Browsing by Author "Esmail, Aliasgar"

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    A retrospective review of computed tomography pulmonary angiography image quality and the impact on diagnostic outcome at a tertiary South African hospital
    (2022) Holtzhausen, Jeanette; Moosa, Sulaiman E I; Esmail, Aliasgar
    Background: Computed Tomography Pulmonary Angiography (CTPA) is a key diagnostic imaging modality for pulmonary embolism. These studies are technically challenging to perform. Degraded image quality may result from inadequate pulmonary artery contrast opacification, motion- or streak artefact as well as patient factors. Literature suggests that poor quality scans could lead to indeterminate outcomes and suboptimal clinical decisions with risk of increased mortality. Objective: The study aimed to benchmark the image quality and diagnostic outcomes of CTPA studies in the setting of a tertiary Southern African hospital. The relationships between CTPA image quality and diagnostic and clinical outcomes, as well as related variables such as health risk factors and effective dose, were also explored. Methods: A retrospective cross-sectional study evaluated consecutive CTPA studies performed at Groote Schuur hospital, Cape Town, South Africa, over a six-month period from 1 July 2018 to 31 December 2018. All studies performed for suspected acute or chronic pulmonary embolism (PE) in patients 18 years and older were included. Records were reviewed regarding image quality and diagnostic and clinical outcomes. Correlation tests were performed between continuous variables and chisquare tests among categorical variables. Results: During the study period, 231 CTPA studies were performed, of which 226 were included. The sample comprised 69 % females and 31 % males, with median age of 45 years (range 19-84 years). In 204 (90.3 %) of studies, adequate contrast opacification ≥ 211 HU was obtained. Inadequate contrast opacification was present in 9.7% of cases, in line with previous research. Motion and/ or streak artefacts were present in 45.6%. PE was confirmed in 22% and excluded in 65 % of cases. The number of scans with indeterminate diagnostic results only comprised 30 out of the 226 scans reviewed, however, the percentage was higher than previously reported (13.3% vs mean of 6.4 % in published literature). Amongst these, inadequate contrast opacification occurred in 15 (50 %) of studies and artefacts degraded image quality in 24 (80 %). Patients with a diagnosis of PE had higher mortality, compared to patients with negative and indeterminate scans. Clinicians interpreted indeterminate scans as negative, however, this did not impact adversely on mortality. Conclusions It was encouraging that the percentage of studies with adequate contrast opacification met published bench-marks. Although the higher-than-expected percentage of indeterminate studies may partially be explained by the prevalence of artefacts, it requires further investigation. This did not, however, translate into adverse mortality outcomes.
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    Diagnosing tuberculosis in hospitalized HIV-infected individuals who cannot produce sputum: is urine lipoarabinomannan testing the answer?
    (BioMed Central, 2017-12-28) Sabur, Natasha F; Esmail, Aliasgar; Brar, Mantaj S; Dheda, Keertan
    Background: Up to one third of HIV-infected individuals with suspected TB are sputum-scarce. The Alere Determine™ TB LAM Ag lateral flow strip test can be used to diagnose TB in HIV-infected patients with advanced immunosuppression. However, how urine LAM testing should be incorporated into testing algorithms and in the context of specific patient sub-groups remains unclear. Methods: This study represents a post hoc sub-group analysis of data from a randomized multi-center parent study. The study population consisted of hospitalized HIV-infected patients with suspected TB who were unable to produce sputum and who underwent urine LAM testing. The diagnostic utility of urine LAM for TB in this group was compared to the performance of urine LAM in patients who did produce a sputum sample in the parent study. Results: There were a total of 187 and 2341 patients in the sputum-scarce and sputum-producing cohorts, respectively. 80 of the sputum-scarce patients underwent testing with urine LAM. In comparison to those who did produce sputum, sputum-scarce patients had a younger age, a lower Karnofsky performance score, and a lower weight and BMI at admission. A greater proportion of sputum-scarce patients were urine LAM positive, compared to those who were able to produce sputum (31% vs. 21%, p = 0.04). A higher proportion of sputum-scarce patients died within 8 weeks of admission (32% vs. 24%, p = 0.013). We inferred that 19% of HIV-infected sputum-scarce patients suspected of TB were diagnosed with tuberculosis by urine LAM testing, with an estimated positive predictive value of 63% (95% CI 43–82%). Conclusions: Urine LAM testing can effectively identify tuberculosis in HIV-infected patients who are at a higher risk of mortality yet are unable to generate a sputum sample for diagnostic testing. Our findings support the use of urine LAM testing in sputum-scarce hospitalized HIV-infected patients, and its incorporation into diagnostic algorithms for this patient population.
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    Efficacy and safety of novel and repurposed drugs for the treatment of drug-resistant tuberculosis
    (2020) Olayanju, Olatunde; Dheda, Keertan; Esmail, Aliasgar
    Background: There is widespread concern about the rise of drug-resistant TB because treatment outcomes of affected patients remain poor and treatment options are limited. After more than a forty-year gap without any breakthrough discovery, several new (bedaquiline and delamanid) and repurposed drugs (linezolid) are increasingly becoming available for use. However, data regarding the efficacy and safety of these drugs in drug-resistant TB patients, with or without HIV infection, from a real-life programmatic setting are lacking. This thesis aims to address that knowledge gap and provide information for management of drug-resistant TB in countries with high disease burden. Methods: A total of 326 drug resistant TB patients were prospectively followed up between January 2008 and April 2018. The efficacy and safety of two new drugs (bedaquiline and delamanid) and one repurposed drug (linezolid) was determined in these patients in three studies. In the first study, 24 months treatment outcomes and adverse event profiles were compared between extensively drug resistant (XDR) TB patients who received programmatic treatment regimens with the backbone of second line injectables and fluoroquinolones (nonbedaquiline-based) and those who received a bedaquiline- and/ or linezolid-based treatment regimen. The second study determined the frequency of system-specific adverse events associated with linezolid. The third study interrogated the safety and effectiveness of a strengthened treatment regimen containing a combination of delamanid and bedaquiline in patients with poor prognostic features compared to bedaquiline-based regimen. Results: In the first study, patients who received a bedaquiline-based treatment regimen had a significantly greater favourable outcome rate (66.2% vs 13.2%; p<0.001) ), more than a fourfold reduction in treatment failure rate (5.9% vs 26%; p<0.001 ) and less than a half of mortality rate compared to patients who received a non-bedaquiline-based regimen. The bedaquiline survival and favourable outcome effect remained significant in HIV-infected patients (p<0.001). The second study showed that linezolid interruption was common in patients receiving a bedaquiline-based treatment regimen, and that system-specific toxicity occurred within predictable time frames. It also showed that anaemia (77.3% versus 7.3%; p<0.001), peripheral neuropathy (63.6% versus 14.6%; p=0.003), and optic neuritis (18.2% versus 9.8%; p=0.34) occurred more frequently in linezolid interrupters than in non-interrupters. The third study showed that the use of delamanid-bedaquiline combination regimen was safe and efficacious in drug resistant TB patients with poor prognosis when compared with outcomes in the less sick patients who received a bedaquiline-based regimen. It also showed no significant difference in culture conversion rate at 6 months (92.5% versus 81.8%; p=0.26) or favourable treatment outcome rate (63.4% versus 67.5%; p=0.66) between the two groups. Although patients who received the combination regimen had more frequent occurrence of QTcF prolongation greater than 60 ms from baseline (p=0.001) and more episodes of QTcF greater than 450 ms during treatment (p=0.001), none of them were symptomatic or had delamanid or bedaquiline withdrawn from their regimen. Conclusion: These data demonstrated that new and repurposed drugs remarkably improved treatment outcomes in patients with drug-resistant TB. Although linezolid, which is an important component of the bedaquiline-based treatment regimen, is often associated with system-specific adverse events, these occurred at predictable time frames thereby guiding physicians to make informed management decisions. Lastly, drug resistant TB patients with poor prognosis may benefit from a regimen containing delamanid and bedaquiline which seems relatively safe from an adverse event perspective. These data, despite some limitations, make a case for a widespread and accelerated roll-out of new and repurposed drugs for the treatment of drug resistant TB.
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    Newer and novel sputum versus non-sputum-based tools for the diagnosis of active tuberculosis in different patient sub-populations
    (2025) Esmail, Aliasgar; Dheda, Keertan
    Background Pulmonary tuberculosis (PTB) has a spectrum of presentation ranging from sub clinical/minimally symptomatic disease on one end, usually in community-based patients, to overt symptomatic TB with hospitalisation on the severe end of the spectrum. This spectrum of sub-clinical and clinical presentation of TB along with the site of TB (pulmonary vs. Extra-pulmonary TB) generate a number of sub-populations. Current diagnostic tools are not a ‘one size fits all' and have important differential limitations in these patient sub-populations including those with pauci-bacillary disease (e.g., in HIV-infected patients, minimally symptomatic patients with low burden disease in the community, and in patients with extra-pulmonary TB). Thus, the overarching objective of this PhD was to evaluate the diagnostic performance of frontline tests, including the newer and more sensitive Xpert Ultra and urine LAM in key active TB patient sub-populations (wherein data are limited). The main themes and sub-populations included in my thesis are as follows: 1) Hospitalised HIV-Infected patients (patients in the severe end of PTB spectrum): To determine the optimal and most cost-efficient diagnostic strategy incorporating sputum and LAM (lipoarabinomannan) for the detection of TB (chapter 1). 2) Smear-negative TB: Independent confirmation on the performance of the more sensitive Xpert Ultra (Cepheid MTB/RIF Ultra) in sputum archived samples (chapter 2). 3) Community-based minimally symptomatic patients (patient in the non-severe end of the PTB spectrum): Evaluation of point-of-care (POC) sputum Xpert Ultra for detection of TB in minimally symptomatic/at-risk population for TB and its impact in detecting potentially infectious patients (chapter 3). 4) Extra-pulmonary TB (TB serositis): Evaluation on the performance of conventional diagnostic tools, including Xpert Ultra in tuberculous pericarditis (chapter 4) and pleuritis (chapter 5) compared to a novel immunodiagnostic tool (IRISA-TB). Methods (sub-populations are underlined) In Chapter 1, I describe an evaluation of an algorithm that describes the optimal & cost efficient strategy to combine sputum GeneXpert and urine LAM (tests that are recommended by the WHO) in a hospitalized HIV-infected sub-population: This comprised a post-hoc analysis of 561 HIV-infected sputum-expectorating patients that was part of a larger parent trial. 5 different diagnostic strategies using sputum culture as a reference standard were explored (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 also performed. In Chapter 2, I evaluated the performance of GeneXpert Ultra in 272 selected and well characterized archived sputum samples including 104 patients with smear negative TB and 102 non-TB with a history of previous TB to accentuate and evaluate the clinical significance of trace readouts (i.e., a readout that usually corresponds to the detection of a very small amount of TB DNA). Assay-specific limit-of-detection (LOD) experiments were conducted using serial dilutions of Mycobacterium tuberculosis H37Rv to confirm the assay's detection threshold. In In Chapter 3, I evaluated the diagnostic performance of point-of-care (POC) Xpert Ultra for the detection of TB in minimally symptomatic community-based sub-population: 5,274 participants were rapidly screened to enrol 584 patients with suspected pulmonary TB from peri-urban high burden communities of Cape Town, South Africa. The utility of POC-Xpert Ultra in detecting likely infectious patients was also specifically evaluated. In Chapter 4, I described the diagnostic performance of pericardial fluid unstimulated interferon gamma (measured using the novel IRISA-TBTM test) and compared it to other same-day tests including Xpert Ultra and adenosine deaminase (ADA) in 99 South African patients with suspected pericardial TB using a composite reference standard including pericardial fluid, pericardial tissue TB culture, pericardial tissue histopathology and response to TB treatment. Similarly, In Chapter 5, I described the diagnostic performance of pleural fluid unstimulated interferon gamma (measured using the novel IRISA-TBTM test) and compared to other same-day tests including Xpert Ultra and adenosine deaminase (ADA) in 207 individuals from Cape Town, South Africa and Vellore, India. A composite reference standard including pleural fluid, pleural tissue TB culture, pericardial tissue histopathology and response to TB treatment was used to define the composite reference standard for TB. Results: Chapter 1: In the HIV-infected hospitalised patient sub-population, 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). Chapter 2: Xpert Ultra had a lower sputum-specific LOD compared to that of the G4 version of Xpert MTB/RIF (9 vs. 184 cfu/mL). 94% in both forms of EPTB in chapters 4 & 5. Conclusions: Overall, the performance of currently available diagnostic tools varied in different subpopulations due to differential mycobacterial load, the compartment interrogated, patient phenotype (e.g. HIV-infected), testing strategy, and clinical context (e.g. hospitalized versus community-based). Main findings from each chapter as summarized as follows: Main conclusion in chapter 1: Xpert-Ultra had a considerably lower limit-of-detection compared to older Xpert-MTB/RIF assay, however, trace-readouts in the context of previous TB, reduced the specificity of the assay slight (<5%). A third of the trace results (3/9) were likely false positive. Main conclusion in chapter 2: In sputum-expectorating hospitalized patients with advanced HIV and access to both Xpert and LAM, concurrent testing with sputum Xpert and urine LAM may be the best and most cost-effective strategy for diagnosing TB in this sub-population. Main conclusion in chapter 3: POC-Xpert Ultra, when used as part of a community-based ACF, missed ~50% of patients with culture-positive TB. However, Xpert detected almost all likely infectious cases. Main conclusions in chapters 4 & 5: Conventional TB diagnostic tests performed poorly in pericardial and pleural TB. IRISA-TBTM, a novel same-day immunodiagnostic test, outperformed Xpert Ultra for the diagnosis of pericardial and pleural TB. These data have implications for the clinical utility of newer diagnostic tools in patient sub-populations from TB and HIV endemic settings.