Sputum viability microscopy for tuberculosis

Introduction. Sputum microscopy is the most frequently used tuberculosis laboratory test, but poorly assesses infectiousness and treatment response. The viability stain fluorescein diacetate (FDA) identifies metabolically active cells. Objective. To optimise sputum microscopy for predicting tuberculosis infectiousness and treatment outcome. Foundations. FDA sputum microscopy rapidly indicated the concentration of Mycobacterium tuberculosis that had not been sterilised by boiling and that was culturable. A cohort of 35 patients had FDA microscopy performed on their pre-treatment sputum. Lower FDA microscopy results predicted higher risk of tuberculosis disease in their 209 household contacts (adjusted hazard ratio=3.9, p=0.02). During the first 9 days of first-line therapy, these 35 patients had FDA microscopy on repeated sputum samples that rapidly differentiated patients with drug-susceptible tuberculosis from those with multi-drug resistant tuberculosis (p<0.001). Refinement. To optimise sputum collection for programmatic use, a network meta-analysis of 23 studies demonstrated that pooled sputum, as used in the foundation studies, had similar performance to more easily collected, instructed on-demand “spot” sputum collection (p=1.0). FDA microscopy was optimised for use in basic clinical laboratories. This replaced potentially biohazardous and expensive steps with more practicable alternatives. Evaluation. These refined protocols were used to collect pre-treatment sputum samples from 978 patients. Higher mycobacterial concentrations assessed by culture, PCR, conventional or FDA microscopy all predicted greater risk of tuberculosis disease in their 4311 household contacts (p<0.0001), with concordance (C)-statistics between 58-62%. Paired samples, pre-treatment and after 14 days of tuberculosis treatment, were collected from 384 patients. An alert FDA microscopy result at 14 days of treatment predicted adverse treatment outcomes (relative risk=3.0, p<0.0001), and performed better than currently used prognostic markers with 42% sensitivity and 85% specificity. Conclusion. After methodological optimisation, FDA microscopy predicted patient infectiousness and treatment outcome with similar or greater reliability than currently used laboratory tests.Open Acces

Comparison of sputum collection methods for tuberculosis diagnosis: a systematic review and pairwise and network meta-analysis

Background The performance of laboratory tests to diagnose pulmonary tuberculosis is dependent on the quality of the sputum sample tested. The relative merits of sputum collection methods to improve tuberculosis diagnosis are poorly characterised. We therefore aimed to investigate the effects of sputum collection methods on tuberculosis diagnosis. Methods We did a systematic review and meta-analysis to investigate whether non-invasive sputum collection methods in people aged at least 12 years improve the diagnostic performance of laboratory testing for pulmonary tuberculosis. We searched PubMed, Google Scholar, ProQuest, Web of Science, CINAHL, and Embase up to April 14, 2017, to identify relevant experimental, case-control, or cohort studies. We analysed data by pairwise meta-analyses with a random-effects model and by network meta-analysis. All diagnostic performance data were calculated at the sputum-sample level, except where authors only reported data at the individual patient-level. Heterogeneity was assessed, with potential causes identified by logistic meta-regression. Findings We identified 23 eligible studies published between 1959 and 2017, involving 8967 participants who provided 19 252 sputum samples. Brief, on-demand spot sputum collection was the main reference standard. Pooled sputum collection increased tuberculosis diagnosis by microscopy (odds ratio [OR] 1·6, 95% CI 1·3–1·9, p<0·0001) or culture (1·7, 1·2–2·4, p=0·01). Providing instructions to the patient before sputum collection, during observed collection, or together with physiotherapy assistance increased diagnostic performance by microscopy (OR 1·6, 95% CI 1·3–2·0, p<0·0001). Collecting early morning sputum did not significantly increase diagnostic performance of microscopy (OR 1·5, 95% CI 0·9–2·6, p=0·2) or culture (1·4, 0·9–2·4, p=0·2). Network meta-analysis confirmed these findings, and revealed that both pooled and instructed spot sputum collections were similarly effective techniques for increasing the diagnostic performance of microscopy. Interpretation Tuberculosis diagnoses were substantially increased by either pooled collection or by providing instruction on how to produce a sputum sample taken at any time of the day. Both interventions had a similar effect to that reported for the introduction of new, expensive laboratory tests, and therefore warrant further exploration in the drive to end the global tuberculosis epidemic

A protocol for a systematic review and meta-analysis of tuberculosis care around the time of pregnancy.

Background Tuberculosis is estimated to cause 1.5 million deaths annually and is most common during the reproductive years. Despite that fact, we found that tuberculosis screening, prevention or care recommendations for people around the time of pregnancy were absent from some national policy recommendations and varied in others. Objectives To address the apparent gaps and inconsistencies in policy, we aim to design a systematic review and meta-analysis of the original research evidence informing tuberculosis care around the time of pregnancy. Methods With assistance from librarians at the Biomedical library of the University of Gothenburg, Pubmed, CINAHL and Scopus databases will be searched. Search terms will aim to identify studies generating original research evidence informing care for tuberculosis around the time of pregnancy. Evidence may include: the outcome of TB and/or of pregnancy; the cost-effectiveness or acceptability of any intervention; the sensitivity and specificity of any assessment, selection, diagnostic or test criterion. The output from these literature searches will be screened by two independent reviewers to select the eligible studies for inclusion. Discrepancies will be resolved with a third reviewer. Firstly, publications that provide contextual data will be tabulated, summarising their main contributions. Secondly, studies that provide evidence directly guiding patient care will be our focus and will be considered to be key. The key studies will be subject to quality assessment, data extraction and when possible, meta-analysis. Conclusions This systematic review and meta-analysis aims to guide policy, practice and future research priorities concerning tuberculosis care around the time of pregnancy

Interventions aiming to eliminate catastrophic costs due to tuberculosis: a protocol for a systematic review and meta-analysis

Background: People with tuberculosis disease and their household members may suffer direct out-of-pocket expenses and indirect costs of lost income. These tuberculosis-related costs can worsen poverty, make tuberculosis treatment completion unaffordable, impair quality of life and increase the risk of death. Costs due to tuberculosis are usually defined as catastrophic if they exceed 20% of the pre-disease annual household income. The World Health Organisation strategy to "End TB" and the United Nations Sustainable Development Goals include the target that no households should face catastrophic costs due to tuberculosis. However, there is limited evidence and policy concerning how this global priority of eliminating catastrophic costs due to tuberculosis should be achieved. This systematic review and meta-analysis aims to address this knowledge gap. Methods: Publications assessing interventions that aimed to eliminate catastrophic costs will be identified by searching three electronic databases (PubMed, Scopus and Web of Science) together with reference lists from pertinent publications. We will screen eligible studies, extract data, and assess the risk of bias with the quality assessment tool from the National Heart, Lung, and Blood Institute. Discrepancies will be resolved by discussion between the reviewers. If we find sufficient comparable studies quantifying strategies to eliminate catastrophic costs then a meta-analysis will be performed. This systematic review and meta-analysis is registered with the PROSPERO database (CRD42022292410). Conclusion: This systematic review and meta-analysis aims to rigorously assess the evidence for strategies to eliminate catastrophic costs due to tuberculosis

Empowering patients with tuberculosis to build public trust in treatment outcome data

Tuberculosis has killed more people than any other infection since records began. According to World Health Organization policy and global practice, tuberculosis treatment outcomes are reported as “good” if patients complete all their treatment without persisting positive laboratory tests; or “bad” if treatment is not completed, and/or laboratory tests remain positive. Globally, most patients treated for tuberculosis never have any positive laboratory test, so usually treatment outcome simply assesses whether patients have completed their standardised course of treatment. In an ongoing cohort of 15,000 patients with tuberculosis disease treated in 32 Peruvian shantytowns we have compared programmatic and patient-reported outcomes. Amongst 2152 consecutive patients with tuberculosis, half of the 6.1% of patients whose treatment outcome was “bad” because of death during treatment actually died from unrelated causes, so “good” tuberculosis outcomes were underestimated. Furthermore, patients who die after completing tuberculosis therapy are not included in outcome data, but verbal autopsies defined their cause of death to be tuberculosis for 25% (15/59), so “good” outcomes were overestimated. In a group of 1622 patients, 0.86% (14) were considered programmatically to have “bad” outcome because they were lost to follow-up, but our research team were able to contact them or their families in all but three cases and 91% (8/11) actually had good treatment outcomes, so “good” outcomes were underestimated. Similarly, we completed detailed follow-up for 607 patients who were considered to have had a “good” tuberculosis outcome, but 7.9% of them were diagnosed with tuberculosis again, so “good” outcomes were overestimated. We assessed wellbeing with the EUROHIS-QOL questionnaire for 836 patients after being considered to have had a good treatment outcome and 38% were not satisfied with their overall health, so “good” outcomes were overestimated. Because of these issues, patients with tuberculosis cannot be confident that current statistics indicate what health outcome to expect. We propose that global policy is changed to  empower patients (or if they died, their relatives) to report several months after treatment ends their actual tuberculosis-related health, making tuberculosis treatment outcome statistics more meaningful

Dynamics of Cough Frequency in Adults Undergoing Treatment for Pulmonary Tuberculosis.

Background: Cough is the major determinant of tuberculosis transmission. Despite this, there is a paucity of information regarding characteristics of cough frequency throughout the day and in response to tuberculosis therapy. Here we evaluate the circadian cycle of cough, cough frequency risk factors, and the impact of appropriate treatment on cough and bacillary load. Methods: We prospectively evaluated human immunodeficiency virus-negative adults (n = 64) with a new diagnosis of culture-proven, drug-susceptible pulmonary tuberculosis immediately prior to treatment and repeatedly until treatment day 62. At each time point, participant cough was recorded (n = 670) and analyzed using the Cayetano Cough Monitor. Consecutive coughs at least 2 seconds apart were counted as separate cough episodes. Sputum samples (n = 426) were tested with microscopic-observation drug susceptibility broth culture, and in culture-positive samples (n = 252), the time to culture positivity was used to estimate bacillary load. Results: The highest cough frequency occurred from 1 pm to 2 pm, and the lowest from 1 am to 2 am (2.4 vs 1.1 cough episodes/hour, respectively). Cough frequency was higher among participants who had higher sputum bacillary load (P < .01). Pretreatment median cough episodes/hour was 2.3 (interquartile range [IQR], 1.2-4.1), which at 14 treatment days decreased to 0.48 (IQR, 0.0-1.4) and at the end of the study decreased to 0.18 (IQR, 0.0-0.59) (both reductions P < .001). By 14 treatment days, the probability of culture conversion was 29% (95% confidence interval, 19%-41%). Conclusions: Coughs were most frequent during daytime. Two weeks of appropriate treatment significantly reduced cough frequency and resulted in one-third of participants achieving culture conversion. Thus, treatment by 2 weeks considerably diminishes, but does not eliminate, the potential for airborne tuberculosis transmission

Non-invasive diagnostic tests for Helicobacter pylori infection

BACKGROUND: Helicobacter pylori (H pylori) infection has been implicated in a number of malignancies and non-malignant conditions including peptic ulcers, non-ulcer dyspepsia, recurrent peptic ulcer bleeding, unexplained iron deficiency anaemia, idiopathic thrombocytopaenia purpura, and colorectal adenomas. The confirmatory diagnosis of H pylori is by endoscopic biopsy, followed by histopathological examination using haemotoxylin and eosin (H & E) stain or special stains such as Giemsa stain and Warthin-Starry stain. Special stains are more accurate than H & E stain. There is significant uncertainty about the diagnostic accuracy of non-invasive tests for diagnosis of H pylori. OBJECTIVES: To compare the diagnostic accuracy of urea breath test, serology, and stool antigen test, used alone or in combination, for diagnosis of H pylori infection in symptomatic and asymptomatic people, so that eradication therapy for H pylori can be started. SEARCH METHODS: We searched MEDLINE, Embase, the Science Citation Index and the National Institute for Health Research Health Technology Assessment Database on 4 March 2016. We screened references in the included studies to identify additional studies. We also conducted citation searches of relevant studies, most recently on 4 December 2016. We did not restrict studies by language or publication status, or whether data were collected prospectively or retrospectively. SELECTION CRITERIA: We included diagnostic accuracy studies that evaluated at least one of the index tests (urea breath test using isotopes such as13C or14C, serology and stool antigen test) against the reference standard (histopathological examination using H & E stain, special stains or immunohistochemical stain) in people suspected of having H pylori infection. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the references to identify relevant studies and independently extracted data. We assessed the methodological quality of studies using the QUADAS-2 tool. We performed meta-analysis by using the hierarchical summary receiver operating characteristic (HSROC) model to estimate and compare SROC curves. Where appropriate, we used bivariate or univariate logistic regression models to estimate summary sensitivities and specificities. MAIN RESULTS: We included 101 studies involving 11,003 participants, of which 5839 participants (53.1%) had H pylori infection. The prevalence of H pylori infection in the studies ranged from 15.2% to 94.7%, with a median prevalence of 53.7% (interquartile range 42.0% to 66.5%). Most of the studies (57%) included participants with dyspepsia and 53 studies excluded participants who recently had proton pump inhibitors or antibiotics.There was at least an unclear risk of bias or unclear applicability concern for each study.Of the 101 studies, 15 compared the accuracy of two index tests and two studies compared the accuracy of three index tests. Thirty-four studies (4242 participants) evaluated serology; 29 studies (2988 participants) evaluated stool antigen test; 34 studies (3139 participants) evaluated urea breath test-13C; 21 studies (1810 participants) evaluated urea breath test-14C; and two studies (127 participants) evaluated urea breath test but did not report the isotope used. The thresholds used to define test positivity and the staining techniques used for histopathological examination (reference standard) varied between studies. Due to sparse data for each threshold reported, it was not possible to identify the best threshold for each test.Using data from 99 studies in an indirect test comparison, there was statistical evidence of a difference in diagnostic accuracy between urea breath test-13C, urea breath test-14C, serology and stool antigen test (P = 0.024). The diagnostic odds ratios for urea breath test-13C, urea breath test-14C, serology, and stool antigen test were 153 (95% confidence interval (CI) 73.7 to 316), 105 (95% CI 74.0 to 150), 47.4 (95% CI 25.5 to 88.1) and 45.1 (95% CI 24.2 to 84.1). The sensitivity (95% CI) estimated at a fixed specificity of 0.90 (median from studies across the four tests), was 0.94 (95% CI 0.89 to 0.97) for urea breath test-13C, 0.92 (95% CI 0.89 to 0.94) for urea breath test-14C, 0.84 (95% CI 0.74 to 0.91) for serology, and 0.83 (95% CI 0.73 to 0.90) for stool antigen test. This implies that on average, given a specificity of 0.90 and prevalence of 53.7% (median specificity and prevalence in the studies), out of 1000 people tested for H pylori infection, there will be 46 false positives (people without H pylori infection who will be diagnosed as having H pylori infection). In this hypothetical cohort, urea breath test-13C, urea breath test-14C, serology, and stool antigen test will give 30 (95% CI 15 to 58), 42 (95% CI 30 to 58), 86 (95% CI 50 to 140), and 89 (95% CI 52 to 146) false negatives respectively (people with H pylori infection for whom the diagnosis of H pylori will be missed).Direct comparisons were based on few head-to-head studies. The ratios of diagnostic odds ratios (DORs) were 0.68 (95% CI 0.12 to 3.70; P = 0.56) for urea breath test-13C versus serology (seven studies), and 0.88 (95% CI 0.14 to 5.56; P = 0.84) for urea breath test-13C versus stool antigen test (seven studies). The 95% CIs of these estimates overlap with those of the ratios of DORs from the indirect comparison. Data were limited or unavailable for meta-analysis of other direct comparisons. AUTHORS' CONCLUSIONS: In people without a history of gastrectomy and those who have not recently had antibiotics or proton ,pump inhibitors, urea breath tests had high diagnostic accuracy while serology and stool antigen tests were less accurate for diagnosis of Helicobacter pylori infection.This is based on an indirect test comparison (with potential for bias due to confounding), as evidence from direct comparisons was limited or unavailable. The thresholds used for these tests were highly variable and we were unable to identify specific thresholds that might be useful in clinical practice.We need further comparative studies of high methodological quality to obtain more reliable evidence of relative accuracy between the tests. Such studies should be conducted prospectively in a representative spectrum of participants and clearly reported to ensure low risk of bias. Most importantly, studies should prespecify and clearly report thresholds used, and should avoid inappropriate exclusions

PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist for the manuscript "Defining tuberculosis stigma: a protocol for a systematic review, analysis, and thematic synthesis"

Background: Throughout recorded history, tuberculosis is believed to have killed more people than any other infectious disease. Despite the World Health Organization’s determination that preventing and controlling tuberculosis will require understanding and reducing tuberculosis stigma, we noted strikingly diverse definitions and lack of consensus in describing tuberculosis stigma. Furthermore, we found no systematic reviews in the existing tuberculosis stigma literature characterizing, comparing, or assessing existing tuberculosis stigma definitions or their consistency. To address this knowledge gap we intend to conduct a systematic review of existing tuberculosis stigma definitions used in the academic research literature, and through quantitative synthesis of the words and phrases contained within those definitions, identify themes that characterize tuberculosis stigma.Methods: Studies containing definitions of tuberculosis stigma will be identified by searching two electronic databases -- PubMed and PsycINFO – using the Medical Subject Heading (MeSH) terms “stigma[MeSH Major Topic] AND tuberculosis[MeSH Major Topic]”. Study inclusion criteria will consist of: a) original research published in English, (due to logistical constraints); b) qualitative studies using semi-structured interviews and focus group discussions; c) quantitative studies including descriptive studies and trials, questionnaires, and cross-sectional surveys; and d) mixed method studies. Included studies will be searched for definitions of tuberculosis stigma using the search term “defin”. Descriptive words and phrases will be extracted from definitions and categorized into themes, based on noun, verb, adjective, and adverb derivatives; and synonym definitions. Predominant themes will then be identified and further categorized as emotion, thought, or behavior themes. Relative frequencies of definitions, and definition words and phrases, will be compared quantitively.Conclusion: This systematic review and thematic analysis is intended to characterize academic definitions of tuberculosis stigma and identify predominant tuberculosis stigma themes contained within those definitions.</p

Addressing social determinants to end tuberculosis

Leave no one behind. This is the overarching pledge of the Sustainable Development Goals; a pledge that is far from being realised. In 2016, more than 4 million people with tuberculosis were estimated to be undiagnosed or their care and treatment were unknown.1 In the same year, nearly a fifth of the people who were diagnosed and known to be treated for tuberculosis had adverse outcomes, including 1·3 million deaths.1 One reason that millions of people affected by tuberculosis are left behind is an absence of coordinated, international action to combat poverty and inequality