Richard D. Barker

High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.

BACKGROUND Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on sputum culture conversion are absent. METHODS We undertook a multicentre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 patients were allocated to receive 2·5 mg vitamin D(3) or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment. The primary endpoint was time from initiation of antimicrobial treatment to sputum culture conversion. Patients were genotyped for TaqI and FokI polymorphisms of the vitamin D receptor, and interaction analyses were done to assess the influence of the vitamin D receptor genotype on response to vitamin D(3). This trial is registered with ClinicalTrials.gov number NCT00419068. FINDINGS 126 patients were included in the primary efficacy analysis (62 assigned to intervention, 64 assigned to placebo). Median time to sputum culture conversion was 36·0 days in the intervention group and 43·5 days in the placebo group (adjusted hazard ratio 1·39, 95% CI 0·90-2·16; p=0.14). TaqI genotype modified the effect of vitamin D supplementation on time to sputum culture conversion (p(interaction)=0·03), with enhanced response seen only in patients with the tt genotype (8·09, 95% CI 1·36-48·01; p=0·02). FokI genotype did not modify the effect of vitamin D supplementation (p(interaction)=0·85). Mean serum 25-hydroxyvitamin D concentration at 56 days was 101·4 nmol/L in the intervention group and 22·8 nmol/L in the placebo group (95% CI for difference 68·6-88·2; p<0·0001). INTERPRETATION Administration of four doses of 2·5 mg vitamin D(3) increased serum 25-hydroxyvitamin D concentrations in patients receiving intensive-phase treatment for pulmonary tuberculosis. Vitamin D did not significantly affect time to sputum culture conversion in the whole study population, but it did significantly hasten sputum culture conversion in participants with the tt genotype of the TaqI vitamin D receptor polymorphism. FUNDING British Lung Foundation.Summary Background Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on sputum culture conversion are absent. Methods We undertook a multicentre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 patients were allocated to receive 2·5 mg vitamin D 3 or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment. The primary endpoint was time from initiation of antimicrobial treatment to sputum culture conversion. Patients were genotyped for Taq I and Fok I polymorphisms of the vitamin D receptor, and interaction analyses were done to assess the influence of the vitamin D receptor genotype on response to vitamin D 3 . This trial is registered with ClinicalTrials.gov number NCT00419068. Findings 126 patients were included in the primary efficacy analysis (62 assigned to intervention, 64 assigned to placebo). Median time to sputum culture conversion was 36·0 days in the intervention group and 43·5 days in the placebo group (adjusted hazard ratio 1·39, 95% CI 0·90–2·16; p=0.14). Taq I genotype modified the effect of vitamin D supplementation on time to sputum culture conversion (p interaction =0·03), with enhanced response seen only in patients with the tt genotype (8·09, 95% CI 1·36–48·01; p=0·02). Fok I genotype did not modify the effect of vitamin D supplementation (p interaction =0·85). Mean serum 25-hydroxyvitamin D concentration at 56 days was 101·4 nmol/L in the intervention group and 22·8 nmol/L in the placebo group (95% CI for difference 68·6–88·2; p Interpretation Administration of four doses of 2·5 mg vitamin D 3 increased serum 25-hydroxyvitamin D concentrations in patients receiving intensive-phase treatment for pulmonary tuberculosis. Vitamin D did not significantly affect time to sputum culture conversion in the whole study population, but it did significantly hasten sputum culture conversion in participants with the tt genotype of the TaqI vitamin D receptor polymorphism. Funding British Lung Foundation.

Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment

Calcidiol, the major circulating metabolite of vitamin D, supports induction of pleiotropic antimicrobial responses in vitro. Vitamin D supplementation elevates circulating calcidiol concentrations, and thus has a potential role in the prevention and treatment of infection. The immunomodulatory effects of administering vitamin D to humans with an infectious disease have not previously been reported. To characterize these effects, we conducted a detailed longitudinal study of circulating and antigen-stimulated immune responses in ninety-five patients receiving antimicrobial therapy for pulmonary tuberculosis who were randomized to receive adjunctive high-dose vitamin D or placebo in a clinical trial, and who fulfilled criteria for per-protocol analysis. Vitamin D supplementation accelerated sputum smear conversion and enhanced treatment-induced resolution of lymphopaenia, monocytosis, hypercytokinaemia, and hyperchemokinaemia. Administration of vitamin D also suppressed antigen-stimulated proinflammatory cytokine responses, but attenuated the suppressive effect of antimicrobial therapy on antigen-stimulated secretion of IL-4, CC chemokine ligand 5, and IFN-α. We demonstrate a previously unappreciated role for vitamin D supplementation in accelerating resolution of inflammatory responses during tuberculosis treatment. Our findings suggest a potential role for adjunctive vitamin D supplementation in the treatment of pulmonary infections to accelerate resolution of inflammatory responses associated with increased risk of mortality.

Chronic Lung Disease in Adolescents With Delayed Diagnosis of Vertically Acquired HIV Infection

A high burden of chronic lung disease (CLD) was found among 116 consecutive adolescents with vertically acquired human immunodeficiency virus in Zimbabwe. The main cause of HIV-associated CLD appears to be obliterative bronchiolitis, which has not previously been recognized among this patient group.

Ethnic Variation in Inflammatory Profile in Tuberculosis

Distinct phylogenetic lineages of Mycobacterium tuberculosis (MTB) cause disease in patients of particular genetic ancestry, and elicit different patterns of cytokine and chemokine secretion when cultured with human macrophages in vitro. Circulating and antigen-stimulated concentrations of these inflammatory mediators might therefore be expected to vary significantly between tuberculosis patients of different ethnic origin. Studies to characterise such variation, and to determine whether it relates to host or bacillary factors, have not been conducted. We therefore compared circulating and antigen-stimulated concentrations of 43 inflammatory mediators and 14 haematological parameters (inflammatory profile) in 45 pulmonary tuberculosis patients of African ancestry vs. 83 patients of Eurasian ancestry in London, UK, and investigated the influence of bacillary and host genotype on these profiles. Despite having similar demographic and clinical characteristics, patients of differing ancestry exhibited distinct inflammatory profiles at presentation: those of African ancestry had lower neutrophil counts, lower serum concentrations of CCL2, CCL11 and vitamin D binding protein (DBP) but higher serum CCL5 concentrations and higher antigen-stimulated IL-1 receptor antagonist and IL-12 secretion. These differences associated with ethnic variation in host DBP genotype, but not with ethnic variation in MTB strain. 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 differed between patients of African vs. Eurasian ancestry. Our study demonstrates a hitherto unappreciated degree of ethnic heterogeneity in inflammatory profile in tuberculosis patients that associates primarily with ethnic variation in host, rather than bacillary, genotype. Candidate immunodiagnostics and immunological biomarkers of response to antimicrobial therapy should be derived and validated in tuberculosis patients of different ethnic origin.

Comprehensive VTE Prevention Program Incorporating Mandatory Risk Assessment Reduces the Incidence of Hospital-Associated Thrombosis

BACKGROUND VTE is a common complication of hospitalization and is associated with significant morbidity and mortality. The use of appropriate thromboprophylaxis can significantly reduce the risk of VTE but remains underutilized. In England, a comprehensive approach to VTE prevention was launched in 2010. This study aimed to evaluate the impact of the implementation of the national program in a single center. METHODS A prospective quality improvement program was established at Kings College Hospital NHS Foundation Trust in 2010. The multidisciplinary thrombosis team launched mandatory documented VTE risk assessment and updated thromboprophylaxis guidance. Root cause analysis of hospital-associated thrombosis (HAT) was implemented to identify system failures, enable outcome measurement, and facilitate learning to improve VTE prevention practice. The key outcomes were the incidence of HAT and the proportion of events preventable with appropriate thromboprophylaxis. RESULTS Documented VTE risk assessment improved from <40% to > 90% in the first 9 months. Four hundred twenty-five episodes of HAT were identified over 2 years. A significant reduction in the incidence of HAT was observed following sustained achievement of 90% risk assessment (risk ratio, 0.88; 95% CI, 0.74-0.98; P = .014). The proportion of HAT attributable to inadequate thromboprophylaxis fell significantly from 37.5% to 22.4% (P = .005). CONCLUSIONS Mandatory VTE risk assessment can significantly reduce preventable HAT and thereby improve patient safety.

Neutrophilia independently predicts death in tuberculosis

To the Editor: Experimental animal work indicates that neutrophils play a key role in the immune response to mycobacteria [1, 2]. They appear protective against early infection [3] but in established disease, neutrophilia associates with pathology [1, 4]. In humans, higher neutrophil counts at tuberculosis diagnosis predict slower sputum conversion to negative during therapy [5, 6], but the overall prognostic significance of neutrophilia in human tuberculosis remains elusive. We therefore aimed to analyse this phenomenon in a study powered to detect an independent relationship with mortality. Tuberculosis patients were identified by database/case-note review at Newham University Hospital Trust and King’s College Hospital, London, UK. All patients diagnosed between 1999 and 2006 were eligible for inclusion in an analysis of neutrophilia at baseline; those with a recorded outcome of successfully completing treatment or death were included in an analysis of determinants of mortality. Healthy contacts of tuberculosis cases were recruited from the same hospitals. Data were extracted on patient age, sex, ethnicity, comorbidity, use of immunosuppressive medication, HIV status and site of disease. Laboratory data were collected from samples taken on the date of tuberculosis diagnosis: serum sodium, bilirubin and albumin concentrations; peripheral blood haemoglobin concentration; and peripheral blood neutrophil, monocyte, lymphocyte and platelet counts. Blood culture results were recorded where performed. Protocols were approved by the Barking and Havering NHS Research Ethics Committee (REC 08/H0702/25) and North East London Research Ethics Committee (REC P/02/146). We calculated that 584 patients (34 deaths and 550 survivors) would be required to detect a three-fold difference in mortality in the presence of neutrophilia with 80% power (5% significance level), assuming a 15% prevalence of neutrophilia and a death/survival …

Variation in vitamin D deficiency among tuberculosis patients by ethnic group and geographical region of birth: evidence from a diverse south London population.

Numerous studies have demonstrated an important association of vitamin D deficiency with tuberculosis (TB) [1, 2]. Vitamin D is important for immune function and an appropriate host response to Mycobacterium tuberculosis [3, 4]; 25-hydroxyvitamin D (25(OH)D) is the primary circulating form of vitamin D and is used to measure deficiency. Ethnicity & some geographical regions of birth strongly associated with risk of vitamin D deficiency in TB patients http://ow.ly/MiXR302uUPh

High-dose vitamin D3 during intensive phase treatment of pulmonary tuberculosis: a double-blind randomised controlled trial

BACKGROUND Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on sputum culture conversion are absent. METHODS We undertook a multicentre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 patients were allocated to receive 2·5 mg vitamin D(3) or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment. The primary endpoint was time from initiation of antimicrobial treatment to sputum culture conversion. Patients were genotyped for TaqI and FokI polymorphisms of the vitamin D receptor, and interaction analyses were done to assess the influence of the vitamin D receptor genotype on response to vitamin D(3). This trial is registered with ClinicalTrials.gov number NCT00419068. FINDINGS 126 patients were included in the primary efficacy analysis (62 assigned to intervention, 64 assigned to placebo). Median time to sputum culture conversion was 36·0 days in the intervention group and 43·5 days in the placebo group (adjusted hazard ratio 1·39, 95% CI 0·90-2·16; p=0.14). TaqI genotype modified the effect of vitamin D supplementation on time to sputum culture conversion (p(interaction)=0·03), with enhanced response seen only in patients with the tt genotype (8·09, 95% CI 1·36-48·01; p=0·02). FokI genotype did not modify the effect of vitamin D supplementation (p(interaction)=0·85). Mean serum 25-hydroxyvitamin D concentration at 56 days was 101·4 nmol/L in the intervention group and 22·8 nmol/L in the placebo group (95% CI for difference 68·6-88·2; p<0·0001). INTERPRETATION Administration of four doses of 2·5 mg vitamin D(3) increased serum 25-hydroxyvitamin D concentrations in patients receiving intensive-phase treatment for pulmonary tuberculosis. Vitamin D did not significantly affect time to sputum culture conversion in the whole study population, but it did significantly hasten sputum culture conversion in participants with the tt genotype of the TaqI vitamin D receptor polymorphism. FUNDING British Lung Foundation.Summary Background Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on sputum culture conversion are absent. Methods We undertook a multicentre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 patients were allocated to receive 2·5 mg vitamin D 3 or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment. The primary endpoint was time from initiation of antimicrobial treatment to sputum culture conversion. Patients were genotyped for Taq I and Fok I polymorphisms of the vitamin D receptor, and interaction analyses were done to assess the influence of the vitamin D receptor genotype on response to vitamin D 3 . This trial is registered with ClinicalTrials.gov number NCT00419068. Findings 126 patients were included in the primary efficacy analysis (62 assigned to intervention, 64 assigned to placebo). Median time to sputum culture conversion was 36·0 days in the intervention group and 43·5 days in the placebo group (adjusted hazard ratio 1·39, 95% CI 0·90–2·16; p=0.14). Taq I genotype modified the effect of vitamin D supplementation on time to sputum culture conversion (p interaction =0·03), with enhanced response seen only in patients with the tt genotype (8·09, 95% CI 1·36–48·01; p=0·02). Fok I genotype did not modify the effect of vitamin D supplementation (p interaction =0·85). Mean serum 25-hydroxyvitamin D concentration at 56 days was 101·4 nmol/L in the intervention group and 22·8 nmol/L in the placebo group (95% CI for difference 68·6–88·2; p Interpretation Administration of four doses of 2·5 mg vitamin D 3 increased serum 25-hydroxyvitamin D concentrations in patients receiving intensive-phase treatment for pulmonary tuberculosis. Vitamin D did not significantly affect time to sputum culture conversion in the whole study population, but it did significantly hasten sputum culture conversion in participants with the tt genotype of the TaqI vitamin D receptor polymorphism. Funding British Lung Foundation.

P114 Non-tuberculous mycobacteria–An increasing problem with many companions

Introduction Infections secondary to non-tuberculous mycobacteria (NTM) are emerging with increasing frequency in various clinical settings. The determination of the clinical and prognostic significance of NTM isolates remains challenging and, in the absence of large trials, the evidence around the different therapeutic options is limited[1]. We aimed to identify the number of patients with single/multiple NTM isolates in our hospitals and evaluate their complexity with respect to coexistent microbiology. Method A retrospective case review of patients in whom NTM were isolated over the last two years in two large teaching hospitals. Results 195 patients were diagnosed with an NTM within the specified time period. Of those, 29 patients (14.8%) had cystic fibrosis (CF) and 11 patients (5.6%) were HIV-positive. In the non-CF population, in 112 of 166 patients (67.5%) NTM were isolated in 1 sample, in 24 patients (14.5%) in 2 samples and in 30 patients (18%) in 3 or more samples. In 8 patients (4.8%) 2 or more different NTM species were isolated in the same samples. The NTM source was: sputum in 130 patients (78.3%), bronchial washings in 23 patients (13.8%) and other pulmonary/non-pulmonary sites in 13 patients (7.9%). Table 1 shows the NTM species isolated. 61 patients (36.7%) were co-infected with other organisms; most commonly with Pseudomonas aeruginosa, Staphylococcus aureus and Haemophilus influenzae. Co-infection with other organisms was not related to the NTM species, or to the number of NTM isolates. 114 patients (68.7%) were reviewed by a respiratory physician; this included all patients with 3 or more NTM isolates. 122 patients (73.5%) underwent CT imaging. 36 patients (21.7%) were commenced on treatment. Abstract P114 Table 1. NTM species isolated and number of patients treated Mycobacterium species Number of patients growing NTM Number of patients treated M. avium complex (MAC) 36 10 M. fortuitum 34 2 M. kansasii 28 17 M. gordonae 22 1 M. xenopi 17 2 M. peregrinum 12 0 M. chelonae 7 1 M. abscessus 6 1 M. mucogenicum 4 0 M. malmoense 4 1 M. scrofulaceum 2 0 M. hassiacum 1 0 M. szulgai 1 1 M. smegmatis 1 0 M. marinum 1 0 M. neoaurum 1 0 Conclusion NTM infection is an increasing and often complex challenge in respiratory medicine that requires specialist input. Further studies are needed to clarify whether co-infection with other organisms is related to the nature (e.g. bronchiectasis, cavitation) or severity of respiratory disease. References Griffith DE et al; “An Official ATS/IDSA Statement: Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Diseases”, AJRCCM 175: 367–416 (2007)

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.