Tobacco Exposure and Efficacy of Biologic Therapy in Patients With Severe Asthma: A Nationwide Study From the Danish Severe Asthma Register.

BACKGROUND: Randomized trials of biologics in severe, uncontrolled asthma have excluded patients with a cumulative tobacco exposure of more than 10 pack-years. Therefore, our knowledge of the impact of smoking exposure on the clinical effects of biologics in severe asthma remains incomplete. However, because many patients with asthma are current or former smokers, investigating the potential impacts of tobacco exposure on the effects of biologic treatment is clinically important. OBJECTIVE: To investigate the impact of smoking history and tobacco exposure on the effectiveness of biologic therapy in real-life patients with severe asthma. METHODS: We used data from a complete nationwide cohort of patients with severe asthma who were receiving biologics, the Danish Severe Asthma Register. We divided patients according to smoking history and cumulative tobacco exposure and analyzed data at baseline and after 12 months of biologic treatment. RESULTS: A total of 724 bio-naive patients were identified in the Danish Severe Asthma Register, 398 of whom had never been smokers (55%), 316 were previous smokers (44%), and 10 were current smokers (1%). Within the group of current and former smokers, 37% had 1 to 9 pack-years of tobacco exposure, 26% had 10 to 19 pack-years, and 37% had 20 or more pack-years of tobacco exposure. Patients with tobacco exposure had similar reductions in the number of exacerbations, reductions in maintenance oral corticosteroid use, and improvements in asthma symptoms compared with patients with 0 pack-years. CONCLUSION: Former smoking history and lifetime tobacco exposure do not have an impact on the efficacy of biologics in patients with severe asthma.

Clinical Response and Remission in Patients With Severe Asthma Treated With Biologic Therapies.

BACKGROUND: The development of novel targeted biologic therapies for severe asthma has provided an opportunity to consider remission as a new treatment goal. RESEARCH QUESTION: How many patients with severe asthma treated with biologic therapy achieve clinical remission, and what predicts response to treatment? STUDY DESIGN AND METHODS: The Danish Severe Asthma Register is a nationwide cohort including all adult patients receiving biologic therapy for severe asthma in Denmark. This observational cohort study defined "clinical response" to treatment following 12 months as a ≥ 50% reduction in exacerbations and/or a ≥ 50% reduction in maintenance oral corticosteroid dose, if required. "Clinical remission" was defined by cessation of exacerbations and maintenance oral corticosteroids, as well as a normalization of lung function (FEV1 > 80%) and a six-question Asthma Control Questionnaire score ≤ 1.5 following 12 months of treatment. RESULTS: Following 12 months of treatment, 104 (21%) of 501 biologic-naive patients had no response to treatment, and 397 (79%) had a clinical response. Among the latter, 97 (24%) fulfilled the study criteria of clinical remission, corresponding to 19% of the entire population. Remission was predicted by shorter duration of disease and lower BMI in the entire population of patients treated with biologic therapy. INTERPRETATION: Clinical response was achieved in most adult patients initiating biologic therapy, and clinical remission was observed in 19% of the patients following 12 months of treatment. Further studies are required to assess the long-term outcome of achieving clinical remission with biologic therapy.

Global Variability in Administrative Approval Prescription Criteria for Biologic Therapy in Severe Asthma.

BACKGROUND: Regulatory bodies have approved five biologics for severe asthma. However, regional differences in accessibility may limit the global potential for personalized medicine. OBJECTIVE: To compare global differences in ease of access to biologics. METHODS: In April 2021, national prescription criteria for omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab were reviewed by severe asthma experts collaborating in the International Severe Asthma Registry. Outcomes (per country, per biologic) were (1) country-specific prescription criteria and (2) development of the Biologic Accessibility Score (BACS). The BACS composite score incorporates 10 prescription criteria, each with a maximum score of 10 points. Referenced to European Medicines Agency marketing authorization specifications, a higher score reflects easier access. RESULTS: Biologic prescription criteria differed substantially across 28 countries from five continents. Blood eosinophil count thresholds (usually ≥300 cells/µL) and exacerbations were key requirements for anti-IgE/anti-IL-5/5R prescriptions in around 80% of licensed countries. Most countries (40% for dupilumab to 54% for mepolizumab) require two or more moderate or severe exacerbations, whereas numbers ranged from none to four. Moreover, 0% (for reslizumab) to 21% (for omalizumab) of countries required long-term oral corticosteroid use. The BACS highlighted marked between-country differences in ease of access. For omalizumab, mepolizumab, benralizumab, and dupilumab, only two, one, four, and seven countries, respectively, scored equal or higher than the European Medicines Agency reference BACS. For reslizumab, all countries scored lower. CONCLUSIONS: Although some differences were expected in country-specific biologic prescription criteria and ease of access, the substantial differences found in the current study present a challenge to implementing precision medicine across the world.

Are Vitamin D3 Tablets and Oil Drops Equally Effective in Raising S-25-Hydroxyvitamin D Concentrations? A Post-Hoc Analysis of an Observational Study on Immunodeficient Patients.

BACKGROUND: Vitamin D3 supplements are available as tablets or oil drops, but there is no consensus as to whether either of these preparations is more effective than the other. METHODS: We compared the effectiveness of tablets versus oil in raising S-25-hydroxyvitamin D (S-25-OHD) in plasma by re-analyzing data from a previously performed observational study in which immunodeficient patients with S-25-OHD concentrations <75 nmol/L were randomly prescribed vitamin D3 tablets (1600 IU/day) or vitamin D3 oil-drops (1500 IU/day) for twelve months. Tablets and oil were compared for the effect on S-25-OHD concentrations after 3-5 months and antibiotic use. RESULTS: Data on S-25-OHD after ≥ 3 months was available for 137 patients treated with tablets and 69 with oil drops. Both groups exhibited a significant increase in S-25-OHD-oil-drops from 55 to 86 nmol/L and tablets from 52 to 87 nmol/L-with no difference between groups (p = 0.77). In a subgroup of patients without immunoglobulin replacement, vitamin D3 supplementation with oil drops (n = 34) but not with tablets (n = 60) resulted in significantly lower antibiotic administration (p < 0.001 and p = 0.58). CONCLUSION: Vitamin D3 supplementation with tablets and oil drops were equally efficient in raising S-25-OHD concentrations. Only oil drops caused a reduction in antibiotic consumption in immuno-deficient patients who did not receive immunoglobulin replacement.

Fat intake during pregnancy and risk of preeclampsia: a prospective cohort study in Denmark.

BACKGROUND: Previous studies suggest that eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA), may decrease the risk of preeclampsia, but many suffer from important methodological limitations. METHODS: We prospectively examined the association between fat intake during pregnancy and preeclampsia and among 65,220 singleton pregnancies in the Danish National Birth Cohort (1996-2002). Women were asked to report their diet around gestation week 20 with a food frequency questionnaire. Preeclampsia diagnosis was obtained via linkage with the Danish National Patient Registry. We estimated relative risks (RR) and 95% confidence intervals (95% CI) of preeclampsia and severe preeclampsia according to fat intake using logistic regression models with generalized estimating equations to account for repeated pregnancies per woman while adjusting for potential confounders. RESULTS: We documented 1302 cases of preeclampsia, including 301 cases of severe preeclampsia. Intake of long-chain omega-3 fatty acids was associated to preeclampsia. Women in the top quintile of DHA intake had a lower risk of preeclampsia (RR 0.67 (0.51-0.89)) and severe preeclampsia (RR 0.46 (0.25-0.83)) than women in the bottom quintile. Women who met daily recommended intake of EPA+DHA according to the Dietary Guidelines for Americans (≥250 mg/day), had a lower risk of severe preeclampsia (RR 0.77 (0.60-0.99)), but not of preeclampsia (RR 0.93 (0.82-1.05)). Conversely, ALA intake was associated with higher risk of severe preeclampsia (RR 1.71 (1.07-2.75)). CONCLUSIONS: Higher intake of DHA is inversely related to preeclampsia and severe preeclampsia, whereas ALA increases the risk of severe preeclampsia among Danish women.

Fish Intake in Pregnancy and Offspring Metabolic Parameters at Age 9⁻16-Does Gestational Diabetes Modify the Risk?

Oily fish, an important source of marine n-3 long-chain polyunsaturated fatty acids (LCPUFA), has shown to reduce cardiometabolic risk in adults. Whether maternal fish intake affects offspring metabolic health is less established, especially among high-risk pregnancies. We aimed to examine the association of fish intake in pregnancy with offspring metabolic health who were either exposed or unexposed to gestational diabetes mellitus (GDM). Our study included 1234 mother-offspring dyads (608 with a GDM index pregnancy and 626 control dyads) nested within the Danish National Birth Cohort, which is a prebirth cohort. Maternal seafood and marine n-3 LCPUFA consumption was quantified by a food frequency questionnaire (gestational week 25) and a sub-sample with interview data (weeks 12 and 30). The offspring were clinically examined at 9⁻16 years, including a Dual energy X-ray Absorptiometry (DXA) scan and a fasting blood sample. We calculated multivariable effect estimates and 95% confidence intervals (CI) for anthropometric, adiposity, and metabolic parameters. The median (IQR) intake of total seafood was 23(24) g/day. We found largely no association for total seafood and marine n-3 LCPUFA with offspring metabolic parameters in either group. Using interview data, GDM-exposed women reporting no fish in week 12 and 30 (versus intake >2 times/week) had offspring with a higher Body Mass Index (BMI) (ratio of geometric means (RGM): 1.28, 95% CI: 1.06, 1.55), waist circumference (RGM: 1.22, 95% CI: 1.05, 1.40), triglycerides (RGM: 1.77, 95% CI: 1.03, 3.03), and homeostatic model assessment of insulin resistance HOMA-IR (RGM: 2.16, 95% CI: 1.17, 3.97). We found no associations of n-3 LCPUFA and seafood intake with offspring metabolic outcomes. However, GDM-exposed women who consistently reported eating no fish had offspring with a poorer metabolic profile. Fish intake in pregnancy may mitigate some adverse effects of intrauterine hyperglycemia, however, these findings need replication in better powered studies.

Fish oil supplementation during pregnancy and allergic respiratory disease in the adult offspring.

BACKGROUND: Maternal supplementation with long-chain n-3 polyunsaturated fatty acids can have immunologic effects on the developing fetus through several anti-inflammatory pathways. However, there is limited knowledge of the long-term programming effects. OBJECTIVE: In a randomized controlled trial from 1990 with 24 years of follow-up, our aim was to determine whether supplementation with 2.7 g of long-chain n-3 polyunsaturated fatty acids in pregnancy can reduce the risk of asthma in offspring and allergic respiratory disease. METHODS: The randomized controlled trial included 533 women who were randomly assigned to receive fish oil during the third trimester of pregnancy, olive oil, or no oil in the ratio 2:1:1. The offspring were followed in a mandatory national prescription register, with complete follow-up for prescriptions related to the treatment of asthma and allergic rhinitis as primary outcomes. Furthermore, the offspring were invited to complete a questionnaire (74% participated) and attend a clinical examination (47% participated) at age 18 to 19 years. RESULTS: In intention-to-treat analyses the probability of having had asthma medication prescribed was significantly reduced in the fish oil group compared with the olive oil group (hazard ratio, 0.54, 95% CI, 0.32-0.90; P = .02). The probability of having had allergic rhinitis medication prescribed was also reduced in the fish oil group compared with the olive oil group (hazard ratio, 0.70, 95% CI, 0.47-1.05; P = .09), but the difference was not statistically significant. Self-reported information collected at age 18 to 19 years supported these findings. No associations were detected with respect to lung function outcomes or allergic sensitization at 18 to 19 years of age. CONCLUSION: Maternal supplementation with fish oil might have prophylactic potential for long-term prevention of asthma in offspring.

Vitamin D3 Supplementation and Antibiotic Consumption - Results from a Prospective, Observational Study at an Immune-Deficiency Unit in Sweden.

BACKGROUND: Vitamin D supplementation has been proposed to improve clinical symptoms during respiratory tract infections (RTIs), but results from randomized, placebo-controlled trials (RCT) are inconclusive. Previously, we performed an RCT in patients with various immune-disorders and observed that supplementation with 4000 IU vitamin D/day during 12 months significantly reduced antibiotic consumption and RTIs. This formed the basis for new guidelines at our unit; i.e. patients with insufficient levels of 25-hydroxyvitamin D (≤75 nmol/L) are now offered vitamin D supplementation. The aim of this prospective follow-up study was to evaluate the outcome of these new recommendations with regard to antibiotic consumption in our unit. METHOD: 277 patients with insufficiency were supplemented with vitamin D3, 1500-1600 IU/day for 12 months. Each patient was its own control and data on antibiotic consumption was monitored 12 months before and 12 months after initiation of vitamin D3 supplementation. RESULTS: Vitamin D3 supplementation resulted in a significantly reduced antibiotic consumption, from 20 to 15 days/patient (p<0.05). The number of antibiotic-free patients increased from 52 to 81 after vitamin D3 supplementation; OR 1.79; 95% CI 1.20-2.66 (p<0.01). The number of antibiotic-prescriptions decreased significantly, a finding that mainly was attributed to a reduction of respiratory tract antibiotics (p<0.05). Subgroup analysis showed that only patients without immunoglobulin substitution (n = 135) had a significant effect of vitamin D supplementation. CONCLUSION: Vitamin D3 supplementation of 1600 IE /day is safe to use in immunodeficient patients with 25-OHD levels less than 75 nmol/L and significantly reduced the antibiotic consumption in patients without immunoglobulin substitution.

Vitamin D supplementation improves well-being in patients with frequent respiratory tract infections: a post hoc analysis of a randomized, placebo-controlled trial.

BACKGROUND: The aim of this study was to test the hypothesis that vitamin D supplementation improves well-being in patients with frequent respiratory tract infections (RTIs). We performed a post hoc analysis of a randomized, placebo-controlled and double-blind study in which patients with frequent RTIs were randomized to placebo or vitamin D (4000 IE/day for 1 year, n = 124). At the last visit of the study, patients were asked to perform a general assessment of their well-being during the study. RESULTS: The majority of patients, both placebo- and vitamin D treated, stated that they had felt 'better' during the study; 52% in the placebo group and 70% in the vitamin D group, relative risk 1.3 (95% CI 1.0-1.8; p = 0.06, Fisher's exact test). Statement of better well-being was associated with an increase in 25-hydroxyvitamin D (25-OHD) levels (p < 0.001). In contrast, worse well-being was associated with unchanged 25-OHD levels. Notably, a 25-OHD level above 100 nmol/L at the study end was associated with a higher chance of having a better well-being (p < 0.01). Four patients on anti-depressive treatment could terminate their antidepressant medication during the study. These patients had a significant increase in 25-OHD levels from low levels at study-start. CONCLUSION: Vitamin D supplementation to patients with frequent RTIs might be beneficial, not only for infections, but also for their general well-being. However, given the post hoc design of this study, these findings need to be confirmed in additional clinical trials before firm conclusions can be drawn. TRIAL REGISTRATION: http://www.clinicaltrials.gov (NCT01131858), registered March 22, 2010.

Vitamin D supplementation to patients with frequent respiratory tract infections: a post hoc analysis of a randomized and placebo-controlled trial.

BACKGROUND: Vitamin D is considered to be important for a healthy immune system. The aim of this study was to test the hypothesis that vitamin D supplementation reduces number of respiratory tract infections (RTIs) and prolong the time to the first RTI in adult patients with frequent RTIs. METHODS: We performed a post hoc analysis of a randomized, placebo-controlled and double-blinded study, where adult patients with a high burden of RTIs were randomized to placebo or vitamin D (4000 IE/day for 1 year, n = 124 in the per protocol cohort presented here). RESULTS: Vitamin D supplementation increased the probability to stay free of RTI during the study year (RR 0.64, 95% CI 0.43-0.94). Further, the total number of RTIs was also reduced in the vitamin D-group (86 RTIs) versus placebo (120 RTIs; p = 0.05). Finally, the time to the first RTI was significantly extended in the vitamin D-group (HR 1.68, 95% CI 1.03-2.68, p = 0.0376). CONCLUSION: Vitamin D supplementation was found to significantly increase the probability of staying infection free during the study period. This finding further supports the notion that vitamin D-status should be monitored in adult patients with frequent RTIs and suggests that selected patients with vitamin D deficiency are supplemented. This could be a safe and cheap way to reduce RTIs and improve health in this vulnerable patient population. The original trial was registered at http://www.clinicaltrials.gov (NCT01131858).

Maternal intake of vitamins A, E and K in pregnancy and child allergic disease: a longitudinal study from the Danish National Birth Cohort.

Fat-soluble vitamins A, E and K have been shown to play roles in immunity and inflammation, but studies on child allergic disease have been few and inconsistent. The aim of the present study was to examine the relationship between maternal intake of vitamins A, E and K in mid-pregnancy and child asthma and allergic rhinitis. We used data on 44 594 mother-child pairs from the Danish National Birth Cohort. Maternal intake of fat-soluble vitamins was calculated based on the information from a validated FFQ completed in mid-pregnancy. At 18 months, interviews with the mothers were conducted to evaluate doctor-diagnosed child asthma. At age 7 years, we assessed child asthma and allergic rhinitis using questions from the International Study of Asthma and Allergies in Childhood questionnaire and by national registries on hospital contacts and medication use. Current asthma was defined as asthma diagnosis and wheeze in the past 12 months by maternal report. We calculated multivariable risk ratios and 95 % CI by comparing the highest v. lowest quintile (Q) of maternal vitamin A, E and K intake in relation to child allergic disease outcomes. Maternal total vitamin K intake was directly associated with ever admitted asthma (Q5 v. Q1: 1·23, 95 % CI 1·01, 1·50) and current asthma at 7 years (Q5 v. Q1: 1·30, 95 % CI 0·99, 1·70). Weak inverse associations were present for maternal vitamin A and E intake during pregnancy with child allergic rhinitis. Maternal vitamin K intake during pregnancy may increase the risk of child asthma, and should be explored further on a mechanistic level. Conversely, maternal vitamin A and E intake may protect against child allergic rhinitis.

Vitamin D intake in mid-pregnancy and child allergic disease - a prospective study in 44,825 Danish mother-child pairs.

BACKGROUND: Past studies suggest that maternal vitamin D intake during pregnancy may protect against child wheeze but studies on asthma are limited. Our objective was to examine the relation between intake of vitamin D in mid-pregnancy and child asthma and allergic rhinitis at 18 months and 7 years. METHODS: We examined data from 44,825 women enrolled during pregnancy in the longitudinal Danish National Birth Cohort (1996-2002). We estimated vitamin D intake from diet and supplements based on information from a validated food frequency questionnaire completed in gestational week 25. At 18 months, we evaluated child asthma using data from phone interviews. We assessed asthma and allergic rhinitis by self-report at age 7 and asthma by using records from national registries. Current asthma at age 7 was defined as lifetime asthma diagnosis and wheeze in the past 12 months. We calculated multivariable risk ratios with 95% CIs comparing highest vs. lowest quintile of vitamin D intake in relation to child allergic disease outcomes. RESULTS: The median (5%-95%ile) intake of total vitamin D was 11.7(3.0-19.4) µg/day (68% from supplements). In multivariable analysis, mothers in the highest (vs. lowest) quintile of total vitamin D intake were less likely to have children classified with current asthma at 7 years (Q5 vs. Q1: 0.74, 95% CI: 0.56, 0.96, P = 0.02) and they were less likely to have children admitted to the hospital due to asthma (Q5 vs. Q1: 0.80, 95% CI: 0.64, 1.00, P = 0.05). We found no associations with child asthma at 18 months or with allergic rhinitis at 7 years. CONCLUSIONS: Our findings suggest a weak inverse relationship between high total vitamin D and asthma outcomes in later, but not early, childhood. The data did not suggest a clear threshold of vitamin D intake above which risk of asthma was reduced.

Vitamin D analog EB1089 inhibits aromatase expression by dissociation of comodulator WSTF from the CYP19A1 promoter-a new regulatory pathway for aromatase.

The enzyme aromatase, encoded by the CYP19A1 gene, catalyzes the production of estrogens and inhibition of aromatase has therefore become one of the key strategies in breast cancer treatment. We have studied the effects of the vitamin D analog EB1089 on aromatase gene expression and enzyme activity in breast cancer cells. We found that EB1089 was able to decrease the gene expression and enzyme activity as well as inhibit aromatase-dependent cell growth. Furthermore, a low dose of EB1089 combined with low doses of clinically used aromatase inhibitors such as anastrozole, letrozole and exemestane were able to effectively inhibit aromatase-dependent growth of breast cancer cells. The molecular mechanism for this effect of EB1089 on the aromatase gene expression was investigated and we found that it is mediated by the vitamin D receptor (VDR), vitamin D receptor interacting repressor (VDIR) and Williams syndrome transcription factor (WSTF). ChIP and Re-ChIP assays revealed that EB1089 mediates dissociation of WSTF from the CYP19A1 promoter and thereby decreases the gene expression. Regulation of aromatase via WSTF has not been reported previously. Furthermore, gene silencing of WSTF results in decreased gene expression of CYP19A1 and aromatase activity, showing that WSTF is an interesting drug target for development of new anti-cancer drugs. In summary, we report that the vitamin D analog EB1089 is able to decrease the gene expression and enzyme activity of aromatase via a novel regulatory pathway for aromatase and suggest that EB1089 may be a new treatment option for estrogen dependent breast cancer.

Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study.

BACKGROUND: Low serum levels of 25-hydroxyvitamin D(3) are associated with an increased risk of respiratory tract infections (RTIs). Clinical trials with vitamin D(3) against various infections have been carried out but data are so far not conclusive. Thus, there is a need for additional randomised controlled trials of effects of vitamin D(3) on infections. OBJECTIVE: To investigate if supplementation with vitamin D(3) could reduce infectious symptoms and antibiotic consumption among patients with antibody deficiency or frequent RTIs. DESIGN: A double-blind randomised controlled trial. SETTING: Karolinska University Hospital, Huddinge. PARTICIPANTS: 140 patients with antibody deficiency (selective IgA subclass deficiency, IgG subclass deficiency, common variable immune disorder) and patients with increased susceptibility to RTIs (>4 bacterial RTIs/year) but without immunological diagnosis. INTERVENTION: Vitamin D(3) (4000 IU) or placebo was given daily for 1 year. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was an infectious score based on five parameters: symptoms from respiratory tract, ears and sinuses, malaise and antibiotic consumption. Secondary endpoints were serum levels of 25-hydroxyvitamin D(3), microbiological findings and levels of antimicrobial peptides (LL-37, HNP1-3) in nasal fluid. RESULTS: The overall infectious score was significantly reduced for patients allocated to the vitamin D group (202 points) compared with the placebo group (249 points; adjusted relative score 0.771, 95% CI 0.604 to 0.985, p=0.04). LIMITATIONS: A single study centre, small sample size and a selected group of patients. The sample size calculation was performed using p=0.02 as the significance level whereas the primary and secondary endpoints were analysed using the conventional p=0.05 as the significance level. CONCLUSIONS: Supplementation with vitamin D(3) may reduce disease burden in patients with frequent RTIs.