SUNScholar - Browsing by Author "Malherbe, Stephanus T."

Browsing by Author "Malherbe, Stephanus T."

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Cardiovascular risk and endothelial function in people living with HIV/AIDS: design of the multi-site, longitudinal EndoAfrica study in the Western Cape Province of South Africa
(BioMed Central, 2017-01-07) Strijdom, Hans; De Boever, Patrick; Walzl, Gerhard; Essop, M. Faadiel; Nawrot, Tim S.; Webster, Ingrid; Westcott, Corli; Mashele, Nyiko; Everson, Frans; Malherbe, Stephanus T.; Stanley, Kim; Kessler, Harald H.; Stelzl, Evelyn; Goswami, Nandu
Background: There is growing evidence of an interaction between HIV-infection, anti-retroviral therapy (ART) and cardiovascular diseases (CVD). Epidemiological studies in Europe and North America have been observing a shift towards an increased incidence of coronary heart disease and acute myocardial infarctions in HIV-infected populations compared to the general population even after adjusting for traditional cardiovascular risk factors. Despite South Africa (and sub-Saharan Africa, SSA) being regarded as the epicentre of the global HIV epidemic, very little is known about the prevalence of cardiovascular risk factors and precursors of vascular disease in HIV-infected populations in this region. The knowledge gap is further widened by the paucity of data from prospective studies. We present the rationale, objectives and key methodological features of the EndoAfrica study, which aims to determine whether HIVinfection and ART are associated with altered cardiovascular risk and changes in vascular endothelial structure and function in adults living in the Western Cape Province of South Africa. Methods: In this longitudinal study, comprehensive cardiovascular assessments of HIV-negative and HIV-positive (with and without ART) study participants are performed by clinical and biochemical screening for traditional cardiovascular risk factors and biomarkers of CVD. Vascular and endothelial function is determined by brachial artery flow-mediated dilatation (FMD), carotid-intima-thickness (IMT) measurements and quantitative retinal blood vessel analyses, complemented by vascular endothelial biomarker assays. Finally, we aim to statistically determine whether HIVinfection and/or ART are associated with increased cardiovascular risk and vascular endothelial dysfunction, and determine whether there is progression/regression in these endpoints 18 months after the baseline assessments. Discussion: The EndoAfrica study provides a unique opportunity to recruit a cohort of HIV-infected patients and HIVnegative controls who will be comprehensively and longitudinally assessed for cardiovascular risk and disease profile with vascular endothelial function as a potentially important intermediate cardiovascular phenotype. To our knowledge, it is the first time that such a systematic study has been established in the context of SSA and South Africa.
Combining host-derived biomarkers with patient characteristics improves signature performance in predicting tuberculosis treatment outcomes
(Springer Nature, 2020) Sivakumaran, Dhanasekaran; Jenum, Synne; Vaz, Mario; Selvam, Sumithra; Ottenhoff, Tom H. M.; Haks, Marielle C.; Malherbe, Stephanus T.; Doherty, Mark; Ritz, Christian; Grewal, Harleen M. S.
Tuberculosis (TB) is a global health concern. Treatment is prolonged, and patients on anti-TB therapy (ATT) often experience treatment failure for various reasons. There is an urgent need to identify signatures for early detection of failure and initiation of a treatment switch.We investigated how gene biomarkers and/or basic patient characteristics could be used to define signatures for treatment outcomes in Indian adult pulmonary-TB patients treated with standard ATT. Using blood samples at baseline, a 12-gene signature combined with information on gender, previously-diagnosed TB, severe thinness, smoking and alcohol consumption was highly predictive of treatment failure at 6 months. Likewise a 4-protein biomarker signature combined with the same patient characteristics was almost as highly predictive of treatment failure. Combining biomarkers and basic patient characteristics may be useful for predicting and hence identification of treatment failure at an early stage of TB therapy.
Diabetes mellitus among pulmonary tuberculosis patients from 4 tuberculosis-endemic countries : the TANDEM study
(Oxford University Press, 2019-04) Ugarte-Gil, Cesar; Alisjahbana, Bachti; Ronacher, Katharina; Lelia Riza, Anca; Koesoemadinata, Raspati C.; Malherbe, Stephanus T.; Cioboata, Ramona; Llontop, Juan Carlos; Kleynhans, Leanie; Lopez, Sonia; Santoso, Prayudi; Marius, Ciontea; Villaizan, Katerine; Ruslami, Rovina; Walzl, Gerhard; Panduru, Nicolae Mircea; Dockrell, Hazel M.; Hill, Philip C.; Allister, Susan Mc; Pearson, Fiona; Moore, David A. J.; Critchley, Julia A.; van Crevel, Reinout
Background Diabetes mellitus (DM) increases active tuberculosis (TB) risk and worsens TB outcomes, jeopardizing TB control especially in TB-endemic countries with rising DM prevalence rates. We assessed DM status and clinical correlates in TB patients across settings in Indonesia, Peru, Romania, and South Africa. Methods Age-adjusted DM prevalence was estimated using laboratory glycated hemoglobin (HbA1c) or fasting plasma glucose in TB patients. Detailed and standardized sociodemographic, anthropometric, and clinical measurements were made. Characteristics of TB patients with or without DM were compared using multilevel mixed-effect regression models with robust standard errors. Results Of 2185 TB patients (median age 36.6 years, 61.2% male, 3.8% human immunodeficiency virus–infected), 12.5% (267/2128) had DM, one third of whom were newly diagnosed. Age-standardized DM prevalence ranged from 10.9% (South Africa) to 19.7% (Indonesia). Median HbA1c in TB–DM patients ranged from 7.4% (Romania) to 11.3% (Indonesia). Compared to those without DM, TB–DM patients were older and had a higher body mass index (BMI) (P value < .05). Compared to those with newly diagnosed DM, TB patients with diagnosed DM had higher BMI and HbA1c, less severe TB, and more frequent comorbidities, DM complications, and hypertension (P value < .05). Conclusions We show that DM prevalence and clinical characteristics of TB–DM vary across settings. Diabetes is primarily known but untreated, hyperglycemia is often severe, and many patients with TB–DM have significant cardiovascular disease risk and severe TB. This underlines the need to improve strategies for better clinical management of combined TB and DM.
Elucidation of a human urine metabolite as a seryl-leucine glycopeptide and as a biomarker of eﬀective anti-tuberculosis therapy
(American Chemical Society, 2018-12-26) Fitzgerald, Bryna L.; Islam, M. Nurul; Graham, Barbara; Mahapatra, Sebabrata; Webb, Kristofor; Boom, W. Henry; Malherbe, Stephanus T.; Joloba, Moses L.; Johnson, John L.; Winter, Jill; Walzl, Gerhard; Belisle, John T.
ENGLISH ABSTRACT: The evaluation of new tuberculosis (TB) therapies is limited by the paucity of biomarkers to monitor treatment response. Previous work detected an uncharacterized urine metabolite with a molecular mass of 874.3547 Da that showed promise as a biomarker for successful TB treatment. Using mass spectrometry combined with enzymatic digestions, the metabolite was structurally characterized as a seryl-leucine core 1 Oglycosylated peptide (SLC1G) of human origin. Examination of SLC1G in urine revealed a signiﬁcant abundance increase in individuals with active TB versus their household contacts and healthy controls. Moreover, diﬀerential decreases in SLC1G levels were observed by week one in TB patients during successful treatment versus those that failed treatment. The SLC1G levels were also associated with clinical parameters used to measure bacterial burden (GeneXpert) and inﬂammation (positron emission tomography-computed tomography (PET-CT)). These results demonstrate the importance of metabolite identiﬁcation and provide strong evidence for applying SLC1G as a biomarker of TB treatment response.
Expression and production of the SERPING1-encoded endogenous complement regulator C1-inhibitor in multiple cohorts of tuberculosis patients
(Elsevier, 2020-03-13) Lubbers, Rosalie; Sutherland, Jayne S.; Goletti, Delia; De Paus, Roelof A.; Dijkstra, Douwe J.; Van Moorsel, Coline H. M.; Veltkamp, Marcel; Vestjens, Stefan M. T.; Bos, Willem J. W.; Petrone, Linda; Malherbe, Stephanus T.; Walzl, Gerhard; Gelderman, Kyra A.; Groeneveld, Geert H.; Geluk, Annemieke; Ottenhoff, Tom H. M.; Joosten, Simone A.; Trouw, Leendert A.
Background To facilitate better discrimination between patients with active tuberculosis (TB) and latent TB infection (LTBI), whole blood transcriptomic studies have been performed to identify novel candidate host biomarkers. SERPING1, which encodes C1-inhibitor (C1-INH), the natural inhibitor of the C1-complex has emerged as candidate biomarker. Here we collated and analysed SERPING1 expression data and subsequently determined C1-INH protein levels in four cohorts of patients with TB. Methods SERPING1 expression data were extracted from online deposited datasets. C1-INH protein levels were determined by ELISA in sera from individuals with active TB, LTBI as well as other disease controls in geographically diverse cohorts. Findings SERPING1 expression was increased in patients with active TB compared to healthy controls (8/11 cohorts), LTBI (13/14 cohorts) and patients with other (non-TB) lung-diseases (7/7 cohorts). Serum levels of C1-INH were significantly increased in The Gambia and Italy in patients with active TB relative to the endemic controls but not in South Africa or Korea. In the largest cohort (n = 50), with samples collected longitudinally, normalization of C1-INH levels following successful TB treatment was observed. This cohort, also showed the most abundant increase in C1-INH, and a positive correlation between C1q and C1-INH levels. Combined presence of increased levels of both C1q and C1-INH had high specificity for active TB (96 %) but only very modest sensitivity 38 % compared to the endemic controls. Interpretation SERPING1 transcript expression is increased in TB patients, while serum protein levels of C1-INH were increased in half of the cohorts analysed.
The functional response of B cells to antigenic stimulation : a preliminary report of latent tuberculosis
(Public Library of Science, 2016-04) Du Plessis, Willem J.; Kleynhans, Leanie; Du Plessis, Nelita; Stanley, Kim; Malherbe, Stephanus T.; Maasdorp, Elizna; Ronacher, Katharina; Chegou, Novel N.; Walzl, Gerhard; Loxton, Andre G.
Mycobacterium tuberculosis (M.tb) remains a successful pathogen, causing tuberculosis disease numbers to constantly increase. Although great progress has been made in delineating the disease, the host-pathogen interaction is incompletely described. B cells have shown to function as both effectors and regulators of immunity via non-humoral methods in both innate and adaptive immune settings. Here we assessed specific B cell functional interaction following stimulation with a broad range of antigens within the LTBI milieu. Our results indicate that B cells readily produce pro- and anti-inflammatory cytokines (including IL-1β, IL-10, IL-17, IL-21 and TNF-α) in response to stimulation. TLR4 and TLR9 based stimulations achieved the greatest secreted cytokine-production response and BCG stimulation displayed a clear preference for inducing IL-1β production. We also show that the cytokines produced by B cells are implicated strongly in cell-mediated communication and that plasma (memory) B cells (CD19+CD27+CD138+) is the subset with the greatest contribution to cytokine production. Collectively our data provides insight into B cell responses, where they are implicated in and quantifies responses from specific B cell phenotypes. These findings warrant further functional B cell research with a focus on specific B cell phenotypes under conditions of active TB disease to further our knowledge about the contribution of various cell subsets which could have implications for future vaccine development or refined B cell orientated treatment in the health setting.
Host urine immunological biomarkers as potential candidates for the diagnosis of tuberculosis
(Elsevier, 2020-10-01) Eribo, Osagie A.; Leqheka, Monkoe S.; Malherbe, Stephanus T.
Objective: To investigate the potential of host urinary biomarkers as diagnostic candidates for tuberculosis (TB). Methods: Adults self-presenting with symptoms requiring further investigation for TB were enrolled in Cape Town, South Africa. Participants were later classified as having TB or other respiratory diseases (ORD) using results from TB confirmatory tests. The concentrations of 29 analytes were evaluated in urine samples from participants using the Luminex platform, and their diagnostic potential was assessed using standard statistical approaches. Results: Of the 151 study participants, 34 (22.5%) were diagnosed with TB and 26 (17.2%) were HIV-positive. Seven biomarkers showed potential as TB diagnostic candidates, with accuracy improving (in HIV-positives) when stratified according to HIV status (area under the receiver operating characteristics curve; AUC ≥0.80). In HIV-positive participants, a four-marker biosignature (sIL6R, MMP-9, IL-2Ra, IFN-γ) diagnosed TB with AUC of 0.96, sensitivity of 85.7% (95% confidence interval (CI) 42.1-99.6%), and specificity of 94.7% (95% CI 74.0-99.9%). In HIV-negatives, the most promising was a two-marker biosignature (sIL6R and sIL-2Ra), which diagnosed TB with AUC of 0.76, sensitivity of 53.9% (95% CI 33.4-73.4%), and specificity of 79.6% (95% CI 70.3-87.1%). Conclusions: Urinary host inflammatory biomarkers possess TB diagnostic potential but may be influenced by HIV infection. The results of this study require validation in larger studies. Keywords: Biomarker; Biosignature; Diagnosis; Inflammatory biomarker; Tuberculosis; Urine.
Impact of intermediate hyperglycaemia as well as diabetes on immune dysfunction in tuberculosis
(Oxford University Press, 2020-01) Eckold, Clare; Kumar, Vinod; Weiner, January; Alisjahbana, Bachti; Riza, Anca-Lelia; Ronacher, Katharina; Coronel, Jorge; Kerry-Barnard, Sarah; Malherbe, Stephanus T.; Kleynhans, Leanie; Stanley, Kim; Ruslami, Rovina; Ioana, Mihai; Ugarte-Gil, Cesar; Walzl, Gerhard; van Crevel, Reinout; Wijmenga, Cisca; Critchley, Julia A.; Dockrell, Hazel M.; Cliff, Jacqueline M.
Background: People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity. Methods: Whole blood samples were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to <6.5%), TB-only patients, and healthy controls in 4 countries: South Africa, Romania, Indonesia, and Peru. Differential blood gene expression was determined by RNA-seq (n = 249). Results: Diabetes increased the magnitude of gene expression change in the host transcriptome in TB, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with IH and TB exhibited blood transcriptomes much more similar to patients with diabetes-TB than to patients with only TB. Both diabetes-TB and IH-TB patients had a decreased type I interferon response relative to TB-only patients. Conclusions: Comorbidity in individuals with both TB and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type I interferon responses in comorbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with IH, showing that altered immunity to TB may also be present in this group. The TB disease outcomes in individuals with IH diagnosed with TB should be investigated further.
Performance and immune characteristics of bronchoalveolar lavage by research bronchoscopy in pulmonary tuberculosis and other lung diseases in the Western Cape, South Africa
(BMC (part of Springer Nature), 2019-06-01) Young, Carly; Ahlers, Petri; Hiemstra, Andriette M.; Loxton, Andre G.; Gutschmidt, Andrea; Malherbe, Stephanus T.; Walzl, Gerhard; Du Plessis, Nelita
Background: Tuberculosis (TB) remains a debilitating, deadly disease that warrants innovative research tools to fully understand the pathogenesis and host immune responses, particularly at the site of infection and disease. In this regard, bronchoscopies with bronchoalveolar lavage (BAL) serve as a valuable technique for site of disease sample retrieval for further clinical- and basic research. Here we investigate the feasibility of research bronchoscopies in a low/middle-income area, where TB remains rife, and assess the value of retrieved BAL cells (BALC) for downstream fluorescent-based cellular evaluations. Methods: Using quantitative and qualitative methods, we evaluate the outcomes, safety, tolerability, participant -perception and -experience, while also providing insight into participant recruitment and screening processes of our study. Using light microscopy differential counting for BALC analysis, we evaluate the cellular composition of BAL fluid (BALF) from TB patients, healthy community controls and patients with other lung diseases. We also use flow cytometry to describe the challenges associated with fluorescence-based phenotypic analysis of autofluorescent BALC. Results: Our findings suggest that research bronchoscopies are safe, acceptable procedures for research participants and are indeed a feasible technique for future study design. We also suggest that the majority of participants are receptive to the proposition of a second research bronchoscopy. This poses an important avenue for research entailing follow-up investigations of the same study participant. Furthermore, our results show that smoking is characterized by retrieval of BALC containing particulate matter, that interferes with fluorescence-based flow cytometry data analysis. Based on light microscopy differential cell counting, our findings suggest that there are differences in the cell yields and cellular composition of the BALF between TB patients, healthy community controls and patients with other lung diseases. We also report on subject characteristics and demographic factors, namely gender and age, that have the potential to affect cell yields and cellular data of BALF. Conclusions: These findings will serve as a valuable reference for appropriate planning and design of studies involving clinical bronchoscopies for TB and lung disease research.
Prospective evaluation of host biomarkers other than interferon gamma in QuantiFERON Plus supernatants as candidates for the diagnosis of tuberculosis in symptomatic individuals
(Elsevier, 2019-07-15) Manngo, Portia M.; Gutschmidt, Andrea; Snyders, Candice I.; Mutavhatsindi, Hygon; Manyelo, Charles M.; Makhoba, Nonjabulo S.; Ahlers, Petri; Hiemstra, Andriette; Stanley, Kim; McAnda, Shirley; Kidd, Martin; Malherbe, Stephanus T.; Walzl, Gerhard; Chegou, Novel N.
Background: There is an urgent need for new tools for the diagnosis of TB. We evaluated the usefulness recently described host biomarkers in supernatants from the newest generation of the QuantiFERON test (QuantiFERON Plus) as tools for the diagnosis of active TB. Methods: We recruited individuals presenting at primary health care clinics in Cape Town, South Africa with symptoms requiring investigation for TB disease, prior to the establishment of a clinical diagnosis. Participants were later classified as TB or other respiratory diseases (ORD) based on the results of clinical and laboratory tests. Using a multiplex platform, we evaluated the concentrations of 37 host biomarkers in QuantiFERON Plus supernatants from study participants as tools for the diagnosis of TB. Results: Out of 120 study participants, 35(29.2%) were diagnosed with active TB, 69(57.5%) with ORD whereas 16(13.3%) were excluded. 14(11.6%) of the study participants were HIV infected. Although individ- ual host markers showed potential as diagnostic candidates, the main finding of the study was the identi- fication of a six-marker biosignature in unstimulated supernatants (Apo-ACIII, CXCL1, CXCL9, CCL8, CCL-1, CD56) which diagnosed TB with sensitivity and specificity of 73.9%(95% CI; 51.6–87.8) and 87.6%(95% CI; 77.2–94.5), respectively, after leave-one-out cross validation. Combinations between TB-antigen specific biomarkers also showed potential (sensitivity of 77.3% and specificity of 69.2%, respectively), with multi- ple biomarkers being significantly different between TB patients, Quantiferon Plus Positive and Quantif- eron Plus negative individuals with ORD, regardless of HIV status. Conclusions: Biomarkers detected in QuantiFERON Plus supernatants may contribute to adjunctive diag- nosis of TB.
Quantitative 18F-FDG PET-CT scan characteristics correlate with tuberculosis treatment response
(SpringerOpen (part of Springer Nature), 2020-02-10) Malherbe, Stephanus T.; Chen, Ray Y.; Dupont, Patrick; Kant, Ilse; Kriel, Magdalena; Loxton, Andre G.; Smith, Bronwyn; Beltran, Caroline G. G.; Van Zyl, Susan; McAnda, Shirely; Abrahams, Charmaine; Maasdorp, Elizna; Doruyter, Alex; Via, Laura E.; Barry, Clifton E.; Alland, David; Richards, Stephanie G.; Ellman, Annare; Peppard, Thomas; Belisle, John; Tromp, Gerard; Ronacher, Katharina; Warwick, James M.; Winter, Jill; Walzl, Gerhard
Background: There is a growing interest in the use of F-18 FDG PET-CT to monitor tuberculosis (TB) treatment response. Tuberculosis lung lesions are often complex and diffuse, with dynamic changes during treatment and persisting metabolic activity after apparent clinical cure. This poses a challenge in quantifying scan-based markers of burden of disease and disease activity. We used semi-automated, whole lung quantification of lung lesions to analyse serial FDG PET-CT scans from the Catalysis TB Treatment Response Cohort to identify characteristics that best correlated with clinical and microbiological outcomes. Results: Quantified scan metrics were already associated with clinical outcomes at diagnosis and 1 month after treatment, with further improved accuracy to differentiate clinical outcomes after standard treatment duration (month 6). A high cavity volume showed the strongest association with a risk of treatment failure (AUC 0.81 to predict failure at diagnosis), while a suboptimal reduction of the total glycolytic activity in lung lesions during treatment had the strongest association with recurrent disease (AUC 0.8 to predict pooled unfavourable outcomes). During the first year after TB treatment lesion burden reduced; but for many patients, there were continued dynamic changes of individual lesions. Conclusions: Quantification of FDG PET-CT images better characterised TB treatment outcomes than qualitative scan patterns and robustly measured the burden of disease. In future, validated metrics may be used to stratify patients and help evaluate the effectiveness of TB treatment modalities.
Quantitative 18F-FDG PET-CT scan characteristics correlate with tuberculosis treatment response
(SpringerOpen (part of Springer Nature), 2020) Malherbe, Stephanus T.; Chen, Ray Y.; Dupont, Patrick; Kant, Ilse; Kriel, Magdalena; Loxton, Andre G.; Smith, Bronwyn; Beltran, Caroline G. G.; Van Zyl, Susan; McAnda, Shirely; Abrahams, Charmaine; Maasdorp, Elizna; Doruyter, Alex; Via, Laura E.; Barry, Clifton E.; Alland, David; Griffith- Richards, Stephanie; Ellman, Annare; Peppard, Thomas; Belisle, John; Tromp, Gerard; Ronacher, Katharina; Warwick, James M.; Winter, Jill; Walzl, Gerhard
Background: There is a growing interest in the use of F-18 FDG PET-CT to monitor tuberculosis (TB) treatment response. Tuberculosis lung lesions are often complex and diffuse, with dynamic changes during treatment and persisting metabolic activity after apparent clinical cure. This poses a challenge in quantifying scan-based markers of burden of disease and disease activity. We used semi-automated, whole lung quantification of lung lesions to analyse serial FDG PET-CT scans from the Catalysis TB Treatment Response Cohort to identify characteristics that best correlated with clinical and microbiological outcomes. Results: Quantified scan metrics were already associated with clinical outcomes at diagnosis and 1 month after treatment, with further improved accuracy to differentiate clinical outcomes after standard treatment duration (month 6). A high cavity volume showed the strongest association with a risk of treatment failure (AUC 0.81 to predict failure at diagnosis), while a suboptimal reduction of the total glycolytic activity in lung lesions during treatment had the strongest association with recurrent disease (AUC 0.8 to predict pooled unfavourable outcomes). During the first year after TB treatment lesion burden reduced; but for many patients, there were continued dynamic changes of individual lesions. Conclusions: Quantification of FDG PET-CT images better characterised TB treatment outcomes than qualitative scan patterns and robustly measured the burden of disease. In future, validated metrics may be used to stratify patients and help evaluate the effectiveness of TB treatment modalities.
A semi-automatic technique to quantify complex tuberculous lung lesions on 18F-fluorodeoxyglucose positron emission tomography/computerised tomography images
(Springer Open, 2018-06-25) Malherbe, Stephanus T.; Dupont, Patrick; Kant, Ilse; Ahlers, Petri; Kriel, Magdalena; Loxton, Andre G.; Chen, Ray Y.; Via, Laura E.; Thienemann, Friedrich; Wilkinson, Robert J; Barry, Clifton E.; Griffith-Richards, Stephanie; Ellman, Annare; Ronacher, Katharina; Winter, Jill; Walzl, Gerhard; Warwick, James M.
Background: There is a growing interest in the use of 18F-FDG PET-CT to monitor tuberculosis (TB) treatment response. However, TB causes complex and widespread pathology, which is challenging to segment and quantify in a reproducible manner. To address this, we developed a technique to standardise uptake (Z-score), segment and quantify tuberculous lung lesions on PET and CT concurrently, in order to track changes over time. We used open source tools and created a MATLAB script. The technique was optimised on a training set of five pulmonary tuberculosis (PTB) cases after standard TB therapy and 15 control patients with lesion-free lungs. Results: We compared the proposed method to a fixed threshold (SUV > 1) and manual segmentation by two readers and piloted the technique successfully on scans of five control patients and five PTB cases (four cured and one failed treatment case), at diagnosis and after 1 and 6 months of treatment. There was a better correlation between the Z-score-based segmentation and manual segmentation than SUV > 1 and manual segmentation in terms of overall spatial overlap (measured in Dice similarity coefficient) and specificity (1 minus false positive volume fraction). However, SUV > 1 segmentation appeared more sensitive. Both the Z-score and SUV > 1 showed very low variability when measuring change over time. In addition, total glycolytic activity, calculated using segmentation by Z-score and lesion-to-background ratio, correlated well with traditional total glycolytic activity calculations. The technique quantified various PET and CT parameters, including the total glycolytic activity index, metabolic lesion volume, lesion volumes at different CT densities and combined PET and CT parameters. The quantified metrics showed a marked decrease in the cured cases, with changes already apparent at month one, but remained largely unchanged in the failed treatment case. Conclusions: Our technique is promising to segment and quantify the lung scans of pulmonary tuberculosis patients in a semi-automatic manner, appropriate for measuring treatment response. Further validation is required in larger cohorts.
Targeting of myeloid-derived suppressor cells by all-trans retinoic acid as host-directed therapy for human tuberculosis
(Elsevier Inc., 2021-06) Leukes, Vinzeigh N.; Dorhoi, Anca; Malherbe, Stephanus T.; Maasdorp, Elizna; Khoury, Justine; McAnda, Shirley; Walzl, Gerhard; Du Plessis, Nelita
Conventional anti-tuberculosis (TB) therapies comprise lengthy antibiotic treatment regimens, exacerbated by multi-drug resistant and extensively drug resistant mycobacterial strains. We assessed the ability of all-trans retinoic acid (ATRA), as repurposed compound serving as host-directed therapy (HDT), to counteract the suppressive effects of myeloid-derived suppressor cells (MDSCs) obtained from active TB cases (untreated or during week one of treatment) on T-cell responsiveness. We show for the first time that MDSCs suppress non-specific T-cell activation and production of interleukin (IL)-2, IL-4, IL-13 and GM-CSF via contact-dependent mechanisms. ATRA treatment decreases MDSC frequency, but fails to mature MDSCs to non-suppressive, terminally differentiated myeloid cells and does not restore T-cell function or cytokine production in the presence of MDSCs. The impact of ATRA treatment on improved immunity, using the concentration tested here, is likely to be minimal, but further identification and development of MDSC-targeting TB host-directed therapies are warranted.

Browsing by Author "Malherbe, Stephanus T."

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