Cj Griffiths

S123 Increased risk of upper respiratory infection with addition of intermittent bolus-dose vitamin D supplementation to a daily low-dose regimen

Introduction and Objectives Meta-analysis of clinical trials of vitamin D supplementation for the prevention of acute respiratory infection (ARI) shows a protective effect in the general population, but there is controversy regarding the optimal dosing regimen. Low-dose vitamin D supplementation is already recommended in older adults for prevention of fractures and falls, but clinical trials investigating whether higher doses could provide additional protection against ARI are lacking. Methods We conducted a double-blind cluster-randomised placebo-controlled trial of high- vs. low-dose vitamin D supplementation in residents and staff of sheltered accommodation schemes in London, UK. 108 schemes were allocated to receive the intervention (vitamin D3 2.4 mg 2-monthly + 10 μg daily for residents; 3 mg 2-monthly for staff) or control (vitamin D3 10 μg daily for residents, nil for staff) over the course of one year. The primary endpoint of the trial was time from first dose of study medication to date of first ARI, determined by a validated acute respiratory symptom score recorded prospectively in a symptom diary. Secondary outcomes included time to first upper / lower respiratory infections (URI/LRI) and mean serum 25-hydroxyvitamin D (25[OH]D) concentration. Results 240 participants were included in the intention-to-treat analysis (137 participants in 54 schemes allocated to intervention, mean baseline 25[OH]D 43.8 nmol/L vs. 103 participants in 54 schemes allocated to control, mean baseline 25[OH]D 43.8 nmol/L). Median time to ARI was 203 days in the intervention arm and 227 days in the control arm (adjusted HR 1.18, 95% CI 0.80 to 1.74, p = 0.42). Allocation to the intervention arm of the trial was associated with increased risk of URI (adjusted HR 1.48, 95% CI 1.02 to 2.16, p = 0.04), but not with altered risk of LRI (adjusted HR 1.12, 95% CI 0.73 to 1.70, p = 0.61). Mean serum 25(OH)D concentration at 1 year was 84.8 nmol/L vs. 58.5 nmol/L in intervention vs. control arms (p < 0.0001). Conclusions Addition of intermittent bolus-dose vitamin D supplementation to a daily low-dose regimen improved vitamin D status in older adults and their carers, but it did not influence risk of ARI, and was less effective at preventing URI.

S57 Diabetes and latent tuberculosis infection: nested case-control study within the PREDICT cohort

Background Diabetes is associated with an increased risk of tuberculosis disease, but it is unclear whether a similar association exists between diabetes and latent tuberculosis infection (LTBI). Methods The ongoing UK PREDICT (Prognostic Evaluation of Diagnostic IGRAs Consortium) cohort study aims to recruit 10,000 participants to assess the predictive values of interferon gamma release assays (IGRAs) for the development of active TB in recent entrants to the UK and contacts of active TB cases. We used a nested case-control design within the first 5000 recruits in this cohort, to investigate the association between diabetes and LTBI. Participants in PREDICT provide demographic, medical and social information, including any history of diabetes. LTBI is detected using the two commercially available IGRAs, Quantiferon Gold In-Tube and TSpot.TB. Cases were individuals who tested positive on either or both IGRAs; controls were negative on both assays (or negative on one and indeterminate on the other). Logistic regression was used to estimate odds ratios and adjust for potential confounders. Assuming a 5% diabetes prevalence, 1084 cases and 3252 controls would allow the detection of a 1.5-fold increase of LTBI with 80% power and 5% error. Results Overall, 1388/4730 (29%) had a positive IGRA. 286/4730 (6%) reported a history of diabetes. Amongst diabetic participants, 168 used insulin and/or oral hypoglycaemic medications and 25 reported control through diet alone (1 participant was being monitored only and for 92 the level of control was unknown). Univariate analysis found an association between diabetes and LTBI (OR = 1.45 [95% CI 1.13–1.86], p = 0.003). After adjustment for age, this association was no longer apparent (OR = 1.15 [95% CI 0.88–1.50], p = 0.30). Adjustment for other variables in addition to age (sex, ethnicity, birthplace outside the UK, previous contact with a TB case, or previous TB diagnosis) did not substantially change the estimated age-adjusted OR relating diabetes to LTBI. Similar results were obtained when the analysis was restricted to contacts. Conclusions In the current PREDICT cohort, diabetes does not appear to be associated with LTBI after adjustment for age. The relationship between diabetes and TB disease observed elsewhere may reflect an increased risk of disease rather than infection.

S31 Prognostic value of interferon gamma release assays and tuberculin skin test in predicting the development of active tuberculosis: the uk predict tb cohort study

Background Tackling tuberculosis (TB) requires testing and treatment of high-risk groups for latent tuberculosis infection. We estimated the predictive values of the tuberculin skin test (TST) and interferon gamma release assays (IGRAs) for development of active TB in migrants and contacts of active TB patients in the UK. Methods Participants were prospectively recruited in clinics and the community and followed for a median of 2.9 years. We administered IGRAs (Quantiferon Gold In-Tube [QFT-GIT] and T-SPOT.TB) and TST (with 3 thresholds: 5 mm (TST5), 10 mm (TST10) and TST15 (5 mm in BCG-naïve, 15 mm in vaccinated). Potential incident TB cases were identified by telephone interview and national TB databases and confirmed by medical note review. Results Ninety-seven (1.0%) of 9610 participants developed active TB (77 of 6386 who had Results for T-SPOT.TB, QFT-GIT and TST). All tests had very low incidence in test negatives (1.2–1.6 per 1000 per year). Incidence rates in test positives were highest for TSpot.TB (13.2 95% CI: (9.9–17.4)), TST15 (11.1 (8.3,14.6)) and QFT.GIT (10.1 (7.4,13.4)); positive test Results for these tests were significantly more predictive of progression than TST10 and TST5, TSpot.TB was also higher than QFT.GIT. TST5 predicted more at high risk (55%) than TST10 (45%), TSpot.TB (33%), TST15 (38%) and QFT.GIT (31%). Conclusions IGRA-based or TST15 strategies are most suited for population screening in low-risk populations. Although TST5 and TST10 detect more TB cases this is at the cost of more individuals being classified at high risk with lower positive predictive values.

S5 Vitamin d for the management of asthma: cochrane systematic review and meta-analysis

Introduction and objectives Several clinical trials of vitamin D to prevent asthma exacerbation and improve asthma control have been conducted in children and adults, but a meta-analysis restricted to double-blind randomised placebo-controlled trials of this intervention is lacking. We conducted a Cochrane systematic review and meta-analysis to evaluate the efficacy of administration of vitamin D in reducing asthma exacerbations treated with systemic corticosteroids (primary outcome) and improving asthma symptom control. Methods Standard Cochrane collaboration procedures were followed. Double-blind randomised placebo-controlled trials of vitamin D in children and adults with asthma evaluating exacerbation risk and/or asthma symptom control were included. Results Seven trials involving a total of 435 children and two trials involving a total of 658 adults were included in the primary analysis. Administration of vitamin D reduced the rate of exacerbations requiring systemic corticosteroids (Rate Ratio 0.63, 95% CI: 0.45 to 0.88; 680 participants; 3 studies; high quality evidence), and decreased the risk of having at least one exacerbation requiring an emergency department visit and/or hospitalisation (Odds Ratio [OR] 0.39, 95% CI: 0.19 to 0.78; number needed to treat for one additional person to experience a beneficial outcome (NNTB), 27; 963 participants; 7 studies; high quality evidence). There was no effect of vitamin D on % predicted forced expiratory volume in one second (Mean Difference [MD] 0.48, 95% CI: −0.93 to 1.89; 387 participants; 4 studies; high quality evidence) or Asthma Control Test scores (MD −0.08, 95% CI: −0.70 to 0.54; participants = 713; studies = 3; high quality evidence). Administration of vitamin D did not influence the risk of serious adverse events (OR 1.01, 95% CI: 0.54 to 1.89; 879 participants; 5 studies; moderate quality evidence). No participant in any included trial suffered a fatal asthma exacerbation. Conclusions Meta-analysis of a modest number of trials in patients with predominantly mild to moderate asthma suggests that vitamin D is likely to reduce the risk of severe asthma exacerbation and reduce health care use.

P193 A role for active Vitamin D in steroid resistant asthma patients who have enhanced production of IL-17A and reduced IL-10

Background Steroid refractory (SR) asthma, a distinct disease phenotype, has a high morbidity and mortality and takes up a disproportional burden of healthcare cost. IL-17A is a pro-inflammatory cytokine that is essential for host defence against pathogens but can also lead to damage of the surrounding tissues associated with immune diseases and is linked with severe asthma. IL-10 has crucial immunregulatory properties, and we have previously shown in vitro, that T cells from steroid refractory asthma patients fail to respond to glucocorticosteroids for the induction of IL-10 synthesis. Methods We assessed IL-17A and IL-10 synthesis in steroid sensitive, SS, (mean% change in FEV1 following 2 weeks of oral prednisolone 16%) versus SR (mean% change FEV1 0%) asthma patients and investigated their response to dexamethasone. Results PBMC from SR individuals synthesised 7-fold higher levels of IL-17A than disease-severity matched SS patients (by flow cytometry and CBA). Interestingly IL-17A levels inversely correlated with changes in lung function following oral steroids whereas higher IL-10 levels were associated with an increase in lung function. Dexamethasone failed to inhibit IL-17A, but, surprisingly, increased protein synthesis, an effect that was also seen in vivo: inhaled glucocorticosteroid dosages correlated with IL-17A protein levels. This suggests the potentially detrimental effects corticosteroids might have in certain asthma phenotypes. The production of IL-10 by T cells was impaired in cultures from SR asthmatics, but not in healthy controls or SS asthma patients implying an associated impaired IL-10 response with poor asthma control. 1alpha,25-dihydroxyvitamin D3 (1,25(OH)D) not only restored the capacity of T cells to produce IL-10 upon stimulation with dexamethasone in SR asthma patients, but also inhibited IL-17A synthesis in culture independently of steroid. Conclusion High IL-17A levels are associated with poor response to steroids and more severe asthma. Our data supports a steroid-enhancing property of 1,25(OH)D in severe asthma through inhibition of IL-17A and via enhancement of IL-10 synthesis.

S2 Ethnic Variation in Inflammatory Profile in Tuberculosis

Introduction and objectives Mycobacterium tuberculosis (MTB) emerged as a pathogen in Africa and has co-evolved with humans following the migration to Europe and Asia some 70,000 years ago. Distinct phylogenetic lineages of MTB associate with hosts of particular genetic ancestry, both in their regions of origin and in distant cosmopolitan urban settings where human populations of different ancestry intermingle. These different strains induce distinct patterns of cytokine and chemokine secretion (‘inflammatory profiles’) in human macrophages. Circulating and antigen-stimulated inflammatory profiles might therefore be expected to vary significantly between tuberculosis patients of different ethnic origin. We therefore conducted a study to determine whether such variation exists. Methods We measured circulating and antigen-stimulated concentrations of 43 soluble inflammatory mediators and 14 haematological parameters in 45 patients of African ancestry and 83 patients of Eurasian ancestry receiving intensive-phase antimicrobial therapy for smear-positive pulmonary tuberculosis in London, UK. Host and bacillary genotypes were also determined. Statistical analyses were performed to compare inflammatory profiles in patients of African vs Eurasian ancestry; to investigate the influence of host and bacillary genotype on inflammatory profile; and to determine immunological correlates of speed of elimination of MTB from sputum. Results Tuberculosis patients of African vs Eurasian ancestry had similar clinical characteristics, but exhibited distinct inflammatory profiles. Patients of African ancestry had lower neutrophil counts, lower serum concentrations of CCL2, CCL11 and vitamin D binding protein (DBP), and lower antigen-stimulated CCL11 secretion than those of Eurasian ancestry, but higher serum CCL5 concentrations and higher antigen-stimulated interleukin 1 receptor antagonist and IL-12 secretion. These differences did not relate to MTB strain variation between groups, but they did associate with ethnic variation in host DBP genotype. Ethnic differences in inflammatory profile became more marked following initiation of antimicrobial therapy, and immunological correlates of speed of elimination of MTB from the sputum were distinct for patients of African vs. Eurasian ancestry. Conclusions Our study demonstrates a hitherto unappreciated degree of ethnic heterogeneity in inflammatory profile in tuberculosis patients. Candidate immunodiagnostics and immunological biomarkers of response to antimicrobial therapy should therefore be derived and validated in tuberculosis patients of different ethnic origin.

P19 Vitamin D in the Prevention of Acute Respiratory Infection: A Systematic Review of Clinical Studies

Introduction and Objectives Acute respiratory infections (ARI) cause significant morbidity and mortality: in the UK, during 2004, 33,957 deaths occurred due to pneumonia alone. Vitamin D metabolites enhance immunity to a wide range of respiratory pathogens in vitro, and numerous clinical studies have investigated whether vitamin D deficiency is a risk factor for ARI, or whether vitamin D supplementation prevents ARI. Systematic reviews of this literature are lacking, however. Our objective was to conduct a systematic review of clinical studies investigating the relationship between vitamin D status or the effect of vitamin D supplementation on risk of ARI. Methods The PubMed database was searched on 7th June 2012 using the terms ‘vitamin D’ and’ respiratory infection’. Cross-sectional studies, case-control studies, cohort studies or clinical trials in human subjects investigating the relationship between serum concentration of vitamin D metabolites or the effect of vitamin D supplementation on risk of ARI were included; ARI was defined as any infection of the respiratory tract with symptom duration of 30days or less. Studies relating exclusively to tuberculosis were excluded, as this is classically regarded as a chronic respiratory tract infection, with symptom duration usually exceeding 30 days. Results Thirty-one studies reporting data from a total of 43,272 participants were included in our review. Of these, 19 were observational studies (3 cross-sectional, 8 case-control and 8 cohort)and 12 were randomised controlled trials. Sixteen of the 19 observational studies reviewed reported statistically significant associations between vitamin D deficiency and susceptibility to ARI, and 3 reported no such association. Six of the 12 clinical trials reviewed reported protective effects of vitamin D against ARI, while five reported null effects, and one reported an adverse effect on pneumonia recurrence. Conclusions Observational studies report consistent associations between vitamin D deficiency and susceptibility to ARI in a wide range of age-groups in diverse clinical settings. By contrast, randomised controlled trials of vitamin D supplementation for the prevention of ARI report conflicting results, possibly reflecting varying prevalence of vitamin D deficiency in study populations and/or heterogeneity in vitamin D supplementation regimens investigated.