A human model to better understand tuberculosis immunopathogenesis and facilitate vaccine development is urgently needed.
We evaluated the feasibility, safety, and immunogenicity of live bacillus ...Calmette-Guérin (BCG) in a lung-oriented controlled human infection model.
We recruited 106 healthy South African participants with varying degrees of tuberculosis susceptibility. Live BCG, sterile PPD, and saline were bronchoscopically instilled into separate lung segments (
= 65). A control group (
= 34) underwent a single bronchoscopy without challenge. The primary outcome was safety. Cellular and antibody immune signatures were identified in BAL before and 3 days after challenge using flow cytometry, ELISA, RNA sequencing, and mass spectrometry.
The frequency of adverse events was low (9.4%;
= 10), similar in the challenge versus control groups (
= 0.8), and all adverse events were mild and managed conservatively in an outpatient setting. The optimal PPD and BCG dose was 0.5 TU and 10
cfu, respectively, based on changes in BAL cellular profiles (
= 0.02) and antibody responses (
= 0.01) at incremental doses before versus after challenge. At 10
versus 10
cfu BCG, there was a significant increase in number of differentially expressed genes (367 vs. 3;
< 0.001) and dysregulated proteins (64 vs. 0;
< 0.001). Immune responses were highly setting specific (
vs.
) and compartment specific (BAL vs. blood) and localized to the challenged lung segments.
A lung-oriented mycobacterial controlled human infection model using live BCG and PPD is feasible and safe. These data inform the study of tuberculosis immunopathogenesis and strategies for evaluation and development of tuberculosis vaccine candidates.
The diagnosis of tuberculosis (TB) in HIV-infected patients is challenging. Both a urinary lipoarabinomannan (LAM) test (Alere TB LAM) and GeneXpert-MTB/RIF (Xpert) are useful for the diagnosis of ...TB. However, how to optimally integrate Xpert and LAM tests into clinical practice algorithms remain unclear. We performed a
analysis of 561 HIV-infected sputum-expectorating patients (median CD4 count of 130 cells/ml) from a previously published randomized controlled trial evaluating the LAM test in hospitalized HIV-infected patients with suspected TB. We evaluated 5 different diagnostic strategies using sputum culture as a reference standard (Xpert alone, LAM alone, sequential Xpert followed by LAM and vice versa LAM in Xpert-negative patients and Xpert in LAM-negative patients, and both tests concurrently LAM + Xpert). A cost-consequence analysis was performed. Strategy-specific sensitivity and specificity, using culture as a reference, were similar with the Xpert-only and sequential and concurrent strategies. However, when any positive TB-specific test was used as a reference, the incremental yield of LAM over Xpert was 29.6% (45/152) and that of Xpert over LAM was 75% (84/11). The incremental yield of LAM increased with decreasing CD4 count. The costs per TB case diagnosed were similar for the sequential and concurrent strategies ($1,617 to $1,626). In sputum-expectorating hospitalized patients with advanced HIV and access to both tests, concurrent testing with Xpert and LAM may be the best strategy for diagnosing TB. These data inform clinical practice in settings where TB and HIV are endemic.
Mobile health (mHealth) technologies for HIV care are developed to provide diagnostic support, health education, risk assessment and self‐monitoring. They aim to either improve or replace part of the ...therapeutic relationship. Part of the therapeutic relationship is affective, with the emergence of feelings and emotion, yet little research on mHealth for HIV care focuses on affect and HIV testing practices. Furthermore, most of the literature exploring affect and care relations with the introduction of mHealth is limited to the European and Australian context. This article explores affective dimensions of HIV self‐testing using a smartphone app strategy in Cape Town, South Africa and Montréal, Canada. This study is based on observation notes, 41 interviews and 1 focus group discussion with study participants and trained HIV healthcare providers from two quantitative studies evaluating the app‐based self‐test strategy. Our paper reveals how fear, apathy, judgement, frustration and comfort arise in testing encounters using the app and in previous testing experiences, as well as how this relates to care providers and test materials. Attending to affective aspects of this app‐based self‐testing practice makes visible certain affordances and limitations of the app within the therapeutic encounter and illustrates how mHealth can contribute to HIV care.
Background. Tuberculous pericarditis (TBP) is a paucibacillary disease, where host biomarkers such as unstimulated interferon gamma (IRISA-TB) have high diagnostic accuracy. However, DNA-based ...diagnostic tests (GeneXpert Ultra), more sensitive than an earlier versions, have recently become available. Given that the diagnosis of TBP is challenging, we performed a comparative diagnostic accuracy study comparing both assays. Methods. We recruited 99 consecutive patients with suspected TBP in Cape Town, South Africa. Definite TBP was defined by microbiological confirmation of tuberculosis (TB) on pericardial fluid culture or an alternative polymerase chain reaction-based test (GeneXpert MTB/RIF) or by use of sputum (polymerase chain reaction or culture). Probable TBP was defined as a high clinical suspicion of TB accompanied by anti-TB treatment, while non-TBP was defined as negative microbiological test results for TB without initiation of TB treatment and/or the presence of an alternative diagnosis. Results. There were 39 patients with definite TBP, 35 with probable TBP, and 23 with non- TBP. Approximately 70% of participants who received TB treatment were HIV coinfected. Overall, IRISA-TB was more sensitive than Xpert Ultra (88.6% 95% CI, 74.1%-95.5% vs 71.5% 55.0%-83.7%, n = 53) and significantly more sensitive in participants who were HIV uninfected (100% 95% CI, 72.3%-100.0% vs 60% 31.3%-83.2%, P = .03). In patients with definite and probable TBP combined (n = 84), sensitivity was significantly higher with IRISA-TB (77.3% 95% CI, 65.9%-85.8% vs 37.9 27.2%-50.0%, P < .0001). A similar pattern was seen in persons who were HIV uninfected (88.3% vs 35.3%, P = .002). Specificity was high for both assays (>95%). Conclusions. Unstimulated interferon gamma (IRISA-TB) was significantly more sensitive than Xpert Ultra for the diagnosis of TB pericarditis in a TB-endemic resource-poor setting. Keywords. accuracy; diagnosis; GeneXpert Ultra; interferon gamma; tuberculous pericarditis.
Abstract
Background
Tuberculous pericarditis (TBP) is a paucibacillary disease, where host biomarkers such as unstimulated interferon γ (IRISA-TB) have high diagnostic accuracy. However, DNA-based ...diagnostic tests (GeneXpert Ultra), more sensitive than an earlier versions, have recently become available. Given that the diagnosis of TBP is challenging, we performed a comparative diagnostic accuracy study comparing both assays.
Methods
We recruited 99 consecutive patients with suspected TBP in Cape Town, South Africa. Definite TBP was defined by microbiological confirmation of tuberculosis (TB) on pericardial fluid culture or an alternative polymerase chain reaction–based test (GeneXpert MTB/RIF) or by use of sputum (polymerase chain reaction or culture). Probable TBP was defined as a high clinical suspicion of TB accompanied by anti-TB treatment, while non-TBP was defined as negative microbiological test results for TB without initiation of TB treatment and/or the presence of an alternative diagnosis.
Results
There were 39 patients with definite TBP, 35 with probable TBP, and 23 with non-TBP. Approximately 70% of participants who received TB treatment were HIV coinfected. Overall, IRISA-TB was more sensitive than Xpert Ultra (88.6% 95% CI, 74.1%–95.5% vs 71.5% 55.0%–83.7%, n = 53) and significantly more sensitive in participants who were HIV uninfected (100% 95% CI, 72.3%–100.0% vs 60% 31.3%–83.2%, P = .03). In patients with definite and probable TBP combined (n = 84), sensitivity was significantly higher with IRISA-TB (77.3% 95% CI, 65.9%–85.8% vs 37.9 27.2%–50.0%, P < .0001). A similar pattern was seen in persons who were HIV uninfected (88.3% vs 35.3%, P = .002). Specificity was high for both assays (>95%).
Conclusions
Unstimulated interferon γ (IRISA-TB) was significantly more sensitive than Xpert Ultra for the diagnosis of TB pericarditis in a TB-endemic resource-poor setting.
Abstract
Background
According to the United Nations Programme on HIV/AIDS (UNAIDS), in 2019, two out of every seven new human immunodeficiency virus (HIV) infections, globally, were among young ...people aged 15 to 24 years old. HIV self-testing (HIVST) is a convenient strategy that helps increase knowledge of HIV serostatus in the young. In 2012, the Food and Drug Administration (FDA) approved the OraQuick In-Home HIV Test with a reported sensitivity of 92%. Digital supports such as applications (Apps) and websites, in conjunction with oral self-tests, have demonstrated a high feasibility, acceptability, and impact, yet data on accuracy with digital supports remain largely unexplored.
Methods
We performed a secondary data analysis of a quasi-randomized trial of oral HIVST with HIVSmart! conducted in South African township populations (2017-2019). We hypothesized that HIVSmart! guided interpretation increased test accuracy. We evaluated the diagnostic accuracy of the HIVSmart! guided interpretation of an oral self-test result against the reference standard (dual Elisa and HIV RNA). Stored picture of a self-test result was uploaded by the participants.
Results
Accuracy data from (n=1489) HIVST participants versus reference standard (2 rapid tests and HIV RNA) demonstrated:
Sensitivity: 95.52% (95% CI: 94.48%-96.56%)
Specificity: 99.93% (95% CI: 99.79%-100.00%)
Positive Predictive Value: 99.22% (95% CI: 98.78%-99.67%)
Negative Predictive Value: 99.57% (95% CI: 99.24%-99.90%)
Conclusion
With the App, we noticed an improved sensitivity to 95.5% (from 92% with self-tests without the use of the App), specificity high at 99%, together with high positive and negative predictive values. Findings demonstrate that Smart-App based digital interpretation removed subjectivity and increased accuracy of test result interpretation, together with recording and storage of data for monitoring purposes. Findings suggest that Smart-App based readers could be useful adjuncts to improve the accuracy estimations of self-tests, translating to increased trust and confidence in self-tests.
Disclosures
All Authors: No reported disclosures
Tuberculosis remains a major problem globally, and is the leading cause of death from an infectious agent. Drug-resistant tuberculosis threatens to marginalise the substantial gains that have ...recently been made in the fight against tuberculosis. Drug-resistant TB has significant associated morbidity and a high mortality, with only half of all multidrug-resistant TB patients achieving a successful treatment outcome. Patients with drug-resistant TB in resource-poor settings are now gaining access to newer and repurposed anti-tuberculosis drugs such as bedaquiline, delamanid and linezolid. However, with ever increasing rates of co-morbidity, there is little guidance on how to manage complex patients with drug-resistant TB. We address that knowledge gap, and outline principles underpinning the management of drug-resistant TB in special situations including HIV co-infection, pregnancy, renal disease, liver disease, diabetes, and in the critically ill.
•Novel techniques are encouraged to identify nontuberculosis mycobacteria (NTM).•An algorithm incorporating direct molecular identification of NTM is suggested.•Rapid NTM identification can assist in ...decision-making and prompt treatment initiation.
Nontuberculous mycobacteria (NTM) are a group of acid-fast mycobacteria other than Mycobacterium tuberculosis complex (MTBC) that cause pulmonary disease that is similar to the disease caused by MTBC. International guidelines for the diagnosis of pulmonary NTM disease are rigid and have remained unchanged for nearly 2 decades. In this opinion piece, we provide a new perspective on the traditional criteria by suggesting a diagnostic algorithm that incorporates direct molecular identification of NTM performed on raw sputum specimens (using Sanger or targeted deep sequencing approaches, among others) paired with traditional culture methods. Our approach ensures a more rapid diagnosis of pulmonary NTM disease, thus, facilitating timeous clinical diagnosis, and prompt treatment initiation, where indicated, and leverages recent advances in novel molecular techniques into routine NTM identification practice.
Breast cancer remains one of the leading causes of cancer-associated death worldwide. Conventional treatment is associated with substantial toxicity and suboptimal efficacy. We, therefore, developed ...and evaluated the in vitro efficacy of an autologous dendritic cell (DC) vaccine to treat breast cancer. We recruited 12 female patients with stage 1, 2, or 3 breast cancer and matured their DCs with autologous tumour-specific lysate, a toll-like receptor (TLR)-3 and 7/8 agonist, and an interferon-containing cocktail. The efficacy of the vaccine was evaluated by its ability to elicit a cytotoxic T-lymphocyte response to autologous breast cancer cells in vitro. Matured DCs (≥ 60% upregulation of CD80, CD86, CD83, and CCR7) produced high levels of the Th1 effector cytokine, IL12-p70 (1.2 ng/ml;
p
< 0.0001), compared to DCs pulsed with tumour lysate, or matured with an interferon-containing cocktail alone. We further showed that matured DCs enhance antigen-specific CD8 + T-cell responses to HER-2 (4.5%;
p
< 0.005) and MUC-1 (19%;
p
< 0.05) tetramers. The mature DCs could elicit a robust and dose-dependent antigen-specific cytotoxic T-lymphocyte response (65%) which was tumoricidal to autologous breast cancer cells in vitro compared to T-lymphocytes that were primed with autologous lysate loaded-DCs (
p
< 0.005). Lastly, we showed that the mature DCs post-cryopreservation maintained high viability, maintained their mature phenotype, and remained free of endotoxins or mycoplasma. We have developed a DC vaccine that is cytotoxic to autologous breast cancer cells in vitro. The tools and technology generated here will now be applied to a phase I/IIa clinical trial.
The Lancet Respiratory Medicine Commission on drug-resistant tuberculosis was published in 2017, which comprehensively reviewed and provided recommendations on various aspects of the disease. Several ...key new developments regarding drug-resistant tuberculosis are outlined in this Commission Update. The WHO guidelines on treating drug-resistant tuberculosis were updated in 2019 with a reclassification of second line anti-tuberculosis drugs. An injection-free MDR tuberculosis treatment regimen is now recommended. Over the past 3 years, advances in treatment include the recognition of the safety and mortality benefit of bedaquiline, the finding that the 9-11 month injectable-based 'Bangladesh' regimen was non-inferior to longer regimens, and promising interim results of a novel 6 month 3-drug regimen (bedaquiline, pretomanid, and linezolid). Studies of explanted lungs from patients with drug-resistant tuberculosis have shown substantial drug-specific gradients across pulmonary cavities, suggesting that alternative dosing and drug delivery strategies are needed to reduce functional monotherapy at the site of disease. Several controversies are discussed including the optimal route of drug administration, optimal number of drugs constituting a regimen, selection of individual drugs for a regimen, duration of the regimen, and minimal desirable standards of antibiotic stewardship. Newer rapid nucleic acid amplification test platforms, including point-of-care systems that facilitate active case-finding, are discussed. The rapid diagnosis of resistance to other drugs, (notably fluoroquinolones), and detection of resistance by targeted or whole genome sequencing will probably change the diagnostic landscape in the near future.
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