Publications by authors named "Mark P Nicol"

166 Publications

Investigating resistance in clinical Mycobacterium tuberculosis complex isolates with genomic and phenotypic antimicrobial susceptibility testing: a multicentre observational study.

Lancet Microbe 2022 Jul 27. Epub 2022 Jul 27.

FIND, Geneva, Switzerland; German Center for Infection Research, Heidelberg, Germany; Division of Clinical Tropical Medicine and German Centre for Infection Research, Heidelberg University Hospital, Heidelberg, Germany. Electronic address:

Background: Whole-genome sequencing (WGS) of Mycobacterium tuberculosis complex has become an important tool in diagnosis and management of drug-resistant tuberculosis. However, data correlating resistance genotype with quantitative phenotypic antimicrobial susceptibility testing (AST) are scarce.

Methods: In a prospective multicentre observational study, 900 clinical M tuberculosis complex isolates were collected from adults with drug-resistant tuberculosis in five high-endemic tuberculosis settings around the world (Georgia, Moldova, Peru, South Africa, and Viet Nam) between Dec 5, 2014, and Dec 12, 2017. Minimum inhibitory concentrations (MICs) and resulting binary phenotypic AST results for up to nine antituberculosis drugs were determined and correlated with resistance-conferring mutations identified by WGS.

Findings: Considering WHO-endorsed critical concentrations as reference, WGS had high accuracy for prediction of resistance to isoniazid (sensitivity 98·8% [95% CI 98·5-99·0]; specificity 96·6% [95% CI 95·2-97·9]), levofloxacin (sensitivity 94·8% [93·3-97·6]; specificity 97·1% [96·7-97·6]), kanamycin (sensitivity 96·1% [95·4-96·8]; specificity 95·0% [94·4-95·7]), amikacin (sensitivity 97·2% [96·4-98·1]; specificity 98·6% [98·3-98·9]), and capreomycin (sensitivity 93·1% [90·0-96·3]; specificity 98·3% [98·0-98·7]). For rifampicin, pyrazinamide, and ethambutol, the specificity of resistance prediction was suboptimal (64·0% [61·0-67·1], 83·8% [81·0-86·5], and 40·1% [37·4-42·9], respectively). Specificity for rifampicin increased to 83·9% when borderline mutations with MICs overlapping with the critical concentration were excluded. Consequently, we highlighted mutations in M tuberculosis complex isolates that are often falsely identified as susceptible by phenotypic AST, and we identified potential novel resistance-conferring mutations.

Interpretation: The combined analysis of mutations and quantitative phenotypes shows the potential of WGS to produce a refined interpretation of resistance, which is needed for individualised therapy, and eventually could allow differential drug dosing. However, variability of MIC data for some M tuberculosis complex isolates carrying identical mutations also reveals limitations of our understanding of the genotype and phenotype relationships (eg, including epistasis and strain genetic background).

Funding: Bill & Melinda Gates Foundation, German Centre for Infection Research, German Research Foundation, Excellence Cluster Precision Medicine of Inflammation (EXC 2167), and Leibniz ScienceCampus EvoLUNG.
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http://dx.doi.org/10.1016/S2666-5247(22)00116-1DOI Listing
July 2022

Treatment Outcomes Among Pregnant Patients With Multidrug-Resistant Tuberculosis: A Systematic Review and Meta-analysis.

JAMA Netw Open 2022 06 1;5(6):e2216527. Epub 2022 Jun 1.

Telethon Kids Institute, Nedlands, Western Australia, Australia.

Importance: The management of multidrug-resistant tuberculosis (MDR-TB) during pregnancy is challenging, yet no systematic synthesis of evidence has accurately measured treatment outcomes.

Objective: To systematically synthesize treatment outcomes and adverse events among pregnant patients with MDR-TB.

Data Sources: PubMed, Scopus, Web of Science, and ProQuest were searched from the inception of each database through August 31, 2021.

Study Selection: Studies containing cohorts of pregnant patients with a defined treatment outcome were eligible.

Data Extraction And Synthesis: Independent reviewers screened studies and assessed the risk of bias. The study followed the Preferring Reporting Items for Systematic Review and Meta-analyses reporting guideline. Meta-analysis was performed using random-effects models. The sources of heterogeneity were explored through metaregression.

Main Outcomes And Measures: The primary outcome was the proportion of patients with each treatment outcome (including treatment success, death, loss to follow-up, and treatment failure), and the secondary outcomes included the proportion of patients experiencing adverse events during pregnancy.

Results: In this systematic review and meta-analysis, 10 studies containing 275 pregnant patients with available data on treatment outcomes were included. The pooled estimate was 72.5% (95% CI, 63.3%-81.0%) for treatment success, 6.8% (95% CI, 2.6%-12.4%) for death, 18.4% (95% CI, 13.1%-24.2%) for loss to follow-up, and 0.6% (95% CI, 0.0%-2.9%) for treatment failure. Treatment success was significantly higher in studies in which the proportion of patients taking linezolid was greater than the median (20.1%) compared with studies in which this proportion was lower than the median (odds ratio, 1.22; 95% CI, 1.05-1.42). More than half of the pregnant patients (54.7%; 95% CI, 43.5%-65.4%) experienced at least 1 type of adverse event, most commonly liver function impairment (30.4%; 95% CI, 17.7%-45.7%), kidney function impairment (14.9%; 95% CI, 6.2%-28.3%), hypokalemia (11.9%; 95% CI, 3.9%-25.6%), hearing loss (11.8%; 95% CI, 5.5%-21.3%), gastrointestinal disorders (11.8%; 95% CI, 5.2%-21.8%), psychiatric disorders (9.1%; 95% CI, 2.5%-21.6%), or anemia (8.9%; 95% CI, 3.6%-17.4%). The pooled proportion of favorable pregnancy outcomes was 73.2% (95% CI, 49.4%-92.1%). The most common types of adverse pregnancy outcomes were preterm birth (9.5%; 95% CI, 0.0%-29.0%), pregnancy loss (6.0%; 95% CI, 1.3%-12.9%), low birth weight (3.9%; 95% CI, 0.0%-18.7%), and stillbirth (1.9%; 95% CI, 0.1%-5.1%). Most of the studies had low-quality (3 studies) or medium-quality (4 studies) scores.

Conclusions And Relevance: In this systematic review and meta-analysis, high treatment success and favorable pregnancy outcomes were reported among pregnant patients with MDR-TB. Further research is needed to design shorter, more effective, and safer treatment regimens for pregnant patients with MDR-TB.
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http://dx.doi.org/10.1001/jamanetworkopen.2022.16527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9187956PMC
June 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.

Lancet Microbe 2022 Jul 26;3(7):e521-e532. Epub 2022 May 26.

Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.

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 447 participants with confirmed tuberculosis by the microbiological reference standard, with a diagnostic yield of 0·37 (95% CI 0·32-0·42). Diagnostic yield increased with lower CD4 count or haemoglobin, and outperformed urine lipoarabinomannan testing in participants with elevated venous lactate. Quantitative blood Xpert Ultra results were more closely associated with mortality than other tuberculosis biomarkers including blood culture, and urine lipoarabinomannan, or urine Xpert (all p<0·05). A principal component of clinical phenotype capturing markers of inflammation, tissue damage, and organ dysfunction was strongly associated with both blood Xpert-Ultra positivity (associated with a SD increase of 1·1 in PC score, p<0·0001) and cycle threshold (r= -0·5; p<0·0001).

Interpretation: Xpert Ultra testing of pre-processed blood could be used as a rapid diagnostic test in critically ill patients with suspected HIV-associated tuberculosis, while also giving additional prognostic information compared with other available markers. A dose-response relationship between quantitative blood Xpert Ultra results, host-response phenotype, and mortality risk adds to evidence that suggests M tuberculosis bloodstream infection bacillary load is causally related to outcomes.

Funding: Wellcome Trust, National Institute of Health Fogarty International Center, South African MRC, UK National Institute of Health Research, National Research Foundation of South Africa.

Translations: For the Xhosa and Afrikaans translations of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S2666-5247(22)00062-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9242865PMC
July 2022

Oral swabs tested with Xpert MTB/RIF Ultra for diagnosis of pulmonary tuberculosis in children: a diagnostic accuracy study.

Clin Infect Dis 2022 May 17. Epub 2022 May 17.

Department of Paediatrics and Child Health and South African Medical Research Council Unit on Child and Adolescent Health, University of Cape Town and Red Cross War Memorial Children's Hospital, Cape Town, South Africa.

Background: Microbiological diagnosis of childhood tuberculosis may be difficult. Oral swabs are a potential non-invasive alternative to sputum for diagnosis.

Methods: A prospective diagnostic accuracy study of oral swabs (buccal and tongue) for pulmonary tuberculosis (PTB) diagnosis in children (aged ≤15 years) in two South African hospital sites. Children with cough of any duration and either: a positive tuberculin skin test, TB contact, loss of weight or chest X-ray suggestive of PTB were enrolled. Two induced sputum specimens were tested with Xpert MTB/RIF (or Ultra) and liquid culture. Oral swabs were taken preceding sputum, frozen and later tested with Xpert MTB/RIF Ultra. Children were classified as microbiologically confirmed TB, Unconfirmed TB (received TB treatment) or unlikely TB according to NIH consensus definitions based on sputum microbiological results.

Results: Among 291 participants (median age 32 [IQR 14-73] months), 57 (20%) were living with HIV and 87 (30%) were malnourished. 90 (31%) had confirmed PTB (six (7%) with rifampicin-resistant TB), 157 (54%) unconfirmed PTB and 44 (15%) unlikely TB. One oral swab was obtained from 126 (43%) participants (96 tongue, 30 buccal) and two swabs from 165 (57%) (110 tongue, 55 buccal). Sensitivity was low; 22% (95% CI 15-32) for all swabs combined (confirmed PTB as reference), but specificity was high (100%, 95% CI 91-100). The highest sensitivity was 33% (15-58) among participants living with HIV. Overall yield was 6.9% with one oral swab, and 7.2% with two.

Conclusions: Ultra on oral swabs provides poor yield for microbiologic PTB confirmation in children.
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http://dx.doi.org/10.1093/cid/ciac332DOI Listing
May 2022

Klebsiella pneumoniae Lower Respiratory Tract Infection in a South African Birth Cohort: a Longitudinal Study.

Int J Infect Dis 2022 Aug 25;121:31-38. Epub 2022 Apr 25.

Division of Medical Microbiology, University of Cape Town; Division of Infection and Immunity, Department of Biomedical Sciences, University of Western Australia.

Objectives: The role of Klebsiella pneumoniae (KP) in lower respiratory tract infection (LRTI) is not well studied. We longitudinally investigated KP colonization and its association with LRTI in a South African birth cohort.

Methods: We conducted a case-control study of infants who developed LRTI and age-matched controls, followed twice weekly through infancy. Nasopharyngeal swabs taken fortnightly and at LRTI for 33-multipex Quantitative multiplex real-time polymerase chain reaction were tested at LRTI and twice weekly from 90 days preceding LRTI. Controls were tested over the equivalent period. Multivariate models investigated the factors associated with LRTI or with KP-associated LRTI (KP-LRTI).

Results: Among 885 infants, there were 439 LRTI episodes, of which 68 (15.5%) were KP-LRTI (OR 1.93; 95% CI 1.25-3.03). Infants with KP-LRTI were younger than those without KP-LRTI (median [IQR] 3.7 [2.1-5.9] vs 4.7 [2.8-7.9] months, P-value=0.009). Clinical features of KP and non-KP-LRTI were similar with 114 (26%) infants hospitalized. Prematurity (adjusted odds ratio [aOR] 11.86; 95% CI 5.22-26.93), HIV exposure (aOR 3.32; 95% CI 1.69-6.53), lower birthweight (aOR 0.68; 95% CI 0.51-0.91), and shorter breastfeeding time (aOR 0.79; 95% CI 0.65-0.96) were associated with KP-LRTI versus non-LRTI. These factors and younger age were associated with KP-LRTI versus non-KP-LRTI.

Conclusion: KP was associated with a substantial proportion of LRTI, particularly in premature or HIV-exposed infants in whom strategies for treatment and prevention should be strengthened.
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http://dx.doi.org/10.1016/j.ijid.2022.04.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174060PMC
August 2022

Treatment Response in Pediatric Pulmonary Tuberculosis-A Prospective Longitudinal Study.

J Pediatric Infect Dis Soc 2022 Jul;11(7):329-336

Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Background: Data are limited on the resolution of symptoms and signs in children treated for pulmonary tuberculosis (PTB) and whether this resolution differs from children with other lower respiratory tract infections (LRTIs).

Methods: A prospective study of children ≤ 15 years presenting with features suggestive of PTB was performed. Clinical, microbiological, and radiological investigations were done at enrollment. Symptoms and clinical features were measured 1, 3, and 6 months after enrollment. Participants were categorized into 3 groups based on National Institutes of Health consensus definitions: confirmed PTB, unconfirmed PTB, and unlikely PTB (children with other LRTIs). Univariable and multivariable logistic regression modeling was used to investigate predictors of persistence of symptoms or signs.

Results: Among 2019 participants, there were 427 (21%) confirmed, 810 (40%) unconfirmed, and 782 (39%) with unlikely PTB. Of 1693/2008 (84%) with cough and 1157/1997 (58%) with loss of appetite at baseline, persistence at 3 months was reported in 24/1222 (2%) and 23/886 (3%), respectively. Of 934/1884 (50%) with tachypnoea and 947/1999 (47%) with abnormal auscultatory findings at baseline, persistence at 3 months occurred in 410/723 (57%) and 216/778 (28%), respectively. HIV infection and abnormal baseline chest radiography were associated with persistence of symptoms or signs at month 3 (adjusted odds ration [aOR] 1.6; 95% confidence interval [CI]: [1.1, 2.3] and aOR 2.3; 95% CI: [1.5, 3.3], respectively]. The resolution of symptoms and signs was similar across categories.

Conclusions: Symptoms resolved rapidly in most children with PTB, but signs resolved more slowly. The pattern and resolution of symptoms or signs did not distinguish children with PTB from those with other LRTIs.
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http://dx.doi.org/10.1093/jpids/piac029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9302696PMC
July 2022

Diagnostic Advances in Childhood Tuberculosis-Improving Specimen Collection and Yield of Microbiological Diagnosis for Intrathoracic Tuberculosis.

Pathogens 2022 Mar 23;11(4). Epub 2022 Mar 23.

University of Bordeaux, National Institute for Health and Medical Research (INSERM), Research Institute for Sustainable Development (IRD), Bordeaux Population Health Research Centre, Team GHiGS, 33000 Bordeaux, France.

There is no microbiological gold standard for childhood tuberculosis (TB) diagnosis. The paucibacillary nature of the disease, challenges in sample collection in young children, and the limitations of currently available microbiological tests restrict microbiological confirmation of intrathoracic TB to the minority of children. Recent WHO guidelines recommend the use of novel rapid molecular assays as initial diagnostic tests for TB and endorse alternative sample collection methods for children. However, the uptake of these tools in high-endemic settings remains low. In this review, we appraise historic and new microbiological tests and sample collection techniques that can be used for the diagnosis of intrathoracic TB in children. We explore challenges and possible ways to improve diagnostic yield despite limitations, and identify research gaps to address in order to improve the microbiological diagnosis of intrathoracic TB in children.
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http://dx.doi.org/10.3390/pathogens11040389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9025862PMC
March 2022

Missing Piece Study protocol: prospective surveillance to determine the epidemiology of group A streptococcal pharyngitis and impetigo in remote Western Australia.

BMJ Open 2022 04 6;12(4):e057296. Epub 2022 Apr 6.

Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia, Australia.

Introduction: Group A β-haemolytic Streptococcus (GAS), a Gram-positive bacterium, causes skin, mucosal and systemic infections. Repeated GAS infections can lead to autoimmune diseases acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Aboriginal and Torres Strait Islander peoples in Australia have the highest rates of ARF and RHD in the world. Despite this, the contemporaneous prevalence and incidence of GAS pharyngitis and impetigo in remote Australia remains unknown. To address this, we have designed a prospective surveillance study of GAS pharyngitis and impetigo to collect coincident contemporary evidence to inform and enhance primary prevention strategies for ARF.

Methods And Analysis: The Missing Piece Study aims to document the epidemiology of GAS pharyngitis and impetigo through collection of clinical, serological, microbiological and bacterial genomic data among remote-living Australian children. The study comprises two components: (1) screening of all children at school for GAS pharyngitis and impetigo up to three times a year and (2) weekly active surveillance visits to detect new cases of pharyngitis and impetigo. Environmental swabbing in remote schools will be included, to inform environmental health interventions. In addition, the application of new diagnostic technologies, microbiome analysis and bacterial genomic evaluations will enhance primary prevention strategies, having direct bearing on clinical care, vaccine development and surveillance for vaccine clinical trials.

Ethics And Dissemination: Ethical approval has been obtained from the Western Australian Aboriginal Health Ethics Committee (Ref: 892) and Human Research Ethics Committee of the University of Western Australia (Ref: RA/4/20/5101). Study findings will be shared with community members, teachers and children at participating schools, together with academic and medical services. Sharing findings in an appropriate manner is important and will be done in a suitable way which includes plain language summaries and presentations. Finally, findings and updates will also be disseminated to collaborators, researchers and health planners through peer-reviewed journal publications.
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http://dx.doi.org/10.1136/bmjopen-2021-057296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8987764PMC
April 2022

Serial measurement of M. tuberculosis in blood from critically-ill patients with HIV-associated tuberculosis.

EBioMedicine 2022 Apr 21;78:103949. Epub 2022 Mar 21.

Institute of Infection and Global Health, University of Liverpool, Liverpool L7 3EA, UK.

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 cell-length increase 0·13 log-µm/day; 95%CrI 0·10-0·16).

Interpretation: Pharmacodynamics of MTBBSI treatment can be captured using DMN-Tre microscopy, blood Xpert-ultra and culture. This could facilitate interventional trials in severe HIV-associated TB.

Funding: Wellcome Trust, NIH Fogarty International Center, South African MRC, NIHR(UK), National Research Foundation of South Africa.
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http://dx.doi.org/10.1016/j.ebiom.2022.103949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8938880PMC
April 2022

Whole-Genome Sequencing Has the Potential To Improve Treatment for Rifampicin-Resistant Tuberculosis in High-Burden Settings: a Retrospective Cohort Study.

J Clin Microbiol 2022 03 16;60(3):e0236221. Epub 2022 Mar 16.

Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Treatment of multidrug-resistant or rifampicin-resistant tuberculosis (MDR/RR-TB), although improved in recent years with shorter, more tolerable regimens, remains largely standardized and based on limited drug susceptibility testing (DST). More individualized treatment with expanded DST access is likely to improve patient outcomes. To assess the potential of TB drug resistance prediction based on whole-genome sequencing (WGS) to provide more effective treatment regimens, we applied current South African treatment recommendations to a retrospective cohort of MDR/RR-TB patients from Khayelitsha, Cape Town. Routine DST and clinical data were used to retrospectively categorize patients into a recommended regimen, either a standardized short regimen or a longer individualized regimen. Potential regimen changes were then described with the addition of WGS-derived DST. WGS data were available for 1274 MDR/RR-TB patient treatment episodes across 2008 to 2017. Among 834 patients initially eligible for the shorter regimen, 385 (46%) may have benefited from reduced drug dosage or removing ineffective drugs when WGS data were considered. A further 187 (22%) patients may have benefited from more effective adjusted regimens. Among 440 patients initially eligible for a longer individualized regimen, 153 (35%) could have been switched to the short regimen. Overall, 305 (24%) patients had MDR/RR-TB with second-line TB drug resistance, where the availability of WGS-derived DST would have allowed more effective treatment individualization. These data suggest considerable benefits could accrue from routine access to WGS-derived resistance prediction. Advances in culture-free sequencing and expansion of the reference resistance mutation catalogue will increase the utility of WGS resistance prediction.
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http://dx.doi.org/10.1128/jcm.02362-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8925891PMC
March 2022

The impact of long-term azithromycin on antibiotic resistance in HIV-associated chronic lung disease.

ERJ Open Res 2022 Jan 7;8(1). Epub 2021 Feb 7.

Department of Molecular and Cell Biology & Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.

Selection for resistance to azithromycin (AZM) and other antibiotics such as tetracyclines and lincosamides remains a concern with long-term AZM use for treatment of chronic lung diseases (CLD). We investigated the impact of 48 weeks of AZM on the carriage and antibiotic resistance of common respiratory bacteria among children with HIV-associated CLD. Nasopharyngeal (NP) swabs and sputa were collected at baseline, 48 and 72 weeks from participants with HIV-associated CLD randomised to receive weekly AZM or placebo for 48 weeks and followed post-intervention until 72 weeks. The primary outcomes were prevalence and antibiotic resistance of (SP), (SA), (HI) and (MC) at these timepoints. Mixed-effects logistic regression and Fisher's exact test were used to compare carriage and resistance, respectively. Of 347 (174 AZM, 173 placebo) participants (median age 15 years (IQR 13-18), female 49%), NP carriage was significantly lower in the AZM (n=159) compared to placebo (n=153) arm for SP (18% 41%, <0.001), HI (7% 16%, p=0.01) and MC (4% 11%, p=0.02); SP resistance to AZM (62% (18 out of 29) 13% (8 out of 63), <0.0001) or tetracycline (60% (18 out of 29) 21% (13 out of 63), <0.0001) was higher in the AZM arm. Carriage of SA resistant to AZM (91% (31 out of 34) 3% (1 out of 31), <0.0001), tetracycline (35% (12 out of 34) 13% (4 out of 31), p=0.05) and clindamycin (79% (27 out of 34) 3% (1 out of 31), <0.0001) was also significantly higher in the AZM arm and persisted at 72 weeks. Similar findings were observed for sputa. The persistence of antibiotic resistance and its clinical relevance for future infectious episodes requiring treatment needs further investigation.
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http://dx.doi.org/10.1183/23120541.00491-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8819245PMC
January 2022

A citywide, clonal outbreak of Pseudomonas aeruginosa.

Int J Infect Dis 2022 Apr 22;117:74-86. Epub 2022 Jan 22.

Division of Medical Microbiology, University of Cape Town, and National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa. Electronic address:

Background: Outbreaks of community-acquired Pseudomonas aeruginosa are typically small and localized. We investigated an increase in community-acquired infections with P. aeruginosa in Cape Town, South Africa.

Methods: Cases were defined as P. aeruginosa isolated from any clinical sample, and "wild-type" as those susceptible to all antibiotics tested. The residential addresses of community-acquired wild-type cases were mapped. Whole-genome sequencing and multilocus sequence typing were used to determine clonality and identify virulence genes. A clinical study in a subset of patients with bloodstream infection compared demographic and clinical characteristics between sequence types (STs).

Results: The outbreak lasted 10 months from December 2016 to September 2017 with 3,321 documented cases. At the peak, cases reached 2.3-fold baseline rates. Cases were distributed widely across the city. Multilocus ST 303 was predominant during the outbreak. A total of 51 virulence genes were differentially present in ST303 compared with other STs, including genes involved in biofilm formation, iron uptake, and gut penetration.

Conclusion: The investigation confirmed a citywide outbreak of P. aeruginosa. We identified a predominant outbreak-associated clone, ST303, which harbored genes that could contribute to virulence and survival in adverse environmental conditions such as those associated with drought.
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http://dx.doi.org/10.1016/j.ijid.2022.01.039DOI Listing
April 2022

Correction to: Human microbiota research in Africa: a systematic review reveals gaps and priorities for future research.

Microbiome 2022 Jan 19;10(1):10. Epub 2022 Jan 19.

Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

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http://dx.doi.org/10.1186/s40168-022-01226-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8772064PMC
January 2022

Human microbiota research in Africa: a systematic review reveals gaps and priorities for future research.

Microbiome 2021 12 15;9(1):241. Epub 2021 Dec 15.

Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Background: The role of the human microbiome in health and disease is an emerging and important area of research; however, there is a concern that African populations are under-represented in human microbiome studies. We, therefore, conducted a systematic survey of African human microbiome studies to provide an overview and identify research gaps. Our secondary objectives were: (i) to determine the number of peer-reviewed publications; (ii) to identify the extent to which the researches focused on diseases identified by the World Health Organization [WHO] State of Health in the African Region Report as being the leading causes of morbidity and mortality in 2018; (iii) to describe the extent and pattern of collaborations between researchers in Africa and the rest of the world; and (iv) to identify leadership and funders of the studies.

Methodology: We systematically searched Medline via PubMed, Scopus, CINAHL, Academic Search Premier, Africa-Wide Information through EBSCOhost, and Web of Science from inception through to 1st April 2020. We included studies that characterized samples from African populations using next-generation sequencing approaches. Two reviewers independently conducted the literature search, title and abstract, and full-text screening, as well as data extraction.

Results: We included 168 studies out of 5515 records retrieved. Most studies were published in PLoS One (13%; 22/168), and samples were collected from 33 of the 54 African countries. The country where most studies were conducted was South Africa (27/168), followed by Kenya (23/168) and Uganda (18/168). 26.8% (45/168) focused on diseases of significant public health concern in Africa. Collaboration between scientists from the United States of America and Africa was most common (96/168). The first and/or last authors of 79.8% of studies were not affiliated with institutions in Africa. Major funders were the United States of America National Institutes of Health (45.2%; 76/168), Bill and Melinda Gates Foundation (17.8%; 30/168), and the European Union (11.9%; 20/168).

Conclusions: There are significant gaps in microbiome research in Africa, especially those focusing on diseases of public health importance. There is a need for local leadership, capacity building, intra-continental collaboration, and national government investment in microbiome research within Africa. Video Abstract.
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http://dx.doi.org/10.1186/s40168-021-01195-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672519PMC
December 2021

Cytomegalovirus acquisition in infancy and the risk of tuberculosis disease in childhood: a longitudinal birth cohort study in Cape Town, South Africa.

Lancet Glob Health 2021 12;9(12):e1740-e1749

Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital and South African Medical Research Council Unit on Child and Adolescent Health, Cape Town, South Africa. Electronic address:

Background: The risk of tuberculosis disease after recent exposure is greatest before age 5 years; however, the mechanisms explaining this increased risk are not well elucidated. Acquisition of viral infections, such as cytomegalovirus, in early life might modulate the immune system. We aimed to evaluate the acquisition of cytomegalovirus infection in infancy and the development of tuberculosis disease in children.

Methods: In this prospective, birth cohort study we enrolled pregnant women who were between 20 and 28 weeks of gestation attending antenatal care in Paarl, a periurban setting outside of Cape Town, South Africa. Participants were recruited from two clinics (TC Newman and Mbekweni). Infants were given Bacillus Calmette-Guérin vaccination at birth as per national policy. Nasopharyngeal swabs for cytomegalovirus detection using qPCR were done for infants at birth, age 3 and 6 weeks, and age 3, 6, 12, and 24 months. Children were prospectively followed up for tuberculosis disease until age 9 years using tuberculin skin testing, radiographic examinations, GeneXpert, and sputum testing. Tuberculin skin tests were done at the 6-month visit and then at age 12, 24, 36, 48, and 60 months, and at the time of lower respiratory tract infection. We compared tuberculosis disease incidence after age 1 year or after age 6 months in children with and without cytomegalovirus infection using Cox regression and hazard ratios (HRs) with 95% CIs.

Findings: Between March 5, 2012, and March 31, 2015, 1225 pregnant women were recruited and enrolled in the birth cohort. 88 (7%) women were excluded because of loss to antenatal follow-up or pregnancy losses. Of 1143 livebirths, 68 (6%) mother-infant pairs were excluded. In total, 963 children were serially tested for cytomegalovirus (7186 cytomegalovirus measurements taken; median six tests per child, IQR 2-11). The prevalence of congenital cytomegalovirus at age younger than 3 weeks was 2% (18 of 816). Cytomegalovirus positivity increased continuously with age from 3% (27 of 825) by age 6 weeks to 21% (183 of 882) by 3 months, 35% (315 of 909) by 6 months, and 42% (390 of 933) by 12 months. Mother-infant pairs were followed up for a median of 6·9 years (IQR 6·0-7·8). The risk of tuberculosis disease in children after age 1 year was higher in those with cytomegalovirus infection by age 6 weeks (adjusted HR 4·1, 95% CI 1·2-13·8; p=0·022), 3 months (2·8, 1·4-5·8; p=0·0040), 6 months (3·6, 1·7-7·3; p<0·0001), 12 months (3·2, 1·6-6·4; p=0·0010), and 24 months (4·2, 2·0-8·8; p<0·0001). The risk of microbiologically confirmed tuberculosis disease was also higher among children acquiring cytomegalovirus infection before age 3 months (adjusted HR 3·2, 95% CI 1·0-10·6; p=0·048), 6 months (3·9, 1·2-13·0; p=0·027), 12 months (4·4, 1·2-16·3; p=0·027), and 24 months (6·1, 1·3-27·9; p=0·020). In children older than 1 year, the risk of tuberculosis disease was consistently greater in those with high cytomegalovirus loads than in those with low cytomegalovirus loads that were acquired before age 3 months (adjusted HR 2·0 vs 3·7; p=0·0020; both groups compared with cytomegalovirus negative reference) and before age 12 months (2·7 vs 3·7; p=0·0009).

Interpretation: Infants that acquire cytomegalovirus in the first year of life are at high risk of subsequently developing tuberculosis disease. Efforts to prevent tuberculosis in early childhood in high-burden countries might need to deter or delay acquisition of cytomegalovirus perinatally or in the first months of life.

Funding: Bill & Melinda Gates Foundation, MRC South Africa, National Research Foundation South Africa, and Wellcome Trust.
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http://dx.doi.org/10.1016/S2214-109X(21)00407-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8609281PMC
December 2021

Potential contribution of HIV during first-line tuberculosis treatment to subsequent rifampicin-monoresistant tuberculosis and acquired tuberculosis drug resistance in South Africa: a retrospective molecular epidemiology study.

Lancet Microbe 2021 11;2(11):e584-e593

DST-NRF Centre of Excellence for Biomedical Tuberculosis Research/SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa.

Background: South Africa has a high burden of rifampicin-resistant tuberculosis (including multidrug-resistant [MDR] tuberculosis), with increasing rifampicin-monoresistant (RMR) tuberculosis over time. Resistance acquisition during first-line tuberculosis treatment could be a key contributor to this burden, and HIV might increase the risk of acquiring rifampicin resistance. We assessed whether HIV during previous treatment was associated with RMR tuberculosis and resistance acquisition among a retrospective cohort of patients with MDR or rifampicin-resistant tuberculosis.

Methods: In this retrospective cohort study, we included all patients routinely diagnosed with MDR or rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa, between Jan 1, 2008, and Dec 31, 2017. Patient-level data were obtained from a prospective database, complemented by data on previous tuberculosis treatment and HIV from a provincial health data exchange. Stored MDR or rifampicin-resistant tuberculosis isolates from patients underwent whole-genome sequencing (WGS). WGS data were used to infer resistance acquisition versus transmission, by identifying genomically unique isolates (single nucleotide polymorphism threshold of five). Logistic regression analyses were used to assess factors associated with RMR tuberculosis and genomic uniqueness.

Findings: The cohort included 2041 patients diagnosed with MDR or rifampicin-resistant tuberculosis between Jan 1, 2008, and Dec 31, 2017; of those, 463 (22·7%) with RMR tuberculosis and 1354 (66·3%) with previous tuberculosis treatment. In previously treated patients, HIV positivity during previous tuberculosis treatment versus HIV negativity (adjusted odds ratio [OR] 2·07, 95% CI 1·35-3·18), and three or more previous tuberculosis treatment episodes versus one (1·96, 1·21-3·17) were associated with RMR tuberculosis. WGS data showing MDR or rifampicin-resistant tuberculosis were available for 1169 patients; 360 (30·8%) isolates were identified as unique. In previously treated patients, RMR tuberculosis versus MDR tuberculosis (adjusted OR 4·96, 3·40-7·23), HIV positivity during previous tuberculosis treatment (1·71, 1·03-2·84), and diagnosis in 2013-17 (1·42, 1·02-1·99) versus 2008-12, were associated with uniqueness. In previously treated patients with RMR tuberculosis, HIV positivity during previous treatment (adjusted OR 5·13, 1·61-16·32) was associated with uniqueness as was female sex (2·50 [1·18-5·26]).

Interpretation: These data suggest that HIV contributes to rifampicin-resistance acquisition during first-line tuberculosis treatment and that this might be driving increasing RMR tuberculosis over time. Large-scale prospective cohort studies are required to further quantify this risk.

Funding: Swiss National Science Foundation, South African National Research Foundation, and Wellcome Trust.
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http://dx.doi.org/10.1016/S2666-5247(21)00144-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563432PMC
November 2021

Antibodies to Seasonal Coronaviruses Rarely Cross-React With SARS-CoV-2: Findings From an African Birth Cohort.

Pediatr Infect Dis J 2021 12;40(12):e516-e519

Great Ormond Street Institute of Child Health, University College London.

Antibodies to seasonal human-coronaviruses (sHCoV) may cross-protect against SARS-CoV-2. We investigated antibody responses in biobanked serum obtained before the pandemic from infants with polymerase chain reaction-confirmed sHCoV. Among 141 samples with antibodies to sHCoV, 4 (2.8%) were positive for SARS-CoV-2-S1 and 8 (5.7%) for SARS-CoV-2-S2. Antibodies to sHCoV rarely cross-react with SARS-CoV-2 antigens and are unlikely to account for mild pediatric illness.
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http://dx.doi.org/10.1097/INF.0000000000003325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575088PMC
December 2021

Longitudinal Dynamics of a Blood Transcriptomic Signature of Tuberculosis.

Am J Respir Crit Care Med 2021 12;204(12):1463-1472

Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.

Performance of blood transcriptomic tuberculosis (TB) signatures in longitudinal studies and effects of TB-preventive therapy and coinfection with HIV or respiratory organisms on transcriptomic signatures has not been systematically studied. We evaluated longitudinal kinetics of an 11-gene blood transcriptomic TB signature, RISK11, and effects of TB-preventive therapy (TPT) and respiratory organisms on RISK11 signature score, in HIV-uninfected and HIV-infected individuals. RISK11 was measured in a longitudinal study of RISK11-guided TPT in HIV-uninfected adults, a cross-sectional respiratory organisms cohort, or a longitudinal study in people living with HIV (PLHIV). HIV-uninfected RISK11 participants were randomized to TPT or no TPT; RISK11 participants received no TPT. PLHIV received standard-of-care antiretroviral therapy and TPT. In the cross-sectional respiratory organisms cohort, viruses and bacteria in nasopharyngeal and oropharyngeal swabs were quantified by real-time quantitative PCR. RISK11 status was transient in most of the 128 HIV-negative participants with longitudinal samples; more than 70% of RISK11 participants reverted to RISK11 by 3 months, irrespective of TPT. By comparison, reversion from a RISK11 state was less common in 645 PLHIV (42.1%). Non-HIV viral and nontuberculous bacterial organisms were detected in 7.2% and 38.9% of the 1,000 respiratory organisms cohort participants, respectively, and among those investigated for TB, 3.8% had prevalent disease. Median RISK11 scores (%) were higher in participants with viral organisms alone (46.7%), viral and bacterial organisms (42.8%), or prevalent TB (85.7%) than those with bacterial organisms other than TB (13.4%) or no organisms (14.2%). RISK11 could not discriminate between prevalent TB and viral organisms. Positive RISK11 signature status is often transient, possibly due to intercurrent viral infection, highlighting potentially important challenges for implementation of these biomarkers as new tools for TB control.
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http://dx.doi.org/10.1164/rccm.202103-0548OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865716PMC
December 2021

Rifampicin-Monoresistant Tuberculosis Is Not the Same as Multidrug-Resistant Tuberculosis: a Descriptive Study from Khayelitsha, South Africa.

Antimicrob Agents Chemother 2021 10 30;65(11):e0036421. Epub 2021 Aug 30.

Division of Medical Microbiology, Department of Pathology, University of Cape Town, Cape Town, South Africa.

Rifampin monoresistance (RMR; rifampin resistance and isoniazid susceptibility) accounts for 38% of all rifampin-resistant tuberculosis (RR-TB) in South Africa and is increasing. We aimed to compare RMR-TB with multidrug-resistant TB (MDR-TB) in a setting with high TB, RR-TB, and HIV burdens. Patient-level clinical data and stored RR Mycobacterium tuberculosis isolates from 2008 to 2017 with available whole-genome sequencing (WGS) data were used to describe risk factors associated with RMR-TB and to compare RR-conferring mutations between RMR-TB and MDR-TB. A subset of isolates with particular RR-conferring mutations were subjected to semiquantitative rifampin phenotypic drug susceptibility testing. Among 2,041 routinely diagnosed RR-TB patients, 463 (22.7%) had RMR-TB. HIV-positive individuals (adjusted odds ratio [aOR], 1.4; 95% confidence interval [CI], 1.1 to 1.9) and diagnosis between 2013 and 2017 versus between 2008 and 2012 (aOR, 1.3; 95% CI, 1.1 to 1.7) were associated with RMR-TB. Among 1,119 (54.8%) patients with available WGS data showing RR-TB, significant differences in the distribution of RR-conferring mutations between RMR and MDR isolates were observed. Mutations associated with high-level RR were more commonly found among MDR isolates (811/889 [90.2%] versus 162/230 [70.4%] among RMR isolates;  < 0.0001). In particular, the L430P mutation, conferring low-level RR, was identified in 32/230 (13.9%) RMR isolates versus 10/889 (1.1%) in MDR isolates ( < 0.0001). Among 10 isolates with an L430P mutation, 7 were phenotypically susceptible using the critical concentration of 0.5 μg/ml (range, 0.125 to 1 μg/ml). The majority (215/230 [93.5%]) of RMR isolates showed susceptibility to all other TB drugs, highlighting the potential benefits of WGS for simplified treatment. These data suggest that the evolution of RMR-TB differs from MDR-TB with a potential contribution from HIV infection.
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http://dx.doi.org/10.1128/AAC.00364-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522772PMC
October 2021

Vitamin D Concentrations in Infancy and the Risk of Tuberculosis Disease in Childhood: A Prospective Birth Cohort in Cape Town, South Africa.

Clin Infect Dis 2022 06;74(11):2036-2043

Department of Pediatrics and Child Health, Red Cross War Memorial Children's Hospital, and SA-MRC Uniton Child and Adolescent Health, University of Cape Town, Cape Town, South Africa.

Background: Low vitamin D levels may increase the risk of tuberculosis disease; however, previous observational cohort studies showed variable results. We investigated the relationship between vitamin D levels in infancy and subsequent development of tuberculosis disease throughout childhood.

Methods: We enrolled pregnant women at 20-28 weeks' gestation attending antenatal care in a periurban South African setting in the Drakenstein Child Health Study. Serum 25(OH)D concentrations were measured in newborn infants aged 6-10 weeks. Children were followed prospectively for tuberculosis infection and disease using annual tuberculin skin testing, radiographic examinations, and microbiological diagnosis with GeneXpert, culture, and smear testing. Univariable and multivariable Cox regression was performed and HRs with 95% CIs were calculated.

Results: Children were followed for tuberculosis disease for a median of 7.2 years (IQR, 6.2-7.9). Among 744 children (<1% with human immunodeficiency virus (HIV), 21% HIV-exposed without HIV), those who were vitamin D deficient in early infancy were not at increased risk of developing tuberculosis disease (adjusted HR, .8; 95% CI, .4-1.6). Infants in the lowest vitamin D concentration tertile were at similar risk of tuberculosis as the highest tertile (adjusted HR, .7; 95% CI, .4-1.4). Vitamin D deficiency was associated with tuberculin conversion ≤2 years of age at a <30-nmol/L (adjusted OR, 1.9; 95% CI, 1.2-3.2), but not <50-nmol/L (adjusted OR, 1.5; 95% CI, .8-2.9), cutoff.

Conclusions: In a setting with hyperendemic rates of tuberculosis, vitamin D concentrations in infancy did not predict tuberculosis disease at any point in childhood. However, very low vitamin D levels were associated with tuberculin conversion in young children.
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http://dx.doi.org/10.1093/cid/ciab735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9187320PMC
June 2022

Factors associated with serious outcomes of pneumonia among children in a birth cohort in South Africa.

PLoS One 2021 13;16(8):e0255790. Epub 2021 Aug 13.

Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital and SA-MRC Unit on Child and Adolescent Health, University of Cape Town, Cape Town, South Africa.

Background: Child hospitalization for pneumonia remains common, and pneumonia is a major cause of child mortality. Early identification of clinical factors associated with serious outcomes may help target risk-mitigation strategies.

Methods: Pneumonia cases occurring in the Drakenstein Child Health Study, a prospective birth cohort outside Cape Town, South Africa were analysed, and factors associated with serious outcomes of pneumonia were identified. Pregnant women were enrolled antenatally, followed through pregnancy, and mother-child pairs from birth to 2 years. Active surveillance for pneumonia was done. Children hospitalized with pneumonia had chest radiography and blood drawn for inflammatory markers; course, outcome and duration of hospitalization were investigated. Serious outcomes were defined as in-hospital mortality or admission to intensive care unit (ICU). Prolonged hospitalization was also explored as a proxy for severity. Features associated with serious outcomes or prolonged hospitalization were analysed using modified Poisson regression.

Results: Among 1143 live born infants, there were 174 hospitalized pneumonia events in 133 children under 2 years. Three children (1.7%) died, 14 (8%) required ICU admission for respiratory support. In modified Poisson regression, age < 2 months, preterm birth, or hypoxia (oxygen saturation <92%) were significantly associated with serious outcomes. Preterm birth, low birth weight, HIV exposure, stunting, or underweight-for-age (UWFA) were associated with prolonged hospitalization. Chest radiography, elevated C reactive protein, white blood cell and neutrophil counts were not useful to predict death or ICU admission in children hospitalized with pneumonia.

Conclusions: In this cohort, death from pneumonia was rare, but clinical features associated with serious outcomes and prolonged hospitalization were identified. These may help with risk stratification, to identify children who may benefit from enhanced monitoring or earlier escalation to respiratory support.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255790PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363001PMC
December 2021

The association between bacteria colonizing the upper respiratory tract and lower respiratory tract infection in young children: a systematic review and meta-analysis.

Clin Microbiol Infect 2021 Sep 7;27(9):1262-1270. Epub 2021 Jun 7.

Division of Medical Microbiology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Division of Infection and Immunity, School of Biomedical Sciences, University of Western Australia, Perth, Australia.

Background: Bacteria colonizing the upper respiratory tract (URT) of young children play a key role in the pathogenesis of lower respiratory tract infection (LRTI).

Objectives: To systematically review the literature on the association between bacteria colonizing the URT and LRTI among young children.

Data Sources: MEDLINE, Academic Search Premier, Africa-Wide Information and CINAHL, Scopus and Web of Science.

Study Eligibility Criteria: Studies published between 1923 and 2020, investigating URT bacteria from LRTI cases and controls.

Participants: Children under 5 years with and without acute LRTI.

Methods: Three reviewers independently screened titles, abstracts and full texts. Meta-analysis was done using Mantel-Haenszel fixed- or random-effects models.

Results: Most eligible studies (41/50) tested nasopharyngeal specimens when investigating URT bacteria. Most studies were of cross-sectional design (44/50). Twenty-four studies were performed in children in lower- or lower-middle-income countries (LMICs). There was higher prevalence of Haemophilus influenzae (pooled OR 1.60; 95% CI 1.23-2.07) and Klebsiella spp. (pooled OR 2.04; 95% CI 1.17-3.55) from URT specimens of cases versus controls. We observed a positive association between the detection of Streptococcus pneumoniae from URT specimens and LRTI after excluding studies where there was more antibiotic treatment prior to sampling in cases vs. controls (pooled OR 1.41; 95% CI 1.04-1.90). High density colonization with S. pneumoniae (>6.9 log copies/mL) was associated with an increased risk for LRTI. The associations between both Streptococcus and Haemophilus URT detection and LRTI were supported, at genus level, by 16S rRNA sequencing. Evidence for the role of Moraxella catarrhalis and Staphylococcus aureus was inconclusive.

Conclusions: Detection of H. influenzae or Klebsiella spp. in the URT was associated with LRTI, while evidence for association with S. pneumoniae was less conclusive. Longitudinal studies assessing URT microbial communities, together with environmental and host factors are needed to better understand pathogenesis of childhood LRTI.
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http://dx.doi.org/10.1016/j.cmi.2021.05.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437050PMC
September 2021

Molecular epidemiology of Staphylococcus aureus in African children from rural and urban communities with atopic dermatitis.

BMC Infect Dis 2021 Apr 13;21(1):348. Epub 2021 Apr 13.

Department of Molecular and Cell Biology, Faculty of Science, University of Cape Town, Cape Town, South Africa.

Background: Staphylococcus aureus has been associated with the exacerbation and severity of atopic dermatitis (AD). Studies have not investigated the colonisation dynamics of S. aureus lineages in African toddlers with AD. We determined the prevalence and population structure of S. aureus in toddlers with and without AD from rural and urban South African settings.

Methods: We conducted a study of AD-affected and non-atopic AmaXhosa toddlers from rural Umtata and urban Cape Town, South Africa. S. aureus was screened from skin and nasal specimens using established microbiological methods and clonal lineages were determined by spa typing. Logistic regression analyses were employed to assess risk factors associated with S. aureus colonisation.

Results: S. aureus colonisation was higher in cases compared to controls independent of geographic location (54% vs. 13%, p < 0.001 and 70% vs. 35%, p = 0.005 in Umtata [rural] and Cape Town [urban], respectively). Severe AD was associated with higher colonisation compared with moderate AD (86% vs. 52%, p = 0.015) among urban cases. Having AD was associated with colonisation in both rural (odds ratio [OR] 7.54, 95% CI 2.92-19.47) and urban (OR 4.2, 95% CI 1.57-11.2) toddlers. In rural toddlers, living in an electrified house that uses gas (OR 4.08, 95% CI 1.59-10.44) or utilises kerosene and paraffin (OR 2.88, 95% CI 1.22-6.77) for heating and cooking were associated with increased S. aureus colonisation. However, exposure to farm animals (OR 0.3, 95% CI 0.11-0.83) as well as living in a house that uses wood and coal (OR 0.14, 95% CI 0.04-0.49) or outdoor fire (OR 0.31, 95% CI 0.13-0.73) were protective. Spa types t174 and t1476, and t272 and t1476 were dominant among urban and rural cases, respectively, but no main spa type was observed among controls, independent of geographic location. In urban cases, spa type t002 and t442 isolates were only identified in severe AD, t174 was more frequent in moderate AD, and t1476 in severe AD.

Conclusion: The strain genotype of S. aureus differed by AD phenotypes and rural-urban settings. Continued surveillance of colonising S. aureus lineages is key in understanding alterations in skin microbial composition associated with AD pathogenesis and exacerbation.
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http://dx.doi.org/10.1186/s12879-021-06044-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045247PMC
April 2021

Pertussis among patients with clinically compatible illness in the Amhara Regional State, Ethiopia.

Int J Infect Dis 2021 May 29;106:421-428. Epub 2021 Mar 29.

Department of Medical Microbiology, University of Gondar, Gondar, Amhara Regional State, Ethiopia.

Background: Pertussis is an acute respiratory tract disease caused by Bordetella pertussis. In 2014, 24.1 million pertussis cases, resulting in 160,700 deaths, were estimated to have occurred worldwide. This study aimed to determine the epidemiology of pertussis among patients with clinically compatible illness who visited selected hospitals in the Amhara Regional State of Ethiopia.

Methods: A cross-sectional study design was used to review pertussis patients with clinically compatible illness. Nasopharyngeal swabs were collected from 515 patients from July 2018 through February 2019. DNA was extracted from all nasopharyngeal swabs and samples were analyzed using real-time (RT-) PCR. Crude and adjusted odds ratios with corresponding 95% confidence intervals were estimated using bivariable and multivariable logistic regression analysis, respectively.

Results: The overall prevalence of Bordetella species among the study participants was 156 of 515 (30.3%) [95% CI = 26.4-34.6] as determined by Bordetella RT-PCR, including: 65 (41.7%) B. pertussis, 89 (57.1%) indeterminate B. pertussis, one (0.6%) Bordetella holmesii and one (0.6%) Bordetella parapertussis.

Conclusions: This study found that pertussis is potentially endemic and a common health problem among patients visiting health institutions in the Amhara Regional State of Ethiopia. More data regarding pertussis in Ethiopia could inform development of effective prevention strategies.
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http://dx.doi.org/10.1016/j.ijid.2021.03.073DOI Listing
May 2021

The child ecosystem and childhood pulmonary tuberculosis: A South African perspective.

Pediatr Pulmonol 2021 07 25;56(7):2212-2222. Epub 2021 Mar 25.

Department of Paediatrics and Child Health, Red Cross Childrens Hospital and SA-MRC Unit on Child & Adolescent Health, University of Cape Town, Cape Town, Western Cape, South Africa.

Introduction: This study investigates drivers of childhood pulmonary tuberculosis (PTB) using a childhood ecosystem approach in South Africa. An ecosystem approach toward identifying risk factors for PTB may identify targeted interventions.

Methods: Data were collected as part of a prospective cohort study of children presenting at a primary care facility or tertiary hospital with possible TB. Characterization of the childhood ecosystem included proximal, medial, and distal determinants. Proximal determinants included child characteristics that could impact PTB outcomes. Medial determinants included relational factors, such as caregiver health, which might impact interactions with the child. Distal determinants included macro-level determinants of disease, such as socioeconomic status and food insecurity. Children who started on TB treatment were followed for up to 6 months. Multivariate regression models tested independent associations between factors associated with PTB in children.

Results: Of 1202 children enrolled, 242 (20%) of children had confirmed PTB, 756 (63%) were started on TB treatment, and 444 (37%) had respiratory conditions other than TB. In univariate analyses, childhood malnutrition and caregiver smoking were associated with treated or confirmed PTB. In multivariate analyses, proximal factors, such as male gender and hospitalization, as well as low socioeconomic status as a distal factor, were associated with PTB.

Conclusions: Interventions may need to target subgroups of children and families with elevated proximal, medial, and distal risk factors for PTB. Screening for risk factors, such as caregiver's health, may guide targeting. The provision of social protection programs to bolster economic security may be an important intervention for attenuating childhood exposure to risk factors.
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http://dx.doi.org/10.1002/ppul.25369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477372PMC
July 2021

Prevalence and antimicrobial resistance profiles of respiratory microbial flora in African children with HIV-associated chronic lung disease.

BMC Infect Dis 2021 Feb 25;21(1):216. Epub 2021 Feb 25.

Department of Molecular and Cell Biology & Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.

Background: HIV-associated chronic lung disease (CLD) is common among children living with HIV (CLWH) in sub-Saharan Africa, including those on antiretroviral therapy (ART). However, the pathogenesis of CLD and its possible association with microbial determinants remain poorly understood. We investigated the prevalence, and antibiotic susceptibility of Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI), and Moraxella catarrhalis (MC) among CLWH (established on ART) who had CLD (CLD+), or not (CLD-) in Zimbabwe and Malawi.

Methods: Nasopharyngeal swabs (NP) and sputa were collected from CLD+ CLWH (defined as forced-expiratory volume per second z-score < - 1 without reversibility post-bronchodilation with salbutamol), at enrolment as part of a randomised, placebo-controlled trial of azithromycin (BREATHE trial - NCT02426112 ), and from age- and sex-matched CLD- CLWH. Samples were cultured, and antibiotic susceptibility testing was conducted using disk diffusion. Risk factors for bacterial carriage were identified using questionnaires and analysed using multivariate logistic regression.

Results: A total of 410 participants (336 CLD+, 74 CLD-) were enrolled (median age, 15 years [IQR = 13-18]). SP and MC carriage in NP were higher in CLD+ than in CLD- children: 46% (154/336) vs. 26% (19/74), p = 0.008; and 14% (49/336) vs. 3% (2/74), p = 0.012, respectively. SP isolates from the NP of CLD+ children were more likely to be non-susceptible to penicillin than those from CLD- children (36% [53/144] vs 11% [2/18], p = 0.036). Methicillin-resistant SA was uncommon [4% (7/195)]. In multivariate analysis, key factors associated with NP bacterial carriage included having CLD (SP: adjusted odds ratio (aOR) 2 [95% CI 1.1-3.9]), younger age (SP: aOR 3.2 [1.8-5.8]), viral load suppression (SP: aOR 0.6 [0.4-1.0], SA: 0.5 [0.3-0.9]), stunting (SP: aOR 1.6 [1.1-2.6]) and male sex (SA: aOR 1.7 [1.0-2.9]). Sputum bacterial carriage was similar in both groups (50%) and was associated with Zimbabwean site (SP: aOR 3.1 [1.4-7.3], SA: 2.1 [1.1-4.2]), being on ART for a longer period (SP: aOR 0.3 [0.1-0.8]), and hot compared to rainy season (SP: aOR 2.3 [1.2-4.4]).

Conclusions: CLD+ CLWH were more likely to be colonised by MC and SP, including penicillin-non-susceptible SP strains, than CLD- CLWH. The role of these bacteria in CLD pathogenesis, including the risk of acute exacerbations, should be further studied.
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http://dx.doi.org/10.1186/s12879-021-05904-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908671PMC
February 2021

'We had to manage what we had on hand, in whatever way we could': adaptive responses in policy for decentralized drug-resistant tuberculosis care in South Africa.

Health Policy Plan 2021 Apr;36(3):249-259

Department of Infectious Diseases, Livingstone Hospital, Lindsay Rd, Industrial, Port Elizabeth, 6020, South Africa.

In 2011, the South African National TB Programme launched a policy of decentralized management of drug-resistant tuberculosis (DR-TB) in order to expand the capacity of facilities to treat patients with DR-TB, minimize delays to access care and improve patient outcomes. This policy directive was implemented to varying degrees within a rapidly evolving diagnostic and treatment landscape for DR-TB, placing new demands on already-stressed health systems. The variable readiness of district-level systems to implement the policy prompted questions not only about differences in health systems resources but also front-line actors' capacity to implement change in resource-constrained facilities. Using a grounded theory approach, we analysed data from in-depth interviews and small group discussions conducted between 2016 and 2018 with managers (n = 9), co-ordinators (n = 15), doctors (n = 7) and nurses (n = 18) providing DR-TB care. Data were collected over two phases in district-level decentralized sites of three South African provinces. While health systems readiness assessments conventionally map the availability of 'hardware', i.e. resources and skills to deliver an intervention, a notable absence of systems 'hardware' meant that systems 'software', i.e. health care workers (HCWs) agency, behaviours and interactions provided the basis of locally relevant strategies for decentralized DR-TB care. 'Software readiness' was manifest in four areas of DR-TB care: re-organization of service delivery, redressal of resource shortages, creation of treatment adherence support systems and extension of care parameters for vulnerable patients. These strategies demonstrate adaptive capacity and everyday resilience among HCW to withstand the demands of policy change and innovation in stressed systems. Our work suggests that a useful extension of health systems 'readiness' assessments would include definition and evaluation of HCW 'software' and adaptive capacities in the face of systems hardware gaps.
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http://dx.doi.org/10.1093/heapol/czaa147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059133PMC
April 2021

A Longitudinal Study of the Epidemiology of Seasonal Coronaviruses in an African Birth Cohort.

J Pediatric Infect Dis Soc 2021 May;10(5):607-614

Department of Paediatrics and Child Health and SA-MRC Unit on Child & Adolescent Health, Red Cross War Memorial Children's Hospital and University of Cape Town, Cape Town, South Africa.

Background: Since non-epidemic, seasonal human coronaviruses (sHCoV) commonly infect children, an improved understanding of the epidemiology of these infections may offer insights into the context of severe acute respiratory syndrome (SARS)-CoV-2. We investigated the epidemiology of sHCoV infection during the first year of life, including risk factors and association with lower respiratory tract infection (LRTI).

Methods: We conducted a nested case-control study of infants enrolled in a birth cohort near Cape Town, South Africa, from 2012 to 2015. LRTI surveillance was implemented, and nasopharyngeal swabs were collected fortnightly over infancy. Quantitative PCR detected respiratory pathogens, including coronaviruses-229E, -NL63, -OC43, and -HKU1. Swabs were tested from infants at the time of LRTI and from the 90 days prior as well as from age-matched control infants from the cohort over the equivalent period.

Results: In total, 885 infants were included, among whom 464 LRTI events occurred. Of the 4751 samples tested for sHCoV, 9% tested positive, with HCoV-NL63 the most common. Seasonal HCoV detection was associated with LRTI; this association was strongest for coronavirus-OC43, which was also found in all sHCoV-associated hospitalizations. Birth in winter was associated with sHCoV-LRTI, but there were no clear seasonal differences in detection. Co-detection of Streptococcus pneumoniae was weakly associated with sHCoV-LRTI (odds ratio: 1.8; 95% confidence interval: 0.9-3.6); detection of other respiratory viruses or bacteria was not associated with sHCoV status.

Conclusions: Seasonal HCoV infections were common and associated with LRTI, particularly sHCoV-OC43, which is most closely related to the SARS group of coronaviruses. Interactions of coronaviruses with bacteria in the pathogenesis of LRTI require further study.
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http://dx.doi.org/10.1093/jpids/piaa168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928775PMC
May 2021

Breath can discriminate tuberculosis from other lower respiratory illness in children.

Sci Rep 2021 02 1;11(1):2704. Epub 2021 Feb 1.

Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.

Pediatric tuberculosis (TB) remains a global health crisis. Despite progress, pediatric patients remain difficult to diagnose, with approximately half of all childhood TB patients lacking bacterial confirmation. In this pilot study (n = 31), we identify a 4-compound breathprint and subsequent machine learning model that accurately classifies children with confirmed TB (n = 10) from children with another lower respiratory tract infection (LRTI) (n = 10) with a sensitivity of 80% and specificity of 100% observed across cross validation folds. Importantly, we demonstrate that the breathprint identified an additional nine of eleven patients who had unconfirmed clinical TB and whose symptoms improved while treated for TB. While more work is necessary to validate the utility of using patient breath to diagnose pediatric TB, it shows promise as a triage instrument or paired as part of an aggregate diagnostic scheme.
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http://dx.doi.org/10.1038/s41598-021-80970-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851130PMC
February 2021

A Novel Bedside Rule-in Test for Tuberculous Meningitis in Human Immunodeficiency Virus-Infected Adults.

Clin Infect Dis 2021 11;73(9):e3435-e3437

Division of Infection and Immunity, School of Biomedical Sciences, University of Western Australia, Perth, Australia.

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http://dx.doi.org/10.1093/cid/ciaa1915DOI Listing
November 2021
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