R Beynon

Protection by BCG Vaccine Against Tuberculosis: A Systematic Review of Randomized Controlled Trials

BACKGROUND Randomized trials assessing BCG vaccine protection against tuberculosis have widely varying results, for reasons that are not well understood. METHODS We examined associations of trial setting and design with BCG efficacy against pulmonary and miliary or meningeal tuberculosis by conducting a systematic review, meta-analyses, and meta-regression. RESULTS We identified 18 trials reporting pulmonary tuberculosis and 6 reporting miliary or meningeal tuberculosis. Univariable meta-regression indicated efficacy against pulmonary tuberculosis varied according to 3 characteristics. Protection appeared greatest in children stringently tuberculin tested, to try to exclude prior infection with Mycobacterium tuberculosis or sensitization to environmental mycobacteria (rate ratio [RR], 0.26; 95% confidence interval [CI], .18-.37), or infants (RR, 0.41; 95% CI, .29-.58). Protection was weaker in children not stringently tested (RR, 0.59; 95% CI, .35-1.01) and older individuals stringently or not stringently tested (RR, 0.88; 95% CI, .59-1.31 and RR, 0.81; 95% CI, .55-1.22, respectively). Protection was higher in trials further from the equator where environmental mycobacteria are less and with lower risk of diagnostic detection bias. These associations were attenuated in a multivariable model, but each had an independent effect. There was no evidence that efficacy was associated with BCG strain. Protection against meningeal and miliary tuberculosis was also high in infants (RR, 0.1; 95% CI, .01-.77) and children stringently tuberculin tested (RR, 0.08; 95% CI, .03-.25). CONCLUSIONS Absence of prior M. tuberculosis infection or sensitization with environmental mycobacteria is associated with higher efficacy of BCG against pulmonary tuberculosis and possibly against miliary and meningeal tuberculosis. Evaluations of new tuberculosis vaccines should account for the possibility that prior infection may mask or block their effects.

Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guérin vaccination against tuberculosis.

BACKGROUND Recent evidence suggests that the duration of protection by bacillus Calmette-Guérin (BCG) may exceed previous estimates with potential implications for estimating clinical and cost-efficacy. OBJECTIVES To estimate the protection and duration of protection provided by BCG vaccination against tuberculosis, explore how this protection changes with time since vaccination, and examine the reasons behind the variation in protection and the rate of waning of protection. DATA SOURCES Electronic databases including MEDLINE, Excerpta Medica Database (EMBASE), Cochrane Databases, NHS Economic Evaluation Database (NHS EED), Database of Abstracts of Reviews of Effects (DARE), Web of Knowledge, Biosciences Information Service (BIOSIS), Latin American and Caribbean Health Sciences Literature (LILACs), MEDCARIB Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from inception to May 2009. Index to Theses, System for Information on Grey Literature in Europe (SIGLE), Centre for Agricultural Bioscience International (CABI) Abstracts, Scopus, Article First, Academic Complete, Africa-Wide Information, Google Scholar, Global Health, British National Bibliography for Report Literature, and clinical trial registration websites were searched from inception to October 2009. REVIEW METHODS Electronic databases searches, screening of identified studies, data extraction and analysis were undertaken. Meta-analysis was used to present numerical and graphical summaries of clinical efficacy and efficacy by time since vaccination. Evidence of heterogeneity was assessed using the tau-squared statistic. Meta-regression allowed the investigation of observed heterogeneity. Factors investigated included BCG strain, latitude, stringency of pre-BCG vaccination tuberculin testing, age at vaccination, site of disease, study design and vulnerability to biases. Rate of waning of protection was estimated using the ratio of the measure of efficacy after 10 years compared with the efficacy in the first 10 years of a study. RESULTS Study selection. A total of 21,030 references were identified, providing data on 132 studies after abstract and full-text review. Efficacy. Protection against pulmonary tuberculosis in adults is variable, ranging from substantial protection in the UK MRC trial {rate ratio 0.22 [95% confidence interval (CI) 0.16 to 0.31]}, to absence of clinically important benefit, as in the large Chingleput trial [rate ratio 1.05 (95% CI 0.88 to 1.25)] and greater in latitudes further away from the equator. BCG vaccination efficacy was usually high, and varied little by form of disease (with higher protection against meningeal and miliary tuberculosis) or study design when BCG vaccination was given only to infants or to children after strict screening for tuberculin sensitivity. High levels of protection against death were observed from both trials and observational studies. The observed protective effect of BCG vaccination did not differ by the strain of BCG vaccine used in trials. DURATION Reviewed studies showed that BCG vaccination protects against pulmonary and extrapulmonary tuberculosis for up to 10 years. Most studies either did not follow up participants for long enough or had very few cases after 15 years. This should not be taken to indicate an absence of effect: five studies (one trial and four observational studies) provided evidence of measurable protection at least 15 years after vaccination. Efficacy declined with time. The rate of decline was variable, with faster decline in latitudes further from the equator and in situations where BCG vaccination was given to tuberculin-sensitive participants after stringent tuberculin testing. LIMITATIONS The main limitation of this review relates to quality of included trials, most of which were conducted before current standards for reporting were formulated. In addition, data were lacking in some areas and the review had to rely on evidence from observational studies. CONCLUSIONS BCG vaccination protection against tuberculosis varies between populations, to an extent that cannot be attributed to chance alone. Failure to exclude those already sensitised to mycobacteria and study latitude closer to the equator were associated with lower efficacy. These factors explained most of the observed variation. There is good evidence that BCG vaccination protection declines with time and that protection can last for up to 10 years. Data on protection beyond 15 years are limited; however, a small number of trials and observational studies suggest that BCG vaccination may protect for longer. Further studies are required to investigate the duration of protection by BCG vaccination. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Systematic review: accuracy of anti-citrullinated Peptide antibodies for diagnosing rheumatoid arthritis

BACKGROUND Early recognition and treatment of rheumatoid arthritis is important to prevent irreversible joint damage. Anti-citrullinated peptide antibodies (ACPA) have been suggested for early diagnosis. PURPOSE To compare the accuracy of ACPA and rheumatoid factor in diagnosing rheumatoid arthritis in patients with early symptoms of the disease. DATA SOURCES 10 medical databases from inception to September 2009, with no language or publication restrictions, and references of included studies. STUDY SELECTION Two independent reviewers screened searches. Full articles were assessed by one reviewer and checked by a second reviewer to identify studies that reported 2 x 2 data on ACPA for the diagnosis of rheumatoid arthritis (by 1987 American College of Rheumatology criteria). DATA EXTRACTION One reviewer abstracted data on patient characteristics, ACPA details, and 2 x 2 data and assessed study quality by using the QUADAS tool. A second reviewer checked extractions. DATA SYNTHESIS 151 studies were included, with considerable heterogeneity in sensitivity (range, 12% to 93%) and specificity (range, 63% to 100%). In cohort studies that investigated second-generation anti-cyclic citrullinated peptide antibodies (anti-CCP2) in patients with early rheumatoid arthritis (<2 years), summary sensitivity and specificity were 57% (95% CI, 51% to 63%) and 96% (CI, 93% to 97%), respectively. Case-control and cross-sectional studies and studies of patients with established rheumatoid arthritis all overestimated sensitivity. Anti-CCP2 had greater specificity than rheumatoid factor (96% vs. 86%), with similar sensitivity. Evidence was insufficient to ascertain whether the combination of anti-CCP2 and rheumatoid factor provides additional benefit over anti-CCP2 alone. LIMITATIONS Most studies used a diagnostic case-control design, which overestimated sensitivity. Items relating to study quality were rarely reported. Publication bias could not be assessed. CONCLUSION Anti-CCP2 should be included in the work-up of patients with early symptoms of rheumatoid arthritis.

Selenium and prostate cancer: systematic review and meta-analysis

BACKGROUND Prostate cancer is a growing public health problem. Several human studies have shown a potentially protective effect of selenium, but the conclusions from published reports are inconsistent. OBJECTIVE The objective was to examine the evidence for relations between selenium intake, selenium status, and prostate cancer risk. DESIGN This was a systematic review and meta-analysis of randomized controlled trials, case-control studies, and prospective cohort studies. The World Cancer Research Fund/American Institute for Cancer Research Continuous Update Project database was searched up to September 2010. The studies included reported measurements of selenium intake or status (plasma, serum, or toenail selenium), assessments of prostate cancer cases (number of events), and the RR in the adult population. Meta-analyses were performed, and study quality, heterogeneity, and small study effects were assessed. Dose-response meta-analyses were used, with restricted cubic splines and fractional polynomials for nonlinear trends, to investigate the association between selenium status and prostate cancer risk. RESULTS Twelve studies with a total of 13,254 participants and 5007 cases of prostate cancer were included. The relation between plasma/serum selenium and prostate cancer in a nonlinear dose-response meta-analysis showed that the risk decreased with increasing plasma/serum selenium up to 170 ng/mL. Three high-quality studies included in the meta-analysis of toenail selenium and cancer risk indicated a reduction in prostate cancer risk (estimated RR: 0.29; 95% CI: 0.14, 0.61) with a toenail selenium concentration between 0.85 and 0.94 μg/g. CONCLUSION The relation between selenium status and decreased prostate cancer risk was examined over a relatively narrow range of selenium status; further studies in low-selenium populations are required.

Height and Prostate Cancer Risk: A Large Nested Case-Control Study (ProtecT) and Meta-analysis

Background: Height, a marker of childhood environmental exposures, is positively associated with prostate cancer risk, perhaps through the insulin-like growth factor system. We investigated the relationship of prostate cancer with height and its components (leg and trunk length) in a nested case-control study and with height in a dose-response meta-analysis. Methods: We nested a case-control study within a population-based randomized controlled trial evaluating treatments for localized prostate cancer in British men ages 50 to 69 years, including 1,357 cases detected through prostate-specific antigen testing and 7,990 controls (matched on age, general practice, assessment date). Nine bibliographic databases were searched systematically for studies on the height-prostate cancer association that were pooled in a meta-analysis. Results: Based on the nested case-control, the odds ratio (OR) of prostate-specific antigen–detected prostate cancer per 10 cm increase in height was 1.06 [95% confidence interval (95% CI): 0.97-1.16; ptrend = 0.2]. There was stronger evidence of an association of height with high-grade prostate cancer (OR: 1.23; 95% CI: 1.06-1.43), mainly due to the leg component, but not with low-grade disease (OR: 0.99; 95% CI: 0.90-1.10). In general, associations with leg or trunk length were similar. A meta-analysis of 58 studies found evidence that height is positively associated with prostate cancer (random-effects OR per 10 cm: 1.06; 95% CI: 1.03-1.09), with a stronger effect for prospective studies of more advanced/aggressive cancers (random-effects OR: 1.12; 95% CI: 1.05-1.19). Conclusion: These data indicate a limited role for childhood environmental exposures—as indexed by adult height—on prostate cancer incidence, while suggesting a greater role for progression, through mechanisms requiring further investigation. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2325–36)

Symptomatic and quality‐of‐life outcomes after treatment for clinically localised prostate cancer: a systematic review

To conduct a systematic review of the risks of short‐term outcomes after major treatments for clinically localised prostate cancer. MEDLINE, EMBASE and the Cochrane Library were searched from 2004 to January 2013. Study arms that included ≥100 men with localised prostate cancer in receipt of surgery, radiotherapy or active surveillance and reported symptomatic and quality‐of‐life (QoL) data from 6 to 60 months after treatment were eligible. Data were extracted by one reviewer and checked by another. In all, 64 studies (80 treatment cohorts) were included. Most were single treatment cohorts from the USA or Europe. Radiotherapy was the most common treatment (40 cohorts, including 31 brachytherapy cohorts) followed by prostatectomy (39 cohorts), with only one active surveillance cohort. Most frequently measured symptoms were urinary, followed by sexual, and bowel; QoL was assessed in only 17 cohorts. Most studies used validated measures, although poor data reporting and differences between studies meant that it was not possible to pool data. Data on the precise impact of short‐term symptomatic and QoL outcomes after treatment for localised prostate cancer are of insufficient quality for clear guidance to men about the risks to these aspects of their lives. It is important that future studies focus on collecting core outcomes through validated measures and comply with reporting guidelines, so that clear and accurate information can be derived for men considering screening or treatment for prostate cancer.

The diagnostic utility and cost-effectiveness of selective nerve root blocks in patients considered for lumbar decompression surgery: a systematic review and economic model

BACKGROUND Diagnostic selective nerve root block (SNRB) involves injection of local anaesthetic, sometimes in conjunction with corticosteroids, around spinal nerves. It is used to identify symptomatic nerve roots in patients with probable radicular pain that is not fully concordant with imaging findings. OBJECTIVES (1) Determine the diagnostic accuracy of SNRB in patients with low back and radiating pain in a lower limb; (2) evaluate whether or not accuracy varies by patient subgroups; (3) review injection-related adverse events; and (4) evaluate the cost-effectiveness of SNRB. DATA SOURCES MEDLINE, EMBASE, Science Citation Index, Bioscience Information Service (BIOSIS), Latin American and Caribbean Health Sciences Literature (LILACS) and grey literature databases were searched from inception to August 2011. Reference lists of included studies were screened. METHODS A systematic review (SR) of studies that assessed the accuracy of SNRB or adverse events in patients with low back pain and symptoms in a lower limb for the diagnosis of lumbar radiculopathy. Study quality was assessed using the quality assessment of diagnostic accuracy studies (QUADAS)-2 checklist. We used random-effects meta-analysis to pool diagnostic accuracy data. Decision tree and Markov models were developed, combining SR results with information on the costs and outcomes of surgical and non-surgical care. Uncertainty was assessed using probabilistic and deterministic sensitivity analyses. RESULTS Five studies assessed diagnostic accuracy: three diagnostic cohort and two within-patient case-control studies. All were judged to be at high risk of bias and had high concerns regarding applicability. In individual studies, sensitivity ranged from 57% [95% confidence interval (CI) 43% to 70%] to 100% (95% CI 76% to 100%) and specificity from 9.5% (95% CI 1% to 30%) to 86% (95% CI 76% to 93%). The most reliable estimate was judged to come from two cohort studies that used post-surgery outcome as the reference standard; summary sensitivity and specificity were 93% (95% CI 86% to 97%) and 26% (95% CI 5% to 68%), respectively. No study provided sufficient detail to judge whether or not accuracy varied by patient subgroup. Seven studies assessed adverse events. There were no major or permanent complications; minor complications were reported in 0-6% of patients. The addition of SNRB to the diagnostic work-up was not cost-effective with an incremental cost per quality-adjusted life-year of £1,576,007. Sensitivity analyses confirmed that SNRB was unlikely to be a cost-effective method for diagnosis and planning surgical therapy. LIMITATIONS We identified very few studies; all were at high risk of bias. The conduct and interpretation of SNRBs varied and there was no gold standard for diagnosis. Limited information about the impact of SNRB on subsequent care and the long-term costs and benefits of surgery increased uncertainty about cost-effectiveness. CONCLUSIONS There were few studies that estimated the diagnostic accuracy of SNRB in patients with radiculopathy and all were limited by the difficulty of making a reference standard diagnosis. Summary estimates suggest that specificity is low, but results are based on a small number of studies at a high risk of bias. Based on current weak evidence, it is unlikely that SNRB is a cost-effective method for identifying the symptomatic nerve root prior to lumbar spine surgery. Future research should focus on randomised controlled trials to evaluate whether or not SNRB improves patient outcomes at acceptable cost. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Is MRI better than CT for detecting a vascular component to dementia? A systematic review and meta-analysis.

BackgroundIdentification of causes of dementia soon after symptom onset is important, because appropriate treatment of some causes of dementia can slow or halt its progression or enable symptomatic treatment where appropriate. The accuracy of MRI and CT, and whether MRI is superior to CT, in detecting a vascular component to dementia in autopsy confirmed and clinical cohorts of patients with VaD, combined AD and VaD (“mixed dementia”), and AD remain unclear. We conducted a systematic review and meta-analysis to investigate this question.MethodsWe searched eight databases and screened reference lists to identify studies addressing the review question. We assessed study quality using QUADAS. We estimated summary diagnostic accuracy according to imaging finding, and ratios of diagnostic odds ratios (RDORs) for MRI versus CT and high versus low risk of bias.ResultsWe included 7 autopsy and 31 non-autopsy studies. There was little evidence that selective patient enrolment and risk of incorporation bias impacted on diagnostic accuracy (p = 0.12 to 0.95). The most widely reported imaging finding was white matter hyperintensities. For CT (11 studies) summary sensitivity and specificity were 71% (95% CI 53%-85%) and 55% (44%-66%). Corresponding figures for MRI (6 studies) were 95% (87%-98%) and 26% (12%-50%). General infarcts was the most specific imaging finding on MRI (96%; 95% CI 94%-97%) and CT (96%; 93%-98%). However, sensitivity was low for both MRI (53%; 36%-70%) and CT (52%; 22% to 80%). No imaging finding had consistently high sensitivity. Based on non-autopsy studies, MRI was more accurate than CT for six of seven imaging findings, but confidence intervals were wide.ConclusionThere is insufficient evidence to suggest that MRI is superior to CT with respect to identifying cerebrovascular changes in autopsy-confirmed and clinical cohorts of VaD, AD, and ‘mixed dementia’.

Development of a combined database for meta-epidemiological research.

Collections of meta-analyses assembled in meta-epidemiological studies are used to study associations of trial characteristics with intervention effect estimates. However, methods and findings are not consistent across studies. To combine data from 10 meta-epidemiological studies into a single database, and derive a harmonized dataset without overlap between meta-analyses. The database design allowed trials to be contained in different meta-analyses, multiple meta-analyses in systematic reviews, overlapping meta-analyses between systematic reviews, and multiple references to the same trial or review. Unique identifiers were assigned to each reference and used to identify duplicate trials. Sets of meta-analyses with overlapping trials were identified and duplicates removed. Overlapping trials were used to examine agreement between assessments of trial characteristics. The combined database contained 427 reviews, 454 meta-analyses and 4874 trial results. Of these, 258 meta-analyses were unique, while for 196 at least one trial overlapped with another meta-analysis. Median kappa statistics for reliability of assessments were 0.60 for sequence generation, 0.58 for allocation concealment and 0.87 for blinding. Based on inspection of sets of overlapping meta-analyses, 91 meta-analyses containing 1344 trial results were removed. Additionally, 24 duplicated trial results were removed from 16 meta-analyses, to derive a final database containing 363 meta-analyses and 3477 unique trial results. The final database will be used to examine the combined evidence on sources of bias in randomized controlled trials. The strategy used to remove overlap between meta-analyses may be of use for future empirical research. Copyright