Imperial College London

ProfessorRobertWilkinson

Faculty of MedicineDepartment of Infectious Disease

Professor in Infectious Diseases
 
 
 
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Contact

 

r.j.wilkinson Website

 
 
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Location

 

Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

481 results found

Davies M-A, Morden E, Rosseau P, Arendse J, Bam J-L, Boloko L, Cloete K, Cohen C, Chetty N, Dane P, Heekes A, Hsiao N-Y, Hunter M, Hussey H, Jacobs T, Jassat W, Kariem S, Kassanjee R, Laenen I, Roux SL, Lessells R, Mahomed H, Maughan D, Meintjes G, Mendelson M, Mnguni A, Moodley M, Murie K, Naude J, Ntusi NAB, Paleker M, Parker A, Pienaar D, Preiser W, Prozesky H, Raubenheimer P, Rossouw L, Schrueder N, Smith B, Smith M, Solomon W, Symons G, Taljaard J, Wasserman S, Wilkinson RJ, Wolmarans M, Wolter N, Boulle Aet al., 2022, Outcomes of laboratory-confirmed SARS-CoV-2 infection during resurgence driven by Omicron lineages BA.4 and BA.5 compared with previous waves in the Western Cape Province, South Africa., Int J Infect Dis

OBJECTIVE: We aimed to compare clinical severity of Omicron BA.4/BA.5 infection with BA.1 and earlier variant infections among laboratory-confirmed SARS-CoV-2 cases in the Western Cape, South Africa, using timing of infection to infer the lineage/variant causing infection. METHODS: We included public sector patients aged ≥20 years with laboratory-confirmed COVID-19 between 1-21 May 2022 (BA.4/BA.5 wave) and equivalent prior wave periods. We compared the risk between waves of (i) death and (ii) severe hospitalization/death (all within 21 days of diagnosis) using Cox regression adjusted for demographics, comorbidities, admission pressure, vaccination and prior infection. RESULTS: Among 3,793 patients from the BA.4/BA.5 wave and 190,836 patients from previous waves the risk of severe hospitalization/death was similar in the BA.4/BA.5 and BA.1 waves (adjusted hazard ratio (aHR) 1.12; 95% confidence interval (CI) 0.93; 1.34). Both Omicron waves had lower risk of severe outcomes than previous waves. Prior infection (aHR 0.29, 95% CI 0.24; 0.36) and vaccination (aHR 0.17; 95% CI 0.07; 0.40 for at least 3 doses vs. no vaccine) were protective. CONCLUSION: Disease severity was similar amongst diagnosed COVID-19 cases in the BA.4/BA.5 and BA.1 periods in the context of growing immunity against SARS-CoV-2 due to prior infection and vaccination, both of which were strongly protective.

Journal article

Maitre T, Bonnet M, Calmy A, Raberahona M, Rakotoarivelo RA, Rakotosamimanana N, Ambrosioni J, Miró JM, Debeaudrap P, Muzoora C, Davis A, Meintjes G, Wasserman S, Wilkinson R, Eholié S, Nogbou FE, Calvo-Cortes M-C, Chazallon C, Machault V, Anglaret X, Bonnet Fet al., 2022, Intensified tuberculosis treatment to reduce the mortality of HIV-infected and uninfected patients with tuberculosis meningitis (INTENSE-TBM): study protocol for a phase III randomized controlled trial., Trials, Vol: 23

BACKGROUND: Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis (TB), particularly in sub-Saharan Africa. Current anti-TB treatment is poorly effective since TBM mortality reaches 40% in HIV-negative patients and up to 70% in HIV-co-infected patients. To reduce TBM-induced morbidity and mortality, the INTENSE-TBM trial evaluates two interventions in both HIV-infected and uninfected patients: an anti-TB treatment intensification using oral high-dose rifampicin (35 mg/kg daily) and linezolid (1200 mg daily and then 600 mg daily) during the first 8 weeks of the anti-TB treatment and the use of adjunctive aspirin (200 mg daily). METHODS: This is a randomized controlled, phase III, multicenter, 2 × 2 factorial plan superiority trial. The trial has four arms, combining the two experimental treatments (intensified TBM regimen and aspirin) with the two reference treatments (WHO standard TB treatment and placebo), and is open-label for anti-TB treatment and double-blind placebo-controlled for aspirin treatment. This trial is conducted in adults or adolescents of age ≥15 years with TBM defined as "definite," "probable," or "possible" using Tuberculosis Meningitis International Research Consortium criteria, in four African countries: Ivory Coast, Madagascar, Uganda, and South Africa. The primary outcome is all-cause death between inclusion and week 40. DISCUSSION: The INTENSE-TBM trial represents a key opportunity to enhance TBM treatment with widely available existing drugs notably in high-incidence settings of both TB and HIV. The trial design is pragmatic and the results will permit early and effective applications in TBM patient care, in both HIV and TB high-incidence countries. TRIAL REGISTRATION: ClinicalTrials.gov NCT04145258. Registered on October 30, 2019.

Journal article

Davis AG, Dreyer AJ, Albertyn C, Maxebengula M, Stek C, Wasserman S, Marais S, Bateman K, Solms M, Joska J, Wilkinson RJ, Nightingale Set al., 2022, Cognitive Impairment in Tuberculous Meningitis., Clin Infect Dis

BACKGROUND: Cognitive impairment is reported as a common complication in adult tuberculous meningitis (TBM), yet few studies have systematically assessed the frequency and nature of impairment. Moreover, the impact of impairment on functioning and medication adherence is not described. METHODS: A cognitive test battery (10 measures assessing 7 cognitive domains) was administered to 34 participants with HIV-associated TBM 6 months post-diagnosis. Cognitive performance was compared to a comparator group of 66 people living with HIV (PLWH) without a history of TB. A secondary comparison was made between TBM cases and 26 participants with HIV 6-months post diagnosis of TB outside the central nervous system (CNS). Impact on functioning was evaluated, including through assessment of medication adherence. RESULTS: In TBM, 16/34 (47%) of participants had low performance on cognitive testing. Cognition was impaired across all domains. Global cognitive performance was significantly lower in TBM cases compared to PLWH (mean T-score 41 vs 48, p < 0.001). TBM cases also had lower global cognition compared to those with non-CNS TB (mean global T score 41 vs 46, p = 0.016). Functional outcomes did not significantly correlate with cognitive performance in the sub-group of participants where this was assessed (n = 19). CONCLUSIONS: Low cognitive performance following HIV-associated TBM is common. This effect is independent of, and additional to, effects of HIV and non-CNS TB disease. Further studies are needed to understand longer term outcomes, clarify the association with treatment adherence, a key predictor of outcome in TBM, and develop context-specific tools to identify individuals with cognitive difficulties to improve outcomes in TBM.

Journal article

Fendler A, Shepherd STC, Au L, Wu M, Harvey R, Wilkinson KA, Schmitt AM, Tippu Z, Shum B, Farag S, Rogiers A, Carlyle E, Edmonds K, Del Rosario L, Lingard K, Mangwende M, Holt L, Ahmod H, Korteweg J, Foley T, Barber T, Emslie-Henry A, Caulfield-Lynch N, Byrne F, Deng D, Kjaer S, Song O-R, Queval CJ, Kavanagh C, Wall EC, Carr EJ, Caidan S, Gavrielides M, MacRae JI, Kelly G, Peat K, Kelly D, Murra A, Kelly K, O'Flaherty M, Shea RL, Gardner G, Murray D, Popat S, Yousaf N, Jhanji S, Tatham K, Cunningham D, Van As N, Young K, Furness AJS, Pickering L, Beale R, Swanton C, Gandhi S, Gamblin S, Bauer DLV, Kassiotis G, Howell M, Nicholson E, Walker S, Wilkinson RJ, Larkin J, Turajlic Set al., 2022, Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer, Cell Reports Medicine, Vol: 3, ISSN: 2666-3791

Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination.

Journal article

Morfill C, Pankratova S, Machado P, Fernando NK, Regoutz A, Talamona F, Pinna A, Klosowski M, Wilkinson RJ, Fleck RA, Xie F, Porter AE, Kiryushko Det al., 2022, Nanostars Carrying Multifunctional Neurotrophic Dendrimers Protect Neurons in Preclinical In Vitro Models of Neurodegenerative Disorders, ACS APPLIED MATERIALS & INTERFACES, ISSN: 1944-8244

Journal article

Wouters E, Stek C, Swartz A, Buyze J, Schutz C, Thienemann F, Wilkinson RJ, Meintjes G, Lynen L, Nostlinger Cet al., 2022, Prednisone for the prevention of tuberculosis-associated IRIS (randomized controlled trial): Impact on the health-related quality of life, Frontiers in Psychology, Vol: 13, ISSN: 1664-1078

Background: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an important complication in patients with HIV-associated tuberculosis (TB) starting antiretroviral treatment (ART) in sub-Saharan Africa. The PredART-trial recently showed that prophylactic prednisone reduces the incidence of paradoxical TB-IRIS by 30% in a population at high risk. This paper reports the impact of the intervention on health-related quality of life (HRQoL), a secondary endpoint of the trial, measured by an amended version of the PROQOL-HIV instrument—the instrument’s validity and reliability is also assessed.Methods: A total of 240 adult participants (antiretroviral treatment (ART)-naïve, TB-HIV co-infected with CD4 count ≤100 cells/μL) were recruited and randomized (1:1) to (1) a prednisone arm or (2) a placebo arm. In this sub-study of the PredART-trial we evaluated (1) the performance of an HIV-specific HR-QoL instrument amended for TB-IRIS, i.e., the PROQOL-HIV/TB in patients with HIV-associated TB starting ART (reliability, internal and external construct validity and invariance across time) and (2) the impact of prednisone on self-reported HR-QoL in this population through mixed models.Results: The PROQOL-HIV/TB scale displayed acceptable internal reliability and good internal and external validity. This instrument, including the factor structure with the eight sub-dimensions, can thus be applied for measuring HR-QoL among HIV-TB patients at high risk for TB-IRIS. Prophylactic prednisone was statistically significantly associated only with the ‘Physical Health and Symptoms’-subscale: a four-week course of prednisone resulted in an earlier improvement in the physical dimension of HR-QoL compared to placebo.Conclusion: We demonstrated that the PROQOL-HIV/TB scale adequately measures different aspects of self-reported HR-QoL in HIV-TB patients. Although more research is needed to understand how other domains related to H

Journal article

Spies R, Schutz C, Ward A, Balfour A, Shey M, Nicol M, Burton R, Sossen B, Wilkinson R, Barr D, Meintjes Get al., 2022, Rifampicin resistance and mortality in patients hospitalised with HIV-associated tuberculosis, Southern African Journal of HIV Medicine, Vol: 23, ISSN: 1608-9693

Background: Patients with HIV and drug-resistant tuberculosis (TB) are at high risk of death. Objectives: We investigated the association between rifampicin-resistant TB (RR-TB) and mortality in a cohort of patients who were admitted to hospital at the time of TB diagnosis. Method: Adults hospitalised at Khayelitsha Hospital and diagnosed with HIV-associated TB during admission, were enrolled between 2013 and 2016. Clinical, biochemical and microbiological data were prospectively collected and participants were followed up for 12 weeks. Results: Participants with microbiologically confirmed TB (n = 482) were enrolled a median of two days (interquartile range [IQR]: 1-3 days) following admission. Fifty-three participants (11.0%) had RR-TB. Participants with rifampicin-susceptible TB (RS-TB) received appropriate treatment a median of one day (IQR: 1-2 days) following enrolment compared to three days (IQR: 1-9 days) in participants with RR-TB. Eight participants with RS-TB (1.9%) and six participants with RR-TB (11.3%) died prior to the initiation of appropriate treatment. Mortality at 12 weeks was 87/429 (20.3%) in the RS-TB group and 21/53 (39.6%) in the RR-TB group. RR-TB was a significant predictor of 12-week mortality (hazard ratio: 1.88; 95% confidence interval: 1.07-3.29; P = 0.03). Conclusion: Mortality at 12 weeks in participants with RR-TB was high compared to participants with RS-TB. Delays in the initiation of appropriate treatment and poorer regimen efficacy are proposed as contributors to higher mortality in hospitalised patients with HIV and RR-TB.

Journal article

Amaral E, Foreman TW, Namasivayam S, Hilligan KL, Kauffman K, Bomfim CCB, Costa D, Barreto-Duarte B, Gurgel-Rocha C, Santana MF, Cordeiro-Santos M, Du Bruyn E, Riou C, Aberman K, Wilkinson RJ, Barber DL, Mayer-Barber K, Andrade BB, Sher AFet al., 2022, GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection, Journal of Experimental Medicine, Vol: 219, ISSN: 0022-1007

Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes both immunopathology and bacterial dissemination. Glutathione peroxidase-4 (Gpx4) is an enzyme that plays a critical role in preventing iron-dependent lipid peroxidation–mediated cell death (ferroptosis), a process previously implicated in the necrotic pathology seen in Mtb-infected mice. Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide support for the role of ferroptosis in Mtb-induced necrosis and implicate the Gpx4/GSH axis as a target for host-directed therapy of tuberculosis.

Journal article

del Rosario RCH, Poschmann J, Lim C, Cheng CY, Kumar P, Riou C, Ong ST, Gerges S, Hajan HS, Kumar D, Marzuki M, Lu X, Lee A, Wijaya GC, Rayan NA, Zhuang Z, Du Bruyn E, Chee CBE, Lee B, Lum J, Zolezzi F, Poidinger M, Rotzschke O, Khor CC, Wilkinson RJ, Wang YT, Chandy GK, De Libero G, Singhal A, Prabhakar Set al., 2022, Histone acetylome-wide associations in immune cells from individuals with active Mycobacterium tuberculosis infection (vol 7, pg 312, 2022), NATURE MICROBIOLOGY, Vol: 7, Pages: 1943-1943, ISSN: 2058-5276

Journal article

Hussey H, Davies M-A, Heekes A, Williamson C, Valley-Omar Z, Hardie D, Korsman S, Doolabh D, Preiser W, Maponga T, Iranzadeh A, Engelbrecht S, Wasserman S, Schrueder N, Boloko L, Symons G, Raubenheimer P, Viljoen A, Parker A, Cohen C, Jasat W, Lessells R, Wilkinson RJ, Boulle A, Hsiao Met al., 2022, Higher mortality associated with the SARS-CoV-2 Delta variant in the Western Cape, South Africa, using RdRp target delay as a proxy: a cross-sectional study., Gates Open Research, Vol: 6, Pages: 1-10, ISSN: 2572-4754

Background: The SARS-CoV-2 Delta variant (B.1.617.2) has been associated with more severe disease, particularly when compared to the Alpha variant. Most of this data, however, is from high income countries and less is understood about the variant’s disease severity in other settings, particularly in an African context, and when compared to the Beta variant.Methods: A novel proxy marker, RNA-dependent RNA polymerase (RdRp) target delay in the Seegene AllplexTM 2019-nCoV (polymerase chain reaction) PCR assay, was used to identify suspected Delta variant infection in routine laboratory data. All cases diagnosed on this assay in the public sector in the Western Cape, South Africa, from 1 April to 31 July 2021, were included in the dataset provided by the Western Cape Provincial Health Data Centre (PHDC). The PHDC collates information on all COVID-19 related laboratory tests, hospital admissions and deaths for the province. Odds ratios for the association between the proxy marker and death were calculated, adjusted for prior diagnosed infection and vaccination status.Results: A total of 11,355 cases with 700 deaths were included in this study. RdRp target delay (suspected Delta variant) was associated with higher mortality (adjusted odds ratio [aOR] 1.45; 95% confidence interval [CI]: 1.13-1.86), compared to presumptive Beta infection. Prior diagnosed infection during the previous COVID-19 wave, which was driven by the Beta variant, was protective (aOR 0.32; 95%CI: 0.11-0.92) as was vaccination (aOR [95%CI] 0.15 [0.03-0.62] for complete vaccination [≥28 days post a single dose of Ad26.COV2.S or ≥14 days post second BNT162b2 dose]).Conclusion: RdRp target delay, a proxy for infection with the Delta variant, is associated with an increased risk of mortality amongst those who were tested for COVID-19 in our setting.

Journal article

Makatsa MS, Omondi FMA, Bunjun R, Wilkinson RJ, Riou C, Burgers WAet al., 2022, Characterization of Mycobacterium tuberculosis-Specific Th22 Cells and the Effect of Tuberculosis Disease and HIV Coinfection, JOURNAL OF IMMUNOLOGY, Vol: 209, Pages: 446-455, ISSN: 0022-1767

Journal article

Moseki RM, Barber DL, Bruyn ED, Shey M, Van der Plas H, Wilkinson RJ, Meintjes G, Riou Cet al., 2022, Phenotypic profile of <i>Mycobacterium tuberculosis</i>-specific CD4 T cell responses in HIV-positive patients who develop Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome

<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of co-treatment for TB and HIV-1. We characterized Mtb-specific CD4 T cell phenotype and transcription factor profile associated with the development of TB-IRIS.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We examined the role of CD4 T-cell transcription factors in a murine model of mycobacterial IRIS. In humans, we compared longitudinally on antiretroviral therapy (ART) the magnitude, activation, transcription factor profile and cytotoxic potential of Mtb-specific CD4 T cells between TB-IRIS (n=25) and appropriate non-IRIS control patients (n=18) using flow cytometry.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In the murine model, CD4 T cell expression of Eomes, but not Tbet, was associated with experimentally induced IRIS. In patients, TB-IRIS onset was associated with the expansion of Mtb-specific IFNγ+CD4 T cells (p=0.039). TB-IRIS patients had higher HLA-DR expression (p=0.016), but no differences in the expression of T-bet or Eomes were observed. At TB-IRIS onset, Eomes+Tbet+Mtb-specific IFNγ+CD4+ T cells showed higher expression of Granzyme B in TB-IRIS patients (p=0.026).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>While the murine model of MAC-IRIS suggests that Eomes+CD4 T cells underly IRIS, TB-IRIS was not associated with Eomes expression in patients. Mtb-specific IFNγ+CD4 T cell responses in TB-IRIS patients are differentiated, highly activated and potentially cytotoxic.</jats:p></jats:sec>

Journal article

Fowler PW, Wright C, Spiers H, Zhu T, Baeten EML, Hoosdally SW, Gibertoni Cruz AL, Roohi A, Kouchaki S, Walker TM, Peto TEA, Miller G, Lintott C, Clifton D, Crook DW, Walker AS, Zooniverse Volunteer Community, CRyPTIC Consortiumet al., 2022, A crowd of BashTheBug volunteers reproducibly and accurately measure the minimum inhibitory concentrations of 13 antitubercular drugs from photographs of 96-well broth microdilution plates, eLife, Vol: 11, ISSN: 2050-084X

Tuberculosis is a respiratory disease that is treatable with antibiotics. An increasing prevalence of resistance means that to ensure a good treatment outcome it is desirable to test the susceptibility of each infection to different antibiotics. Conventionally, this is done by culturing a clinical sample and then exposing aliquots to a panel of antibiotics, each being present at a pre-determined concentration, thereby determining if the sample isresistant or susceptible to each sample. The minimum inhibitory concentration (MIC) of a drug is the lowestconcentration that inhibits growth and is a more useful quantity but requires each sample to be tested at a range ofconcentrations for each drug. Using 96-well broth micro dilution plates with each well containing a lyophilised pre-determined amount of an antibiotic is a convenient and cost-effective way to measure the MICs of several drugs at once for a clinical sample. Although accurate, this is still an expensive and slow process that requires highly-skilled and experienced laboratory scientists. Here we show that, through the BashTheBug project hosted on the Zooniverse citizen science platform, a crowd of volunteers can reproducibly and accurately determine the MICs for 13 drugs and that simply taking the median or mode of 11-17 independent classifications is sufficient. There is therefore a potential role for crowds to support (but not supplant) the role of experts in antibiotic susceptibility testing.

Journal article

Davies M-A, Morden E, Rosseau P, Arendse J, Bam J-L, Boloko L, Cloete K, Cohen C, Chetty N, Dane P, Heekes A, Hsiao N-Y, Hunter M, Hussey H, Jacobs T, Jassat W, Kariem S, Kassanjee R, Laenen I, Le Roux S, Lessells R, Mahomed H, Maughan D, Meintjes G, Mendelson M, Mnguni A, Moodley M, Murie K, Naude J, Ntusi NAB, Paleker M, Parker A, Pienaar D, Preiser W, Prozesky H, Raubenheimer P, Rossouw L, Schrueder N, Smith B, Smith M, Solomon W, Symons G, Taljaard J, Wasserman S, Wilkinson RJ, Wolmarans M, Wolter N, Boulle Aet al., 2022, Outcomes of laboratory-confirmed SARS-CoV-2 infection during resurgence driven by Omicron lineages BA.4 and BA.5 compared with previous waves in the Western Cape Province, South Africa., Publisher: PubMedCentral

Objective: We aimed to compare clinical severity of Omicron BA.4/BA.5 infection with BA.1 and earlier variant infections among laboratory-confirmed SARS-CoV-2 cases in the Western Cape, South Africa, using timing of infection to infer the lineage/variant causing infection. Methods: We included public sector patients aged ≥20 years with laboratory-confirmed COVID-19 between 1-21 May 2022 (BA.4/BA.5 wave) and equivalent prior wave periods. We compared the risk between waves of (i) death and (ii) severe hospitalization/death (all within 21 days of diagnosis) using Cox regression adjusted for demographics, comorbidities, admission pressure, vaccination and prior infection. Results: Among 3,793 patients from the BA.4/BA.5 wave and 190,836 patients from previous waves the risk of severe hospitalization/death was similar in the BA.4/BA.5 and BA.1 waves (adjusted hazard ratio [aHR] 1.12; 95% confidence interval [CI] 0.93; 1.34). Both Omicron waves had lower risk of severe outcomes than previous waves. Prior infection (aHR 0.29, 95% CI 0.24; 0.36) and vaccination (aHR 0.17; 95% CI 0.07; 0.40 for boosted vs. no vaccine) were protective. Conclusion: Disease severity was similar amongst diagnosed COVID-19 cases in the BA.4/BA.5 and BA.1 periods in the context of growing immunity against SARS-CoV-2 due to prior infection and vaccination, both of which were strongly protective.

Working paper

Ariza-Vioque E, Ello F, Andriamamonjisoa H, Machault V, González-Martín J, Calvo-Cortés MC, Eholié S, Tchabert GA, Ouassa T, Raberahona M, Rakotoarivelo R, Razafindrakoto H, Rahajamanana L, Wilkinson RJ, Davis A, Maxebengula M, Abrahams F, Muzoora C, Nakigozi N, Nyehangane D, Nanjebe D, Mbega H, Kaitano R, Bonnet M, Debeaudrap P, Miró JM, Anglaret X, Rakotosamimanana N, Calmy A, Bonnet F, Ambrosioni J, INTENSE-TBM Groupet al., 2022, Capacity building in Sub-Saharan Africa as part of the INTENSE-TBM Project during the COVID-19 pandemic, Infectious Diseases and Therapy, Vol: 11, Pages: 1327-1341, ISSN: 2193-8229

Tuberculous meningitis (TBM) is the most severe and disabling form of tuberculosis (TB), with at least 100,000 cases per year and a mortality rate of up to 50% in individuals co-infected with human immunodeficiency virus type 1 (HIV-1). To evaluate the efficacy and safety of an intensified anti-tubercular regimen and an anti-inflammatory treatment, the INTENSE-TBM project includes a phase III randomised clinical trial (TBM-RCT) in four countries in sub-Saharan Africa (SSA). Within this framework, we designed a comprehensive capacity-building work package ensuring all centres had, or would acquire, the ability to conduct the TBM-RCT and developing a network of skilled researchers, clinical centres and microbiology laboratories. Here, we describe these activities, identify strengths/challenges and share tools adaptable to other projects, particularly in low- and lower-middle income countries with heterogeneous settings and during the coronavirus disease 2019 (COVID-19) pandemic. Despite major challenges, TBM-RCT initiation was achieved in all sites, promoting enhanced local healthcare systems and encouraging further clinical research in SSA. In terms of certified trainings, the achievement levels were 95% (124/131) for good clinical practice, 91% (39/43) for good clinical laboratory practice and 91% (48/53) for infection prevention and control. Platform-based research, developed as part of capacity-building activities for specific projects, may be a valuable tool in fighting future infectious diseases and in developing high-level research in Africa.

Journal article

Davies M-A, Kassanjee R, Rousseau P, Morden E, Johnson L, Solomon W, Hsiao N-Y, Hussey H, Meintjes G, Paleker M, Jacobs T, Raubenheimer P, Heekes A, Dane P, Bam J-L, Smith M, Preiser W, Pienaar D, Mendelson M, Naude J, Schrueder N, Mnguni A, Le Roux S, Murie K, Prozesky H, Mahomed H, Rossouw L, Wasserman S, Maughan D, Boloko L, Smith B, Taljaard J, Symons G, Ntusi NAB, Parker A, Wolter N, Jassat W, Cohen C, Lessells R, Wilkinson RJ, Arendse J, Kariem S, Moodley M, Wolmarans M, Cloete K, Boulle A, Western Cape and South African National Departments of Health in collaboration with the National Institute for Communicable Diseases in South Africa Affiliationset al., 2022, Outcomes of laboratory-confirmed SARS-CoV-2 infection in the Omicron-driven fourth wave compared with previous waves in the Western Cape Province, South Africa., Tropical medicine & international health : TM & IH, Vol: 27, Pages: 564-573, ISSN: 1360-2276

<h4>Objectives</h4>The objective was to compare COVID-19 outcomes in the Omicron-driven fourth wave with prior waves in the Western Cape, assess the contribution of undiagnosed prior infection to differences in outcomes in a context of high seroprevalence due to prior infection and determine whether protection against severe disease conferred by prior infection and/or vaccination was maintained.<h4>Methods</h4>In this cohort study, we included public sector patients aged ≥20 years with a laboratory-confirmed COVID-19 diagnosis between 14 November and 11 December 2021 (wave four) and equivalent prior wave periods. We compared the risk between waves of the following outcomes using Cox regression: death, severe hospitalisation or death and any hospitalisation or death (all ≤14 days after diagnosis) adjusted for age, sex, comorbidities, geography, vaccination and prior infection.<h4>Results</h4>We included 5144 patients from wave four and 11,609 from prior waves. The risk of all outcomes was lower in wave four compared to the Delta-driven wave three (adjusted hazard ratio (aHR) [95% confidence interval (CI)] for death 0.27 [0.19; 0.38]. Risk reduction was lower when adjusting for vaccination and prior diagnosed infection (aHR: 0.41, 95% CI: 0.29; 0.59) and reduced further when accounting for unascertained prior infections (aHR: 0.72). Vaccine protection was maintained in wave four (aHR for outcome of death: 0.24; 95% CI: 0.10; 0.58).<h4>Conclusions</h4>In the Omicron-driven wave, severe COVID-19 outcomes were reduced mostly due to protection conferred by prior infection and/or vaccination, but intrinsically reduced virulence may account for a modest reduction in risk of severe hospitalisation or death compared to the Delta-driven wave.

Journal article

Boloko L, Schutz C, Sibiya N, Balfour A, Ward A, Shey M, Nicol MP, Burton R, Wilkinson RJ, Maartens G, Meintjes G, Barr DAet al., 2022, Xpert Ultra testing of blood in severe HIV-associated tuberculosis to detect and measure Mycobacterium tuberculosis blood stream infection: a diagnostic and disease biomarker cohort study, The Lancet Microbe, Vol: 3, ISSN: 2666-5247

BACKGROUND: Mycobacterium tuberculosis bloodstream infection is a leading cause of death in people living with HIV and disseminated bacillary load might be a key driver of disease severity. We aimed to assess Xpert MTB/RIF Ultra (Xpert Ultra) testing of blood as a diagnostic for M tuberculosis bloodstream infection and investigate cycle threshold as a quantitative disease biomarker. METHODS: In this cohort study, we obtained biobanked blood samples from a large and well characterised cohort of adult patients admitted to hospital in Western Cape, South Africa with suspected HIV-associated tuberculosis and a CD4 count less than 350 cells per μL. Patients already receiving antituberculosis therapy were excluded. Samples were obtained on recruitment within 72 h of admission to hospital, and patients were followed up for 12 weeks to determine survival. We tested the biobanked blood samples using the Xpert Ultra platform after lysis and wash processing of the blood. We assessed diagnostic yield (proportion of cases detected, with unavailable test results coded as negative) against a microbiological reference, both as a function of markers of critical-illness and compared with other rapid diagnostics (urine lipoarabinomannan and sputum Xpert). Quantitative blood Xpert Ultra results were evaluated as a disease biomarker by assessing association with disease phenotype defined by principal component analysis of 32 host-response markers. Prognostic value compared to other tuberculosis biomarkers was assessed using likelihood ratio testing of nested models predicting 12-week mortality. FINDINGS: Between Jan 16, 2014, and Oct 19, 2016, of the 659 participants recruited to the parent study, 582 had an available biobanked blood sample. 447 (77%) of 582 met the microbiological reference standard for tuberculosis diagnosis. Median CD4 count was 62 (IQR 221-33) cells per μL, and 123 (21%) of participants died by 12-weeks follow-up. Blood Xpert Ultra was positive in 165 (37%) of

Journal article

Hussey H, Davies M-A, Heekes A, Williamson C, Valley-Omar Z, Hardie D, Korsman S, Doolabh D, Preiser W, Maponga T, Iranzadeh A, Wasserman S, Boloko L, Symons G, Raubenheimer P, Parker A, Schrueder N, Solomon W, Rousseau P, Wolter N, Jassat W, Cohen C, Lessells R, Wilkinson RJ, Boulle A, Hsiao N-Yet al., 2022, Assessing the clinical severity of the Omicron variant in the Western Cape Province, South Africa, using the diagnostic PCR proxy marker of RdRp target delay to distinguish between Omicron and Delta infections - a survival analysis, International Journal of Infectious Diseases, Vol: 118, Pages: 150-154, ISSN: 1201-9712

BACKGROUND: The extent to which the reduced risk of severe disease seen with SARS-CoV-2 Omicron is due to a decrease in variant virulence, or higher levels of population immunity, is currently not clear. METHODS: RdRp target delay (RTD) in the Seegene AllplexTM 2019-nCoV PCR assay is a proxy marker for the Delta variant. The absence of this proxy marker in the transition period was used to identify suspected Omicron infections. Cox regression was performed for the outcome of hospital admission in those who tested positive for SARS-CoV-2 on the Seegene AllplexTM assay from 1 November to 14 December 2021 in the Western Cape Province, South Africa, public sector. Vaccination status and prior diagnosed infection, were adjusted for. RESULTS: 150 cases with RTD and 1486 cases without RTD were included. Cases without RTD had a lower hazard of admission (adjusted Hazard Ratio [aHR] of 0.56, 95%CI 0.34-0.91). Complete vaccination was protective of admission with an aHR of 0.45 (95%CI 0.26-0.77). CONCLUSION: Omicron has resulted in a lower risk of hospital admission, compared to contemporaneous Delta infection, when using the proxy marker of RTD. Under-ascertainment of reinfections with an immune escape variant remains a challenge to accurately assessing variant virulence.

Journal article

Mbandi SK, Painter H, Penn-Nicholson A, Toefy A, Erasmus M, Hanekom WA, Scriba TJ, Lai RPJ, Marais S, Fletcher HA, Meintjes G, Wilkinson RJ, Cotton MF, Pahwa S, Cameron MJ, Nemes Eet al., 2022, Host transcriptomic signatures of tuberculosis can predict immune reconstitution inflammatory syndrome in HIV patients, European Journal of Immunology, Vol: 52, Pages: 1112-1119, ISSN: 0014-2980

Immune reconstitution inflammatory syndrome (IRIS) can be a complication of antiretroviral therapy (ART) in patients with advanced HIV, but its pathogenesis is uncertain. In tuberculosis (TB) endemic countries, IRIS is often associated with mycobacterial infections or Bacille-Calmette-Guerin (BCG) vaccination in children. With no predictive or confirmatory tests at present, IRIS remains a diagnosis of exclusion.We tested whether RISK6 and Sweeney3, validated immune-based blood transcriptomic signatures for TB, could predict or diagnose IRIS in HIV+ children and adults.Transcripts were measured by RT-qPCR in BCG-vaccinated children and by microarray in HIV+ adults with TB including TB meningitis (TBM). Signature scores before ART initiation and up to IRIS diagnosis were compared between participants who did or did not develop IRIS.In children, RISK6 and Sweeney3 discriminated IRIS cases from non-IRIS controls before ART, and at diagnosis. In adults with TB, RISK6 discriminated IRIS cases from controls after half-week on ART and at TB-IRIS onset. In adults with TBM, only Sweeney3 discriminated IRIS cases from controls before ART, while both signatures distinguished cases from controls at TB-IRIS onset.Parsimonious whole blood transcriptomic signatures for TB showed potential to predict and diagnose IRIS in HIV+ children and adults.

Journal article

Fendler A, Shepherd STC, Au L, Wilkinson KA, Wu M, Schmitt AM, Tippu Z, Farag S, Rogiers A, Harvey R, Carlyle E, Edmonds K, Del Rosario L, Lingard K, Mangwende M, Holt L, Ahmod H, Korteweg J, Foley T, Barber T, Emslie-Henry A, Caulfield-Lynch N, Byrne F, Shum B, Gerard CL, Deng D, Kjaer S, Song O-R, Queval C, Kavanagh C, Wall EC, Carr EJ, Namjou S, Caidan S, Gavrielides M, MacRae JI, Kelly G, Peat K, Kelly D, Murra A, Kelly K, O'Flaherty M, Shea RL, Gardner G, Murray D, Popat S, Yousaf N, Jhanji S, Van As N, Young K, Furness AJS, Pickering L, Beale R, Swanton C, Crick COVID19 consortium, Gandhi S, Gamblin S, Bauer DLV, Kassiotis G, Howell M, Nicholson E, Walker S, Wilkinson RJ, Larkin J, Turajlic S, CAPTURE consortiumet al., 2022, Immune responses following third COVID-19 vaccination are reduced in patients with hematological malignancies compared to patients with solid cancer., Cancer Cell, Vol: 40, Pages: 438-438, ISSN: 1535-6108

In this report from the CAPTURE study (NCT03226886), we demonstrate that a third dose of COVID-19 vaccine boosts neutralizing antibody (NAb) and cellular responses in patients with cancer, including those that had undetectable NAb titers (NAbT) following two vaccine doses or for whom NAbT waned. We have noted that one key member of the CAPTURE consortium—Sanjay Popat—was inadvertently not included in the author list. We now include him as a co-author. There are no additional changes to the declaration of interests statement, since Dr. Popat declares no competing conflict of interest. This author list change is now reflected in the online version of this letter.

Journal article

Keeton R, Tincho MB, Ngomti A, Baguma R, Benede N, Suzuki A, Khan K, Cele S, Bernstein M, Karim F, Madzorera SV, Moyo-Gwete T, Mennen M, Skelem S, Adriaanse M, Mutithu D, Aremu O, Stek C, du Bruyn E, Van Der Mescht MA, de Beer Z, de Villiers TR, Bodenstein A, van den Berg G, Mendes A, Strydom A, Venter M, Giandhari J, Naidoo Y, Pillay S, Tegally H, Grifoni A, Weiskopf D, Sette A, Wilkinson RJ, de Oliveira T, Bekker L-G, Gray G, Ueckermann V, Rossouw T, Boswell MT, Bhiman JN, Moore PL, Sigal A, Ntusi NAB, Burgers WA, Riou Cet al., 2022, Author Correction: T cell responses to SARS-CoV-2 spike cross-recognize Omicron., Nature, Vol: 604, Pages: E25-E25, ISSN: 0028-0836

Journal article

Martin DP, Lytras S, Lucaci AG, Maier W, Grüning B, Shank SD, Weaver S, MacLean OA, Orton RJ, Lemey P, Boni MF, Tegally H, Harkins G, Scheepers C, Bhiman JN, Everatt J, Amoako DG, San JE, Giandhari J, Sigal A, NGS-SA, Williamson C, Hsiao N-Y, von Gottberg A, De Klerk A, Shafer RW, Robertson DL, Wilkinson RJ, Sewell BT, Lessells R, Nekrutenko A, Greaney AJ, Starr TN, Bloom JD, Murrell B, Wilkinson E, Gupta RK, de Oliveira T, Kosakovsky Pond SLet al., 2022, Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function., Publisher: BioRxiv

Among the 30 non-synonymous nucleotide substitutions in the Omicron S-gene are 13 that have only rarely been seen in other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of the S-gene at sites that will likely impact (i) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (ii) interactions of Spike with ACE2 receptors, and (iii) the priming of Spike for membrane fusion. We show here that, based on both the rarity of these 13 mutations in intrapatient sequencing reads and patterns of selection at the codon sites where the mutations occur in SARS-CoV-2 and related sarbecoviruses, prior to the emergence of Omicron the mutations would have been predicted to decrease the fitness of any genomes within which they occurred. We further propose that the mutations in each of the three clusters therefore cooperatively interact to both mitigate their individual fitness costs, and adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron over all previously known SARS-CoV-2 lineages, it is crucial to determine both how such complex and highly adaptive mutation constellations were assembled within the Omicron S-gene, and why, despite unprecedented global genomic surveillance efforts, the early stages of this assembly process went completely undetected.

Working paper

Georghiou SB, Rodwell TC, Korobitsyn A, Abbadi SH, Ajbani K, Alffenaar J-W, Alland D, Alvarez N, Andres S, Ardizzoni E, Aubry A, Baldan R, Ballif M, Barilar I, Bottger EC, Chakravorty S, Claxton PM, Cirillo DM, Comas I, Coulter C, Denkinger CM, Derendinger B, Desmond EP, de Steenwinkel JEM, Dheda K, Diacon AH, Dolinger DL, Dooley KE, Egger M, Farhat MR, Fattorini L, Finci I, Le Ray LF, Furio V, Groenheit R, Gumbo T, Heysell SK, Hillemann D, Hoffmann H, Hsueh P-R, Hu Y, Huang H, Hussain A, Ismail F, Izumi K, Jagielski T, Johnson JL, Kambli P, Kaniga K, Karunaratne GHRE, Sharma MK, Keller PM, Kelly EC, Kholina M, Kohli M, Kranzer K, Laurenson IF, Limberis J, Lin S-YG, Liu Y, Lopez-Gavin A, Lyander A, Machado D, Martinez E, Masood F, Mitarai S, Mvelase NR, Niemann S, Nikolayevskyy V, Maurer FP, Merker M, Miotto P, Omar S, Otto-Knapp R, Palaci M, Palacios Gutierrez JJ, Peacock SJ, Peloquin CA, Perera J, Pierre-Audigier C, Pholwat S, Posey JE, Prammananan T, Rigouts L, Robledo J, Rockwood N, Rodrigues C, Salfinger M, Schechter MC, Seifert M, Sengstake S, Shinnick T, Shubladze N, Sintchenko V, Sirgel F, Somasundaram S, Sterling TR, Spitaleri A, Streicher E, Supply P, Svensson E, Tagliani E, Tahseen S, Takaki A, Theron G, Torrea G, Van Deun A, Van Rie A, van Soolingen D, Vargas R, Venter A, Veziris N, Villellas C, Viveiros M, Warren R, Wen S, Werngren J, Wilkinson RJ, Yang C, Zhang T, Zimenkov D, Ismail N, Schon T, Koser CU, Ehsani S, van Ingen J, Yilmaz FFet al., 2022, Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment, European Respiratory Journal, Vol: 59, ISSN: 0903-1936

Journal article

Barr DA, Schutz C, Balfour A, Shey M, Kamariza M, Bertozzi CR, de Wet TJ, Dinkele R, Ward A, Haigh KA, Kanyik J-P, Mizrahi V, Nicol MP, Wilkinson RJ, Lalloo DG, Warner DF, Meintjes G, Davies Get al., 2022, Serial measurement of M. tuberculosis in blood from critically-ill patients with HIV-associated tuberculosis, EBioMedicine, Vol: 78, ISSN: 2352-3964

BACKGROUND: Despite being highly prevalent in hospitalised patients with severe HIV-associated tuberculosis (TB) and sepsis, little is known about the mycobacteriology of Mycobacterium tuberculosis bloodstream infection (MTBBSI). We developed methods to serially measure bacillary load in blood and used these to characterise MTBBSI response to anti-TB therapy (ATT) and relationship with mortality. METHODS: We established a microscopy method for direct visualisation of M. tuberculosis bacilli in blood using a novel lysis-concentration protocol and the fluorescent probe, 4-N,N-dimethylaminonaphthalimide-trehalose (DMN-Tre). We tested blood using GeneXpert® MTB/RIF-Ultra (Xpert-ultra) and Myco/F lytic culture after processing blood through lysis-wash steps to remove PCR inhibitors and anti-microbial drug carry-over. HIV-positive patients predicted to have MTBBSI gave blood samples 0, 4, 24, 48 and 72 h after ATT initiation. Bacillary loads were quantified using microscopy, Xpert-ultra cycle threshold, and culture time-to-positivity. Pharmacodynamics were modelled using these measures combined on an ordinal scale, including association with 12-week mortality. FINDINGS: M. tuberculosis was detected in 27 of 28 recruited participants; 25 (89%) by blood Xpert-ultra, 22 (79%) by DMN-Tre microscopy, and 21 (75%) by Myco/F lytic blood culture. Eight (29%) participants died by 12-week follow-up. In a combined pharmacodynamic model, predicted probabilities of negative DMN-Tre microscopy, blood Xpert-ultra, or blood culture after 72 h treatment were 0·64, 0·27, and 0·94, respectively, in those who survived, compared with 0·23, 0·06, and 0·71 in those who died (posterior probability of slower clearance of MTBBSI in those that died >0·99). DMN-Tre microscopy of blood demonstrated heterogenous bacillary morphologies, including microcolonies and clumps. Bacillary cell-length varied significantly with ATT exposure (mean

Journal article

Martin DP, Spyros L, Lucaci AG, Maier W, Gruning B, Shank SD, Weaver S, MacLean OA, Orton RJ, Lemey P, Boni MF, Tegally H, Harkins GW, Scheepers C, Bhiman JN, Everatt J, Amoako DG, San JE, Giandhari J, Sigal A, Williamson C, Hsiao N-Y, von Gottberg A, De Klerk A, Shafer RW, Robertson DL, Wilkinson RJ, Sewell TS, Lessells R, Nekrutenko A, Greaney AJ, Starr TN, Bloom JD, Murrell B, Wilkinson E, Gupta RK, de Oliveira T, Kosakovsky Pond SLet al., 2022, Selection analysis identifies clusters of unusual mutational changes in Omicron lineage BA.1 that likely impact Spike function, Molecular Biology and Evolution, Vol: 39, ISSN: 0737-4038

Among the 30 non-synonymous nucleotide substitutions in the Omicron S-gene are 13 that have only rarely been seen in other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of the S-gene at sites that will likely impact (i) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (ii) interactions of Spike with ACE2 receptors, and (iii) the priming of Spike for membrane fusion. We show here that, based on both the rarity of these 13 mutations inintrapatient sequencing reads and patterns of selection at the codon sites where the mutations occur in SARS-CoV-2 and related sarbecoviruses, prior to the emergence of Omicron the mutations would have been predicted to decrease the fitness of any virus within which they occurred. We further propose that the mutations in each of the three clusters therefore coperatively interact to both mitigate their individual fitness costs, and, in combination with other mutations, adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron over all previously known SARS-CoV-2 lineages, it is crucial to determine both how such complex and highly adaptive mutation constellations were assembled within the Omicron S-gene, and why, despite unprecedented global genomic surveillance efforts, the early stages of this assembly process went completely undetected.

Journal article

Gupte A, Kumar P, Araújo-Pereira M, Kulkarni V, Paradkar M, Pradhan N, Menon P, Darasini P, Hanna L-E, Shivakumar SVBY, Rockwood NS, Du Bruyn E, Karyakarte R, Gaikwad S, Bollinger R, Golub J, Gupte N, Viswanathan V, Wilkinson RJ, Mave V, Babu S, Kornfeld H, Andrade BB, Gupta Aet al., 2022, Baseline IL-6 is a biomarker for unfavorable tuberculosis treatment outcomes: a multi-site discovery and validation study, European Respiratory Journal, Vol: 59, ISSN: 0903-1936

Background: Biomarkers of unfavorable tuberculosis treatment outcomes are needed to accelerate new drug and regimen development. Whether plasma cytokine levels can predict unfavorable tuberculosis treatment outcomes is unclear. Methods: We identified and internally validated the association between 20 a-priori selected plasma inflammatory markers and unfavorable treatment outcomes of failure, recurrence and all-cause mortality among adults with drug-sensitive pulmonary tuberculosis in India. We externally validated these findings in two independent cohorts of predominantly diabetic and HIV coinfected tuberculosis patients in India and South Africa, respectively. Results: Pre-treatment IFN-γ, IL-13 and IL-6 were associated with treatment failure in the discovery analysis. Internal validation confirmed higher pre-treatment IL-6 concentrations among failure cases compared to controls. External validation among predominantly diabetic tuberculosis patients found an association between pre59 treatment IL-6 concentrations and subsequent recurrence and death. Similarly, external validation among predominantly HIV coinfected tuberculosis patients found an association between pre-treatment IL-6 concentrations and subsequent treatment failure and death. In a pooled analysis of 363 tuberculosis cases from the Indian and South African validation cohorts, high pre-treatment IL-6 concentrations were associated with higher risk of failure (adjusted odds ratio [aOR]=2.16, 95%CI 1.08-4.33, p=0.02), recurrence (aOR=5.36, 95%CI 2.48-11.57, p<0.001) and death (aOR=4.62, 95%CI 1.95-10.95, p<0.001). Adding baseline IL-6 to a risk-prediction model comprising of low BMI, high smear grade and cavitation improved model performance by 15 percent (C-statistic of 0.66 versus 0.76, p=0.02). Conclusion: Pre-treatment IL-6 is a biomarker for unfavorable tuberculosis treatment outcomes. Future studies should identify optimal IL-6 concentrations for point-of-care risk prediction.

Journal article

Walker TM, Miotto P, Köser CU, Fowler PW, Knaggs J, Iqbal Z, Hunt M, Chindelevitch L, Farhat M, Cirillo DM, Comas I, Posey J, Omar SV, Peto TE, Suresh A, Uplekar S, Laurent S, Colman RE, Nathanson C-M, Zignol M, Walker AS, CRyPTIC Consortium, Seq&Treat Consortium, Crook DW, Ismail N, Rodwell TCet al., 2022, The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis., The Lancet Microbe, Vol: 3, Pages: e265-e273, ISSN: 2666-5247

Background: Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosiscomplex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: A candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: 15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: This first WHO endorsed catalogue of mol

Journal article

Keeton R, Tincho MB, Ngomti A, Baguma R, Benede N, Suzuki A, Khan K, Madzorerera SV, Moyo-Gwete T, Mennen M, SKelem S, Adriaanse M, Muthithu D, Aremu O, Stek C, du Bruyn E, Van Der Mescht MA, de Beer Z, de Villiers TR, Bodenstein A, van der Berg G, Mendes A, Strydom A, Venter M, Giandhari J, Naidoo Y, Pillay S, Tegally H, Grifoni A, Weiskopf D, Sette A, Wilkinson RJ, de Oliveira T, Bekker L-G, Gray G, Ueckermann V, Rossouw T, Boswell MT, Bihman F, Moore PL, Ntusi NN, Burgers WA, Riou Cet al., 2022, T cell responses to SARS-1 CoV-2 spike cross-recognize Omicron, Nature, Vol: 603, Pages: 488-492, ISSN: 0028-0836

The SARS-CoV-2 Omicron variant has multiple Spike (S) protein mutations1,2 that contribute to escape from antibody neutralization3–6 and reduce vaccine protection from infection7,8. The extent to which other components of the adaptive response such as T cells may still target Omicron and contribute to protection from severe outcomes is unknown. We assessed the ability of T cells to react with Omicron spike in participants who were vaccinated with Ad26.CoV2.S, BNT162b2, or unvaccinated convalescent COVID-19 patients (n=70). We found that 70-80% of the CD4+ and CD8+ T cell response to spike was maintained across study groups. Moreover, the magnitude of Omicron cross-reactive T cells was similar to Beta and Delta variants, despite Omicron harboring considerably more mutations. In Omicron-infected hospitalized patients (n=19), there were comparable T cell responses to ancestral spike, nucleocapsid and membrane proteins to those patients hospitalized in previous waves dominated by the ancestral, Beta or Delta variants (n=49). Thus, despite Omicron’s extensive mutations and reduced susceptibility to neutralizing antibodies, the majority of T cell responses, induced by vaccination or infection, cross-recognize the variant. It remains to be determined whether well-preserved T cell immunity to Omicron contributes to protection from severe COVID-19, and is linked to early clinical observations from South Africa and elsewhere9–12.

Journal article

Middelkoop K, Walker N, Stewart J, Delport C, Joliffe DA, Nuttall J, Coussens AK, Naude CE, Tang JCY, Fraser WD, Wilkinson RJ, Bekker L-G, Martineau ARet al., 2022, Prevalence and determinants of vitamin D deficiency in 1,825 Cape Town primary schoolchildren: a cross-sectional study, Nutrients, Vol: 14, Pages: 1-13, ISSN: 2072-6643

Vitamin D deficiency (25-hydroxyvitamin D[25(OH)D] <50 nmol/L) is common among adults in Cape Town, South Africa, but studies investigating vitamin D status of children in this setting are lacking. We conducted a cross-sectional study to determine the prevalence and determinants of vitamin D deficiency in 1825 Cape Town schoolchildren aged 6–11 years. Prevalence of vitamin D deficiency was 7.6% (95% Confidence Interval [CI] 6.5% to 8.9%). Determinants of vitamin D deficiency included month of sampling (adjusted odds ratio [aOR] for July–September vs. January–March 10.69, 95% CI 5.02 to 22.77; aOR for October–December vs. January–March 6.73, 95% CI 2.82 to 16.08), older age (aOR 1.25 per increasing year, 95% CI: 1.01–1.53) and higher body mass index (BMI; aOR 1.24 per unit increase in BMI-for-age Z-score, 95% CI: 1.03–1.49). In a subset of 370 participants in whom parathyroid hormone (PTH) concentrations were measured; these were inversely related to serum 25(OH)D concentrations (p < 0.001). However, no association between participants with hyperparathyroidism (PTH >6.9 pmol/L) and vitamin D deficiency was seen (p = 0.42). In conclusion, we report that season is the major determinant of vitamin D status among Cape Town primary schoolchildren, with prevalence of vitamin D deficiency ranging from 1.4% in January–March to 22.8% in July–September.

Journal article

Abdelgawad N, Chirehwa M, Schutz C, Barr D, Ward A, Janssen S, Burton R, Wilkinson R, Shey M, Wiesner L, McIlleron H, Maartens G, Meintjes G, Denti Pet al., 2022, A comparison of the population pharmacokinetics of rifampicin, isoniazid and pyrazinamide between hospitalized and non-hospitalized tuberculosis patients with or without HIV, Wellcome Open Research, Vol: 7, Pages: 1-20, ISSN: 2398-502X

Background.Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups.Methods.Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM® was used to analyze the data.Results.Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin’s absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9% and 154% more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid’s clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide’s clearance was more variable among hospitalized patients. The variability in clearance among patients was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients. Conclusion.We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem to be underex

Journal article

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