19 research outputs found
Predicting progression to active tuberculosis:A rate-limiting step on the path to elimination
In a Perspective, Ajit Lalvani and colleagues discuss new approaches to predicting progression to active tuberculosis
Engaging with civil society to improve access to LTBI screening for new migrants in England: a qualitative study
Setting: The LTBI programme offers testing and treatment to new entrant migrants from high incidence countries in England. However, the rates of LTBI testing, treatment acceptance and completion are suboptimal and appropriate access must be improved.
Objective: To gain insights from the community, community-based organisations (CBOs), and public sector stakeholders on interventions that facilitate collaboration to improve health care outreach and delivery.
Design: Three stakeholder meetings and five focus group discussions were held using thematic analysis to identify themes arising from the participants’ perspectives.
Results: Four overarching themes emerged from the discussions. These were capacity, collaboration, culture and trust. These highlighted the complementary skills sets different sectors bring to collaboration, as well as the barriers that need surmounting. Stigma could be reduced by making LTBI testing routine, and community members could act as champions for health promotion raising awareness on LTBI testing, and providing a bridge between communities and primary care services.
Conclusion: Public service providers, community members and CBOs have a willingness to collaborate to support primary care delivery of testing for LTBI and other communicable and non-communicable diseases. Policy and commissioning support are needed to facilitate such workings
an observational study
Pulmonary tuberculosis (PTB) results in lung functional impairment and there
are no surrogate markers to monitor the extent of lung involvement. We
investigated the clinical significance of S100A12 and soluble receptor for
advanced glycation end-products (sRAGE) for predicting the extent of lung
involvement. We performed an observational study in India with 119 newly
diagnosed, treatment naïve, sputum smear positive, HIV-negative PTB patients
and 163 healthy controls. All patients were followed-up for six months.
Sociodemographic variables and the serum levels of S100A12, sRAGE, esRAGE,
HMGB-1, TNF-α, IFN-γ and CRP were measured. Lung involvement in PTB patients
was assessed by chest radiography. Compared with healthy controls, PTB
patients had increased serum concentrations of S100A12 while sRAGE was
decreased. S100A12 was an independent predictor of disease occurrence (OR
1.873, 95%CI 1.212–2.891, p = 0.004). Under DOTS therapy, S100A12 decreased
significantly after 4 months whereas CRP significantly decreased after 2
months (p < 0.0001). Importantly, although CRP was also an independent
predictor of disease occurrence, only S100A12 was a significant predictor of
lung alveolar infiltration (OR 2.60, 95%CI 1.35–5.00, p = 0.004). These
results suggest that S100A12 has the potential to assess the extent of
alveolar infiltration in PTB
An Observational Study in Hyderabad/India
Background Existing reading schemes for chest X-ray (CXR) used to grade the
extent of disease severity at diagnosis in patients with pulmonary
tuberculosis (PTB) are often based on numerical scores that summate specific
radiographic features. However, since PTB is known to exhibit a wide
heterogeneity in pathology, certain features might be differentially
associated with clinical parameters of disease severity. Objective We aimed to
grade disease severity in PTB patients at diagnosis and after completion of
DOTS treatment by developing a reading scheme based on five different
radiographic manifestations and analyze their association with the clinical
parameters of systemic involvement and infectivity. Methods 141 HIV-negative
adults with newly diagnosed sputum smear-positive PTB were enrolled in a
prospective observational study in Hyderabad, India. The presence and extent
on CXRs of five radiographic manifestations, i.e., lung involvement, alveolar
infiltration, cavitation, lymphadenopathy and pleural effusion, were
classified using the new reading scheme by using a four-quadrant approach. We
evaluated the inter-reader reliability of each manifestation, and its
association with BMI and sputum smear positivity at diagnosis. The presence
and extent of these radiographic manifestations were further compared with
CXRs on completion of DOTS treatment. Results At diagnosis, an average lung
area of 51.7% +/- 23.3% was affected by radiographic abnormalities. 94% of the
patients had alveolar infiltrates, with 89.4% located in the upper quadrants,
suggesting post primary PTB and in 34.8% of patients cavities were found. We
further showed that the extent of affected lung area was a negative predictor
of BMI (β value -0.035, p 0.019). No significant association of BMI with any
of the other CXR features was found. The extent of alveolar infiltrates, along
with the presence of cavitation, were strongly associated with sputum smear
positivity. The microbiological cure rate in our cohort after 6 months of DOTS
treatment was 95%. The extent of the affected lung area in these patients
decreased from 56.0% +/- 21.5% to 31.0 +/- 20% and a decrease was also
observed in the extent of alveolar infiltrates from 98.4% to 25.8% in at least
one quadrant, presence of cavities from 34.8% to 1.6%, lymphadenopathy from
46.8% to 16.1%, and pleural effusion from 19.4% to 6.5%. Conclusions We
established a new assessment scheme for grading disease severity in PTB by
specifically considering five radiographic manifestations which were
differently associated with the BMI and sputum smear positivity, changed to a
different extent after 6 months of treatment and exhibited an excellent
agreement between radiologists. Our results suggest that this reading scheme
might contribute to the estimation of disease severity with respect to
differences in disease pathology. Further studies are needed to determine a
correlation with short and long-term pulmonary function impairment and whether
there would be any benefit in lengthening or modulating therapy based on this
CXR severity assessment
CD4+ T cell cytokine responses to the DAR-901 booster vaccine in BCG-primed adults:A randomized, placebo-controlled trial
<div><p>Background</p><p>DAR-901 is an inactivated whole cell tuberculosis booster vaccine, prepared using a new scalable, broth-grown method from the master cell bank of SRL172, a vaccine previously shown to prevent tuberculosis. This study examined whether DAR-901 (a) induces CD4+ T cell cytokine profiles previously proposed as correlates of protection and (b) has a specific vaccine-induced immunological signature compared to BCG or placebo.</p><p>Methods</p><p>We analysed CD4+ T cell cytokine immune responses from 10 DAR-901 recipients, 9 BCG recipients and 9 placebo recipients from the Phase I DAR-901 MDES trial. In that study, HIV-negative, IGRA-negative participants with prior BCG immunization were randomized (double-blind) to receive three intradermal injections of DAR-901 or saline placebo or two injections of saline placebo followed by an intradermal injection of BCG. Antigen-specific functional and phenotypic CD4+ T cell responses along with effector phenotype of responder cells were measured by intracellular cytokine staining.</p><p>Results</p><p>DAR-901 recipients exhibited increased DAR-901 antigen-specific polyfunctional or bifunctional T cell responses compared to baseline. Vaccine specific CD4+ IFNγ, IL2, TNFα and any cytokine responses peaked at 7 days post-dose 3. Th1 responses predominated, with most responder cells exhibiting a polyfunctional effector memory phenotype. BCG induced greater CD4+ T cell responses than placebo while the more modest DAR-901 responses did not differ from placebo. Neither DAR-901 nor BCG induced substantial or sustained Th17 /Th22 cytokine responses.</p><p>Conclusion</p><p>DAR-901, a TB booster vaccine grown from the master cell bank of SRL 172 which was shown to prevent TB, induced low magnitude polyfunctional effector memory CD4+ T cell responses. DAR-901 responses were lower than those induced by BCG, a vaccine that has been shown ineffective as a booster to prevent tuberculosis disease. These results suggest that induction of higher levels of CD4+ cytokine stimulation may not be a critical or pre-requisite characteristic for candidate TB vaccine boosters.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT02063555" target="_blank">NCT02063555</a>.</p></div
Transcriptomic signatures for diagnosing tuberculosis in clinical practice: a prospective, multicentre cohort study.
BACKGROUND
Blood transcriptomic signatures for diagnosis of tuberculosis have shown promise in case-control studies, but none have been prospectively designed or validated in adults presenting with the full clinical spectrum of suspected tuberculosis, including extrapulmonary tuberculosis and common differential diagnoses that clinically resemble tuberculosis. We aimed to evaluate the diagnostic accuracy of transcriptomic signatures in patients presenting with clinically suspected tuberculosis in routine practice.
METHODS
The Validation of New Technologies for Diagnostic Evaluation of Tuberculosis (VANTDET) study was nested within a prospective, multicentre cohort study in secondary care in England (IDEA 11/H0722/8). Patients (aged ≥16 years) suspected of having tuberculosis in the routine clinical inpatient and outpatient setting were recruited at ten National Health Service hospitals in England for IDEA and were included in VANTDET if they provided consent for genomic analysis. Patients had whole blood taken for microarray analysis to measure abundance of transcripts and were followed up for 6-12 months to determine final diagnoses on the basis of predefined diagnostic criteria. The diagnostic accuracy of six signatures derived from the cohort and three previously published transcriptomic signatures with potentially high diagnostic performance were assessed by calculating area under the receiver-operating characteristic curves (AUC-ROC), sensitivities, and specificities.
FINDINGS
Between Nov 25, 2011, and Dec 31, 2013, 1162 participants were enrolled. 628 participants (aged ≥16 years) were included in the analysis, of whom 212 (34%) had culture-confirmed tuberculosis, 89 (14%) had highly probable tuberculosis, and 327 (52%) had tuberculosis excluded. The novel signature with highest performance for identifying all active tuberculosis gave an AUC-ROC of 0·87 (95% CI 0·81-0·92), sensitivity of 77% (66-87), and specificity of 84% (74-91). The best-performing published signature gave an AUC-ROC of 0·83 (0·80-0·86), sensitivity of 78% (73-83), and specificity of 76% (70-80). For detecting highly probable tuberculosis, the best novel signature yielded results of 0·86 (0·71-0·95), 77% (56-94%), and 77% (57-95%). None of the relevant cohort-derived or previously published signatures achieved the WHO-defined targets of paired sensitivity and specificity for a non-sputum-based diagnostic test.
INTERPRETATION
In a clinically representative cohort in routine practice in a low-incidence setting, transcriptomic signatures did not have adequate accuracy for diagnosis of tuberculosis, including in patients with highly probable tuberculosis where the unmet need is greatest. These findings suggest that transcriptomic signatures have little clinical utility for diagnostic assessment of suspected tuberculosis.
FUNDING
National Institute for Health Research
Multivariate analysis of factors associated with poor treatment outcome.
Multivariate analysis of factors associated with poor treatment outcome.</p
Contains supporting tables.
BackgroundEvidence on factors contributing to poor treatment outcome and healthcare priorities in vulnerable populations affected by tuberculosis (TB) in urban areas of England other than London is needed to inform setting-specific prevention and care policies. We addressed this knowledge gap in a cohort of TB patients and healthcare providers in Birmingham and Leicester, UK.MethodsA mixed-methods study was performed. Logistic regression was used to identify TB patients more likely to have poor treatment outcomes according to clinical and demographic characteristics and social risk factors (SRFs) in a 2013–18 cohort. 25 semi-structured interviews were undertaken in purposely selected individuals (9 patients and 16 healthcare professionals) to glean insights on their healthcare priorities and the factors that contribute to poor treatment outcome.ResultsThe quantitative cohort comprised 2252 patients. Those who were ≥ 55 years of age, foreign-born from Central Europe, East Asia and Sub Saharan Africa and with MDR-TB were more likely to have poor treatment outcomes. According to patients and healthcare professionals, the factors that contribute to vulnerability to develop TB and poor treatment outcomes include poor working and living conditions, inadequate or absent welfare protection, poor primary healthcare responsiveness, treatment duration and side effects. These factors could be addressed by increased networking, partnership and integration between healthcare and social services and better integration between primary and secondary healthcare.ConclusionsIn both cities, being ≥ 55 years of age, having MDR-TB and being of foreign-birth are predictors of unfavourable treatment outcome. Risk of poor treatment outcome and vulnerability seem to be multidimensional. A better understanding of specific vulnerabilities and how they affect patient care pathway is needed to design adequate support programmes.</div
Topic guide for interviewing TB patients.
BackgroundEvidence on factors contributing to poor treatment outcome and healthcare priorities in vulnerable populations affected by tuberculosis (TB) in urban areas of England other than London is needed to inform setting-specific prevention and care policies. We addressed this knowledge gap in a cohort of TB patients and healthcare providers in Birmingham and Leicester, UK.MethodsA mixed-methods study was performed. Logistic regression was used to identify TB patients more likely to have poor treatment outcomes according to clinical and demographic characteristics and social risk factors (SRFs) in a 2013–18 cohort. 25 semi-structured interviews were undertaken in purposely selected individuals (9 patients and 16 healthcare professionals) to glean insights on their healthcare priorities and the factors that contribute to poor treatment outcome.ResultsThe quantitative cohort comprised 2252 patients. Those who were ≥ 55 years of age, foreign-born from Central Europe, East Asia and Sub Saharan Africa and with MDR-TB were more likely to have poor treatment outcomes. According to patients and healthcare professionals, the factors that contribute to vulnerability to develop TB and poor treatment outcomes include poor working and living conditions, inadequate or absent welfare protection, poor primary healthcare responsiveness, treatment duration and side effects. These factors could be addressed by increased networking, partnership and integration between healthcare and social services and better integration between primary and secondary healthcare.ConclusionsIn both cities, being ≥ 55 years of age, having MDR-TB and being of foreign-birth are predictors of unfavourable treatment outcome. Risk of poor treatment outcome and vulnerability seem to be multidimensional. A better understanding of specific vulnerabilities and how they affect patient care pathway is needed to design adequate support programmes.</div