests for categorical factors and t tests or Wilcoxon rank sum tests for those factors measured on a continuous scale. All analyses were prespecified, except the confirmatory analysis, by using a higher SNQ score cut point of 1.5 for defining sinonasal disease. Within-group changes in 25-hydroxyvitamin D levels from baseline to the follow-up visit were evaluated by using paired t tests, and average follow-up visit levels were compared between groups by using independent t tests. Change in the proportion of participants with sinonasal disease from baseline to follow-up was analyzed by using the McNemar test for paired proportions, whereas the proportion of participants with sinonasal disease at a given time point was compared between groups with x2 tests. The overall rates of treatment failure and exacerbation were compared between those with and without sinonasal disease in each treatment group by fitting Poisson regression models containing an effect for sinonasal disease with additional adjustment for partnership, body mass index, race, baseline percent predicted FEV1, baseline 25-hydroxyvitamin D level, and baseline asthma symptoms. Results from these models are reported in terms of adjusted RRs and corresponding 95% CIs. Multivariable logistic regression was applied to investigate potential predictors of persistent sinonasal disease, which was defined as sinonasal _ 1) present at baseline and 12 weeks. Baseline disease (SNQ score > characteristics were evaluated in the model, and a manual backward selection procedure was applied to determine the most parsimonious model. Variables considered in the full model included regimen, partnership, age, body mass index, race, sex, baseline percent predicted FEV1, baseline sun exposure, skin pigmentation, baseline skin pigmentation level, baseline 25-hydroxyvitamin D level, oral corticosteroid responsiveness, bronchodilator reversibility, number of positive allergen skin test results, and season. Variables remaining in the model after backward selection included partnership, race, sex, age, baseline percent predicted FEV1, and season. Results are reported in terms of adjusted odds ratios, 95% CIs, and P values.
REFERENCES E1. Castro M, King TS, Kunselman SJ, Cabana MD, Denlinger L, Holguin F, et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. JAMA 2014;311:2083-91. E2. Dixon AE, Sugar EA, Zinreich SJ, Slavin RG, Corren J, Naclerio RM, et al. Criteria to screen for chronic sinonasal disease. Chest 2009;136:1324-32.
LETTER TO THE EDITOR 3.e2
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TABLE E1. Baseline characteristics of study subjects Variable
Demographics Male sex Race/ethnicity Black White Hispanic Other* BMI (kg/m2) Age at asthma diagnosis (y) Pulmonary function tests Prebronchodilator FEV1 (L) Prebronchodilator FEV1 (% predicted) Prebronchodilator FVC (L) Prebronchodilator FEV1/FVC ratio Maximum albuterol reversibility (% change [n 5 406]) Methacholine PC20 (n 5 391) Asthma characteristics ACT score AM symptom score (2-wk average) PM symptom score (2-wk average) AM PEF (2-wk average [L/min]) PM PEF (2-wk average [L/min]) Sputum eosinophils (%), median (IQR [n 5 338]) Positive skin test results, median (IQR [n 5 390]) Oral steroid used during the past 12 mo ICS used during the past 12 mo 25-Hydroxyvitamin D (ng/mL)
No sinonasal disease, SNQ score < 1 (n 5 166), no. (%)
Sinonasal disease, _ 1 (n 5 242), no. (%) SNQ score >
61 (36.8)
69 (28.5)
P value
.08 .02
66 74 20 6 32.4 13.7
(39.8) (44.6) (12.1) (3.6) (9.8) (13.6)
65 142 19 16 31.3 15.5
(26.9) (58.7) (7.9) (6.6) (8.2) (14.6)
.21 .20
2.6 78.8 3.6 0.7 16.6 0.6
(0.8) (13.6) (1.0) (0.1) (11.0) (1.6)
2.7 81.9 3.7 0.7 18.2 0.7
(0.8) (14.2) (1.2) (0.1) (12.2) (1.7)
.20 .03 .19 .86 .19 .56
(3.3) (0.4) (0.4) (104.3) (105.8) (0.0-1.3) (2-6) (31.8) (44.6) (6.6)
.48 .007 .006 .06 .08 .33 .39 .62 .54 .02
19.2 0.4 0.4 382.1 388.3 0.3 3 49 69 17.9
(3.2) (0.3) (0.4) (105.2) (106.8) (0.0-1.4) (2-5) (29.5) (41.6) (6.9)
19.0 0.5 0.5 402.0 407.0 0.4 3 77 108 19.5
ACT, Asthma Control Test; BMI, body mass index, FVC, forced vital capacity; IQR, interquartile range; PEF, peak expiratory flow. *Included Asian/Pacific Islanders, American Indians, Alaskan Natives, or participant-selected ‘‘other’’ category. The average score for shortness of breath, chest tightness, wheezing, cough, and phlegm or mucus (0 5 absent, 1 5 mild, 2 5 moderate, 3 5 severe).