Publications by authors named "Anneke C Hesseling"

136 Publications

Moxifloxacin pharmacokinetics, cardiac safety, and dosing for the treatment of rifampicin-resistant tuberculosis in children.

Clin Infect Dis 2021 Jul 21. Epub 2021 Jul 21.

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.

Background: Moxifloxacin is a priority recommended drug for rifampin-resistant tuberculosis (RR-TB) treatment, but there is limited pediatric pharmacokinetic and safety data, especially in young children. We characterize moxifloxacin population pharmacokinetics, QT-interval prolongation and evaluate optimal dosing in children with RR-TB.

Methods: Pharmacokinetic data were pooled from two observational studies in South African children 0-17 years of age with RR-TB routinely treated with oral moxifloxacin once daily. The population pharmacokinetics and Fridericia-corrected QT (QTcF)-interval prolongation were characterized in NONMEM. Pharmacokinetic simulations were performed to predict expected exposure and optimal weight-banded dosing.

Results: Eighty-five children contributed pharmacokinetic data (median [range] age of 4.6 [0.8-15] years); 16 (19%) were <2 years of age, and 8 (9%) were HIV-positive. The median (range) moxifloxacin dose on pharmacokinetic sampling days was 11 mg/kg (6.1 to 17). Apparent clearance was 6.95 L/h for a typical 16 kg child. Stunting and HIV infection increased apparent clearance. Crushed or suspended tablets had faster absorption. The median (range) maximum change in QTcF after moxifloxacin administration was 16.3 (-27.7 to 61.3) ms. No child had QTcF ≥ 500 ms. The concentration-QTcF relationship was nonlinear, with a maximum drug effect (Emax) of 8.80 ms (inter-individual variability = 9.75 ms). Clofazimine use increased Emax by 3.3-fold. Model-based simulations of moxifloxacin pharmacokinetics predicted that current dosing recommendations are too low in children.

Conclusions: Moxifloxacin doses above 10-15 mg/kg are likely required in young children to match adult exposures but require further safety assessment, especially when co-administered with other QT-prolonging agents.
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http://dx.doi.org/10.1093/cid/ciab641DOI Listing
July 2021

Early mortality in tuberculosis patients initially lost to follow up following diagnosis in provincial hospitals and primary health care facilities in Western Cape, South Africa.

PLoS One 2021 14;16(6):e0252084. Epub 2021 Jun 14.

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

In South Africa, low tuberculosis (TB) treatment coverage and high TB case fatality remain important challenges. Following TB diagnosis, patients must link with a primary health care (PHC) facility for initiation or continuation of antituberculosis treatment and TB registration. We aimed to evaluate mortality among TB patients who did not link to a TB treatment facility for TB treatment within 30 days of their TB diagnosis, i.e. who were "initial loss to follow-up (ILTFU)" in Cape Town, South Africa. We prospectively included all patients with a routine laboratory or clinical diagnosis of TB made at PHC or hospital level in Khayelitsha and Tygerberg sub-districts in Cape Town, using routine TB data from an integrated provincial health data centre between October 2018 and March 2020. Overall, 74% (10,208/13,736) of TB patients were diagnosed at PHC facilities and ILTFU was 20.0% (2,742/13,736). Of ILTFU patients, 17.1% (468/2,742) died, with 69.7% (326/468) of deaths occurring within 30 days of diagnosis. Most ILTFU deaths (85.5%; 400/468) occurred in patients diagnosed in hospital. Multivariable logistic regression identified increasing age, HIV positive status, and hospital-based TB diagnosis (higher in the absence of TB treatment initiation and being ILTFU) as predictors of mortality. Although hospitals account for a modest proportion of diagnosed TB patients they have high TB-associated mortality. A hospital-based TB diagnosis is a critical opportunity to identify those at high risk of early and overall mortality. Interventions to diagnose TB before hospital admission, improve linkage to TB treatment following diagnosis, and reduce mortality in hospital-diagnosed TB patients should be prioritised.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252084PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202951PMC
June 2021

The Magnitude of Interferon Gamma Release Assay Responses in Children With Household Tuberculosis Contact Is Associated With Tuberculosis Exposure and Disease Status.

Pediatr Infect Dis J 2021 Aug;40(8):763-770

From the Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa.

Background: The clinical utility of the magnitude of interferon gamma (IFNγ) in response to mycobacterial antigens is unknown. We assessed the association between quantitative IFNγ response and degree of Mycobacterium tuberculosis exposure, infection and tuberculosis (TB) disease status in children.

Methods: We completed cross-sectional analysis of children (≤15 years) exposed to an adult with bacteriologically confirmed TB, 2007-2012 in Cape Town, South Africa. IFNγ values were reported as concentrations and spot forming units for the QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB, respectively. Random-effects linear regression was used to investigate the relation between the M. tuberculosis contact score, clinical phenotype (TB diseased, infected, uninfected) and IFNγ▪response as outcome, adjusted for relevant covariates.

Results: We analyzed data from 669 children (median age, 63 months; interquartile range, 33-108 months). A 1-unit increase in M. tuberculosis contact score was associated with an increase of IFNγ 0.60 international unit/mL (95% confidence interval [CI], 0.44-0.76 international unit/mL), and IFNγ spot forming unit 2 counts (95% CI, 1-3). IFNγ response was significantly lower among children with M. tuberculosis infection compared with children with TB disease (β = -1.42; 95% CI, -2.80 to -0.03) for the QFT-GIT, but not for the T-SPOT.TB. This association was strongest among children 2-5 years (β = -2.35 years; 95% CI, -4.28 to -0.42 years) and absent if <2 years.

Conclusions: The magnitude of IFNγ response correlated with the degree of recent M. tuberculosis exposure, measured by QFT-GIT and T-SPOT.TB, and was correlated with clinically relevant TB phenotypes using the QFT-GIT. IFNγ values are not only useful in estimating the risk of M. tuberculosis infection but may also support the diagnosis of TB disease in children.

Discussion: The magnitude of IFNγ response correlated with the degree of recent M. tuberculosis exposure, measured by QFT-GIT and T-SPOT.TB, and was correlated with clinically relevant TB phenotypes using the QFT-GIT. IFNγ values are not only useful in estimating the risk of M. tuberculosis infection but may also support the diagnosis of TB disease in children.
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http://dx.doi.org/10.1097/INF.0000000000003196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277676PMC
August 2021

Improving child tuberculosis contact identification and screening in Lesotho: Results from a mixed-methods cluster-randomized implementation science study.

PLoS One 2021 20;16(5):e0248516. Epub 2021 May 20.

ICAP, Mailman School of Public Health, Columbia University, New York, New York, United States of America.

Background: Child tuberculosis (TB) contact management is recommended for preventing TB in children but its implementation is suboptimal in high TB/HIV-burden settings. The PREVENT Study was a mixed-methods, clustered-randomized implementation study that evaluated the effectiveness and acceptability of a community-based intervention (CBI) to improve child TB contact management in Lesotho, a high TB burden country.

Methods: Ten health facilities were randomized to CBI or standard of care (SOC). CBI holistically addressed the complex provider-, patient-, and caregiver-related barriers to prevention of childhood TB. Routine TB program data were abstracted from TB registers and cards for all adult TB patients aged >18 years registered during the study period, and their child contacts. Primary outcome was yield (number) of child contacts identified and screened per adult TB patient. Generalized linear mixed models tested for differences between study arms. CBI acceptability was assessed via semi-structured in-depth interviews with a purposively selected sample of 20 healthcare providers and 28 caregivers. Qualitative data were used to explain and confirm quantitative results. We used thematic analysis to analyze the data.

Results: From 01/2017-06/2018, 973 adult TB patients were recorded, 490 at CBI and 483 at SOC health facilities; 64% male, 68% HIV-positive. At CBI and SOC health facilities, 216 and 164 child contacts were identified, respectively (p = 0.16). Screening proportions (94% vs. 62%, p = 0.13) were similar; contact yield per TB case (0.40 vs. 0.20, p = 0.08) was higher at CBI than SOC health facilities, respectively. CBI was acceptable to caregivers and healthcare providers.

Conclusion: Identification and screening for TB child contacts were similar across study arms but yield was marginally higher at CBI compared with SOC health facilities. CBI scale-up may enhance the ability to reach and engage child TB contacts, contributing to efforts to improve TB prevention among children.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248516PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136650PMC
May 2021

Health system determinants of tuberculosis mortality in South Africa: a causal loop model.

BMC Health Serv Res 2021 Apr 26;21(1):388. Epub 2021 Apr 26.

HIV Prevention Research Unit, South African Medical Research Council, KwaZulu-Natal, Pietermaritzburg, South Africa.

Background: Tuberculosis (TB) is a major public health concern in South Africa and TB-related mortality remains unacceptably high. Numerous clinical studies have examined the direct causes of TB-related mortality, but its wider, systemic drivers are less well understood. Applying systems thinking, we aimed to identify factors underlying TB mortality in South Africa and describe their relationships. At a meeting organised by the 'Optimising TB Treatment Outcomes' task team of the National TB Think Tank, we drew on the wide expertise of attendees to identify factors underlying TB mortality in South Africa. We generated a causal loop diagram to illustrate how these factors relate to each other.

Results: Meeting attendees identified nine key variables: three 'drivers' (adequacy & availability of tools, implementation of guidelines, and the burden of bureaucracy); three 'links' (integration of health services, integration of data systems, and utilisation of prevention strategies); and three 'outcomes' (accessibility of services, patient empowerment, and socio-economic status). Through the development and refinement of the causal loop diagram, additional explanatory and linking variables were added and three important reinforcing loops identified. Loop 1, 'Leadership and management for outcomes' illustrated that poor leadership led to increased bureaucracy and reduced the accessibility of TB services, which increased TB-related mortality and reinforced poor leadership through patient empowerment. Loop 2, 'Prevention and structural determinants' describes the complex reinforcing loop between socio-economic status, patient empowerment, the poor uptake of TB and HIV prevention strategies and increasing TB mortality. Loop 3, 'System capacity' describes how fragmented leadership and limited resources compromise the workforce and the performance and accessibility of TB services, and how this negatively affects the demand for higher levels of stewardship.

Conclusions: Strengthening leadership, reducing bureaucracy, improving integration across all levels of the system, increasing health care worker support, and using windows of opportunity to target points of leverage within the South African health system are needed to both strengthen the system and reduce TB mortality. Further refinement of this model may allow for the identification of additional areas of intervention.
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http://dx.doi.org/10.1186/s12913-021-06398-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074279PMC
April 2021

Diagnostic utility of bronchoalveolar lavage in children with complicated intrathoracic tuberculosis.

Pediatr Pulmonol 2021 Jul 13;56(7):2186-2194. Epub 2021 Apr 13.

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Introduction: Bronchoscopy can be a useful tool in children with pulmonary tuberculosis (PTB) with severe disease potentially requiring intervention or in the face of diagnostic dilemmas. The aim of this study was to determine the value of Xpert MTB/RIF assay (Xpert) on bronchoalveolar lavage (BAL) samples in children with complicated PTB.

Methods: Retrospective analysis of children with clinically diagnosed PTB, who underwent routine bronchoscopy over a 5-year period at a large referral hospital. BAL and other respiratory samples were tested by microscopy, culture, and Xpert. We explored whether clinical, radiographic and bronchoscopy findings, and duration of antituberculosis treatment were associated with bacteriological confirmation.

Results: One hundred and twelve out of one hundred and forty-six (76.7%) children (median age 16 months) were on antituberculosis treatment for a median of 10 days at the time of bronchoscopy. Overall, bacteriological confirmation was achieved in 115 (78.7%), with 101 (69.2%) detected on BAL. Of those bacteriologically confirmed on BAL, 61.4% were positive by both Xpert and culture, 34.7% only by Xpert, and 3.9% only by culture. Sensitivity and specificity of Xpert compared with culture on BAL samples for children not on antituberculosis treatment were 94.1% (95% confidence interval [CI]: 71.3, 99.8) and 68.7% (95% CI: 41.3, 89.0), respectively.

Conclusions: In children undergoing bronchoscopy for complicated PTB, Xpert testing of BAL had a high diagnostic yield in children already on antituberculosis treatment. Bronchoscopy should be considered if noninvasive respiratory specimens fail to confirm complicated TB.
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http://dx.doi.org/10.1002/ppul.25405DOI Listing
July 2021

Paediatric tuberculosis - new advances to close persistent gaps.

Int J Infect Dis 2021 Mar 11. Epub 2021 Mar 11.

The Indus Hospital, Karachi, Pakistan.

Young children are most vulnerable to develop severe forms of tuberculosis (TB) and are over-represented among TB deaths. Almost all children estimated to have died from TB were never diagnosed or offered TB treatment. Improved access to TB preventive treatment (TPT) requires major upscaling of household contact investigation with allocation of adequate resources. Symptom-based screening is often discouraged in adults for fear of generating drug resistance, if TB cases are missed. However, the situation in vulnerable young children is different, as they present minimal risk of drug resistance generation. Further, the perceived need for additional diagnostic evaluation presents a major barrier to TPT access and underlies general reluctance to consider pragmatic decentralised models of care. Widespread roll-out of Xpert MTB/RIF Ultra® represents an opportunity for improved case detection in young children, but attaining full impact will require the use of non-sputum specimens. The new Fujifilm SILVAMP TB LAM® urine assay demonstrated good diagnostic accuracy in HIV-positive and malnourished children, but further validation is required. Given the limited accuracy of all available tests and the excellent tolerance of TB drugs in children, the global community may have to accept some over-treatment if we want to close the persistent case detection gap in young children.
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http://dx.doi.org/10.1016/j.ijid.2021.02.003DOI Listing
March 2021

Mortality in South African Children and Adolescents Routinely Treated for Tuberculosis.

Pediatrics 2021 04 10;147(4). Epub 2021 Mar 10.

Desmond Tutu Tuberculosis Centre, Departments of Paediatrics and Child Health and.

Background: In South Africa, tuberculosis (TB) is a leading cause of death among those <20 years of age. We describe changes in TB mortality among children and adolescents in South Africa over a 13-year period, identify risk factors for mortality, and estimate excess TB-related mortality.

Methods: Retrospective analysis of all patients <20 years of age routinely recorded in the national electronic drug-susceptible TB treatment register (2004-2016). We developed a multivariable Cox regression model for predictors of mortality and used estimates of mortality among the general population to calculate standardized mortality ratios (SMRs).

Results: Between 2004 and 2016, 729 463 children and adolescents were recorded on TB treatment; 84.0% had treatment outcomes and 2.5% (18 539) died during TB treatment. The case fatality ratio decreased from 3.3% in 2007 to 1.9% in 2016. In the multivariable Cox regression model, ages 0 to 4, 10 to 14, and 15 to 19 years (compared with ages 5 to 9 years) were associated with increased risk of mortality, as was HIV infection, previous TB treatment, and extrapulmonary involvement. The SMR of 15 to 19-year-old female patients was more than double that of male patients the same age (55.3 vs 26.2). Among 10 to 14-year-olds and those who were HIV-positive, SMRs increased over time.

Conclusions: Mortality in South African children and adolescents treated for TB is declining but remains considerable, with 2% dying during 2016. Adolescents (10 to 19 years) and those people living with HIV have the highest risk of mortality and the greatest SMRs. Interventions to reduce mortality during TB treatment, specifically targeting those at highest risk, are urgently needed.
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http://dx.doi.org/10.1542/peds.2020-032490DOI Listing
April 2021

Tuberculosis in persons with sudden unexpected death, in Cape Town, South Africa.

Int J Infect Dis 2021 Apr 12;105:75-82. Epub 2021 Feb 12.

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Background: Globally, tuberculosis (TB) remains one of the leading causes of death from a single infectious agent, but there has been little work to estimate mortality before the diagnosis of TB. We investigated the burden of diagnosed and undiagnosed TB in adult and child sudden unexpected deaths (SUDs) evaluated at Tygerberg Forensic Pathology Services, South Africa.

Methods: In a retrospective descriptive study spanning 2016, we identified all SUDs where active TB was detected at post-mortem and matched with routine health service data to differentiate decedents who were diagnosed or undiagnosed with TB before death. A patient pathway analysis of the health service activities preceding SUD in adults with active TB was conducted.

Results: Active TB was identified at post-mortem in 6.2% (48/770) of SUDs and was undiagnosed before death in 91.7% (44/48). The prevalence of active TB was 8.1% in adult SUDs (90.1% undiagnosed before SUD) and 1.8% in children (none diagnosed before SUD). Patient pathway analysis was possible for 15 adult SUDs, and this documented primary health care clinic attendances and hospital admissions in the six months preceding death and missed opportunities for TB investigations.

Conclusion: The prevalence of TB among SUDs in the Eastern Metro of Cape Town is high. Most active TB at post-mortem was undiagnosed before death, and multiple missed opportunities for TB investigation and diagnosis were noted. The systematic evaluation of all SUDs for TB could improve the reporting of undiagnosed TB and support risk mitigation for healthcare workers involved with the post-mortem process.
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http://dx.doi.org/10.1016/j.ijid.2021.02.036DOI Listing
April 2021

The impact of the evolving HIV response on the epidemiology of tuberculosis in South African children and adolescents.

Clin Infect Dis 2021 Feb 3. Epub 2021 Feb 3.

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Background: Few studies have evaluated tuberculosis control in children and adolescents. We used routine tuberculosis surveillance data to quantify age- and HIV-stratified trends over time and investigate the relationship between tuberculosis, HIV, age and sex.

Methods: All children and adolescents (0-19 years) routinely treated for drug-susceptible tuberculosis in South Africa and recorded in a de-duplicated national electronic tuberculosis treatment register (2004-2016) were included. Age- and HIV-stratified tuberculosis case notification rates (CNRs) were calculated in four age bands: 0-4, 5-9, 10-14 and 15-19 years. The association between HIV infection, age and sex in children and adolescents with TB was evaluated using multivariable logistic regression.

Results: Of 719,400 children and adolescents included, 339,112 (47%) were 0-4-year-olds. The overall tuberculosis CNR for 0-19-year-olds declined by 54% between 2009 and 2016 (incidence rate ratio [IRR]=0.46, 95% confidence interval [CI] 0.45-0.47). Trends varied by age and HIV, with the smallest reductions (2013-2016) in HIV-positive 0-4-year-olds (IRR=0.90, 95%CI 0.85-0.95) and both HIV-positive (IRR=0.84, 95%CI 0.80-0.88) and HIV-negative (IRR=0.89, 95%CI 0.86-0.92) 15-19-year-olds. Compared to 0-4-year-old males, odds of HIV co-infection among 15-19-year-olds were nearly twice as high in females (adjusted odd's ratio [aOR]=2.49, 95%CI 2.38-2.60) than in males (aOR=1.35, 95%CI 1.29-1.42).

Conclusions: South Africa's national response to the HIV epidemic has made a substantial contribution to the observed declining trends in tuberculosis CNRs in children and adolescents. The slow decline of tuberculosis CNRs in adolescents and young HIV-positive children is concerning. Understanding how tuberculosis affects children and adolescents beyond conventional age bands and by sex, can inform targeted tuberculosis control strategies.
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http://dx.doi.org/10.1093/cid/ciab095DOI Listing
February 2021

Development of a treatment-decision algorithm for HIV-uninfected children evaluated for pulmonary tuberculosis.

Clin Infect Dis 2021 Jan 15. Epub 2021 Jan 15.

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University and Department of Infectious Diseases, Imperial College; Desmond Tutu TB Centre, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa.

Background: Limitations in the sensitivity and accessibility of diagnostic tools for childhood tuberculosis contribute to the substantial gap between estimated cases and cases notified to national tuberculosis programs. Thus, tools to make accurate and rapid clinical diagnoses are necessary to initiate more children on antituberculosis treatment.

Methods: We analyzed data from a prospective cohort of children <13 years being routinely evaluated for pulmonary tuberculosis in Cape Town, South Africa from March 2012 to November 2017. We developed a regression model to describe the contributions of baseline clinical evaluation to the diagnosis of tuberculosis using standardized, retrospective case definitions. We included results from baseline chest radiography and Xpert MTB/RIF to the model to develop an algorithm with at least 90% sensitivity in predicting tuberculosis.

Results: Data from 478 children being evaluated for pulmonary tuberculosis were analyzed (median age: 16.2 months, interquartile range: 9.8-30.9); 242 (50.6%) were retrospectively classified with tuberculosis, of which 104 (43.0%) were bacteriologically-confirmed. The area under the receiver operating characteristic curve for the final model was 0.87. Clinical evidence identified 71.4% of all tuberculosis cases in this cohort, and inclusion of baseline chest radiography results increased the proportion to 89.3%. The algorithm was 90.1% sensitive and 52.1% specific, and maintained a sensitivity of above 90% among children <2 years or with low weight-for-age.

Conclusions: Clinical evidence alone was sufficient to make most clinical antituberculosis treatment decisions. The use of evidence-based algorithms may improve decentralized, rapid treatment-initiation, reducing the global burden of childhood mortality.
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http://dx.doi.org/10.1093/cid/ciab018DOI Listing
January 2021

Opportunities for Mobile App-Based Adherence Support for Children With Tuberculosis in South Africa.

JMIR Mhealth Uhealth 2020 11 11;8(11):e19154. Epub 2020 Nov 11.

Desmond Tutu Tuberculosis Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Tuberculosis is the number one infectious cause of death globally. Young children, generally those younger than 5 years, are at the highest risk of progressing from tuberculosis infection to tuberculosis disease and of developing the most severe forms of tuberculosis. Most current tuberculosis drug formulations have poor acceptability among children and require consistent adherence for prolonged periods of time. These challenges complicate children's adherence to treatment and caregivers' daily administration of the drugs. Rapid developments in mobile technologies and apps present opportunities for using widely available technology to support national tuberculosis programs and patient treatment adherence. Pilot studies have demonstrated that mobile apps are a feasible and acceptable means of enhancing children's treatment adherence for other chronic conditions. Despite this, no mobile apps that aim to promote adherence to tuberculosis treatment have been developed for children. In this paper, we draw on our experiences carrying out research in clinical pediatric tuberculosis studies in South Africa. We present hypothetical scenarios of children's adherence to tuberculosis medication to suggest priorities for behavioral and educational strategies that a mobile app could incorporate to address some of the adherence support gaps faced by children diagnosed with tuberculosis. We argue that a mobile app has the potential to lessen some of the negative experiences that children associate with taking tuberculosis treatment and to facilitate a more positive treatment adherence experience for children and their caregivers.
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http://dx.doi.org/10.2196/19154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688382PMC
November 2020

Tuberculosis prevention in children: a prospective community-based study in South Africa.

Eur Respir J 2021 04 22;57(4). Epub 2021 Apr 22.

Global Tuberculosis Program, Dept of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.

Tuberculosis (TB) preventive therapy reduces TB risk in children. However, the effectiveness of TB preventive therapy in children living in high TB burden settings is unclear.In a prospective observational community-based cohort study in Cape Town, South Africa, we assessed the effectiveness of routine TB preventive therapy in children ≤15 years of age in a high TB and HIV prevalence setting.Among 966 children (median (interquartile range) age 5.07 (2.52-8.72) years), 676 (70%) reported exposure to an adult with TB in the past 3 months and 240 out of 326 (74%) eligible children initiated isoniazid preventive therapy under programmatic guidelines. Prevalent (n=73) and incident (n=27) TB were diagnosed among 100 out of 966 (10%) children. Children who initiated isoniazid preventive therapy were 82% less likely to develop incident TB than children who did not (adjusted OR 0.18, 95% CI 0.06-0.52; p=0.0014). Risk of incident TB increased if children were <5 years of age, living with HIV, had a positive -specific immune response or recent TB exposure. The risk of incident TB was not associated with sex or bacille Calmette-Guérin vaccination status. Number needed to treat (NNT) was lowest in children living with HIV (NNT=15) and children <5 years of age (NNT=19) compared with children of all ages (NNT=82).In communities with high TB prevalence, TB preventive therapy substantially reduces the risk of TB among children who are <5 years of age or living with HIV, especially those with recent TB exposure or a positive -specific immune response in the absence of disease.
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http://dx.doi.org/10.1183/13993003.03028-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060782PMC
April 2021

Positive Mycobacterium tuberculosis Gastric Lavage Cultures from Asymptomatic Children With Normal Chest Radiography.

J Pediatric Infect Dis Soc 2021 Apr;10(4):502-508

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Mycobacterium tuberculosis culture from gastric lavage from apparently healthy children following tuberculin skin test conversion, despite normal chest radiography (CR), is well known but is a contentious subject. A consensus statement regarding classification of childhood tuberculosis excluded this condition, stating that more data were needed. To assist in this discussion, we reviewed early publications that reported the occurrence of this phenomenon and early anatomical pathology studies that described changes that occur in children following tuberculosis infection. Pathology studies describe frequent cavitation in primary foci in children from whom positive M. tuberculosis cultures might easily arise. These foci were very small in some children who might have normal CR. Positive cultures might also arise from ulcerated mediastinal lymph nodes that are invisible on CR. Young children with recent infection very likely have active primary pulmonary tuberculosis.
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http://dx.doi.org/10.1093/jpids/piaa113DOI Listing
April 2021

Pragmatic global dosing recommendations for the 3-month, once-weekly rifapentine and isoniazid preventive TB regimen in children.

Eur Respir J 2021 01 5;57(1). Epub 2021 Jan 5.

Dept of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.

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http://dx.doi.org/10.1183/13993003.01756-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870317PMC
January 2021

Coronavirus Disease 2019 (COVID-19) Pharmacologic Treatments for Children: Research Priorities and Approach to Pediatric Studies.

Clin Infect Dis 2021 03;72(6):1067-1073

Department of Pediatrics, Stony Brook Children's, Stony Brook, New York, USA.

Clinical trials of pharmacologic treatments of coronavirus disease 2019 (COVID-19) are being rapidly designed and implemented in adults. Children are often not considered during development of novel treatments for infectious diseases until very late. Although children appear to have a lower risk compared with adults of severe COVID-19 disease, a substantial number of children globally will benefit from pharmacologic treatments. It will be reasonable to extrapolate efficacy of most treatments from adult trials to children. Pediatric trials should focus on characterizing a treatment's pharmacokinetics, optimal dose, and safety across the age spectrum. These trials should use an adaptive design to efficiently add or remove arms in what will be a rapidly evolving treatment landscape, and should involve a large number of sites across the globe in a collaborative effort to facilitate efficient implementation. All stakeholders must commit to equitable access to any effective, safe treatment for children everywhere.
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http://dx.doi.org/10.1093/cid/ciaa885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337679PMC
March 2021

Trends in Drug Resistance in Childhood Tuberculosis in Cape Town, South Africa.

Pediatr Infect Dis J 2020 07;39(7):604-608

From the Desmond Tutu Tuberculosis Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Background: We determined mycobacterial drug resistance and HIV prevalence among children with bacteriologically confirmed tuberculosis (TB) from March 2013 to February 2017. Results were compared with 5 previous 2-year surveillance studies (2003-2013).

Methods: Prospective surveillance of all bacteriologically confirmed TB in children (0-13 years) completed at Tygerberg Hospital, Cape Town, South Africa. Drug susceptibility testing was done by GenoType MTBDRplus for isoniazid and rifampicin; ofloxacin and amikacin drug susceptibility testing was completed if rifampicin resistance was detected. Xpert MTB/RIF was routinely introduced during this period.

Results: Six hundred sixty-two children, median age 34 months (interquartile range 14-79) had bacteriologically confirmed TB; 587 (88.7%) were culture-confirmed and 75 (11.3%) confirmed by Xpert MTB/RIF only. Of culture-confirmed cases, 509 (86.7%) were pan-susceptible, 47 (8.0%) were multidrug-resistant, 13 (2.2%) were RIF-resistant/INH-susceptible and 18 (3.1%) were INH-resistant/RIF-susceptible. Of Xpert-positive cases, 3/75 (4%), 68/75 (92%) and 4/75 (5%) were RIF-resistant, RIF-susceptible and RIF-indeterminate, respectively. Of 573 (97.6%) children tested, 74 (12.9%) were HIV positive. Compared with previous surveillance periods, RIF mono-resistance increased from 0% to 2.2% (trend test: χ = 7.050, P = 0.0079). HIV prevalence decreased from 29% to 10.6% (trend test: χ = 27.975, P < 0.0001). Of multidrug-resistant cases, 15/47 (32%) were ofloxacin resistant.

Conclusions: The increase in RIF-resistant/INH-susceptible cases and ofloxacin resistance among multidrug-resistant TB cases in children, indicative of recent transmission, is concerning. The prevalence of multidrug-resistant TB remains high in children.
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http://dx.doi.org/10.1097/INF.0000000000002631DOI Listing
July 2020

Provider attitudes about childhood tuberculosis prevention in Lesotho: a qualitative study.

BMC Health Serv Res 2020 May 25;20(1):461. Epub 2020 May 25.

ICAP at Columbia University, Mailman School of Public Health, 722 West 168th Street, MSPH Box 18, New York, NY, 10032, USA.

Background: The World Health Organization estimated that 1.12 million children developed tuberculosis (TB) in 2018, and at least 200,000 children died from TB. Implementation of effective child contact management is an important strategy to prevent childhood TB but these practices often are not prioritized or implemented, particularly in low- and middle-income countries. This study aimed to explore attitudes of healthcare providers toward TB prevention and perceived facilitators and challenges to child contact management in Lesotho, a high TB burden country. Qualitative data were collected via group and individual in-depth interviews with 12 healthcare providers at five health facilities in one district and analyzed using a thematic framework.

Results: Healthcare providers in our study were interested and committed to improve child TB contact management and identified facilitators and challenges to a successful childhood TB prevention program. Facilitators included: provider understanding of the importance of TB prevention and enhanced provider training on child TB contact management, with a particular focus on ruling out TB in children and addressing side effects. Challenges identified by providers were at multiple levels -- structural, clinic, and individual and included: [1] access to care, [2] supply-chain issues, [3] identification and screening of child contacts, and [4] adherence to isoniazid preventive therapy.

Conclusions: Given the significant burden of TB morbidity and mortality in young children and the recent requirement by the WHO to report IPT initiation in child contacts, prioritization of child TB contact management is imperative and should include enhanced provider training on childhood TB and mentorship as well as strategies to eliminate challenges. Strategies that enable more efficient child TB contact management delivery include creating standardized tools that facilitate the implementation, tracking, and monitoring of child TB contact management coupled with guidance and mentorship from the district health management team. To tackle access to care challenges, we propose delivering intensive community health education, conducting community screening more efficiently using standardized tools, and facilitating access to services in the community.
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http://dx.doi.org/10.1186/s12913-020-05324-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249694PMC
May 2020

Tuberculosis in children, adolescents, and women.

Lancet Respir Med 2020 04 27;8(4):335-337. Epub 2020 Feb 27.

Department of Infection, Division of Infection and Immunity, University College London, London, UK; NIHR Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1016/S2213-2600(20)30077-1DOI Listing
April 2020

Identification of subclinical tuberculosis in household contacts using exposure scores and contact investigations.

BMC Infect Dis 2020 Jan 31;20(1):96. Epub 2020 Jan 31.

Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway.

Background: The goal of tuberculosis elimination put forward in the End TB Strategy prioritizes diagnosis and treatment of incipient and subclinical TB, recently defined by key stakeholders as "asymptomatic, early pre-clinical disease during which pathology evolves". Regarded as indicative of a high risk of TB progression, considerable efforts have been made to identify these cases through exploration of biomarkers. The present study aimed to evaluate simple scoring systems for TB exposure as screening tools for subclinical TB, the only identifiable of the incipient and subclinical disease states, in a contact investigation (CI) setting of low HIV-prevalence.

Methods: Nested within a large prospective study in household contacts (HHCs) of smear positive pulmonary TB cases in South-India conducted 2010-2012, we assessed 1) the association between the Tuberculosis Contact Score (TCS) and the Infectivity Score, with established tools for Mycobacterium tuberculosis (Mtb) infection, corrected for established TB risk factors, and 2) the capability of the TB exposure scores to identify subclinical TB defined by Mtb-culture positivity in sputum or gastric aspirate (subjects < 5 years) specimen.

Results: Of 525 HHCs, 29 were Mtb-culture positive and 96.6% of these asymptomatic. The TCS and the Infectivity Score associated with positive Tuberculin Skin Test and QuantiFeron TB-Gold In-tube assay (QFT) results in multivariate analyses (TCS: OR 1.16, 95% CI: 1.01, 1.33; OR 1.33 95% CI: 1.16, 1.51. Infectivity Score: OR 1.39, 95% CI: 1.10, 1.76; OR 1.41 95% CI: 1.16, 1.71). The Infectivity Score showed a moderate capability to identify subclinical TB (AUC of 0.61, 95% CI: 0.52, 0.70).

Conclusions: Although our results did not identify an easily applicable screening tool for subclinical TB, the present study indicates that focusing on TB-related symptoms in CI settings may be of limited value for early identification of HHCs with high risk for TB progression.
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http://dx.doi.org/10.1186/s12879-020-4800-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995184PMC
January 2020

Population Pharmacokinetics and Dosing of Ethionamide in Children with Tuberculosis.

Antimicrob Agents Chemother 2020 02 21;64(3). Epub 2020 Feb 21.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa

Ethionamide has proven efficacy against both drug-susceptible and some drug-resistant strains of Limited information on its pharmacokinetics in children is available, and current doses are extrapolated from weight-based adult doses. Pediatric doses based on more robust evidence are expected to improve antituberculosis treatment, especially in small children. In this analysis, ethionamide concentrations in children from 2 observational clinical studies conducted in Cape Town, South Africa, were pooled. All children received ethionamide once daily at a weight-based dose of approximately 20 mg/kg of body weight (range, 10.4 to 25.3 mg/kg) in combination with other first- or second-line antituberculosis medications and with antiretroviral therapy in cases of HIV coinfection. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. The MDR-PK1 study contributed data for 110 children on treatment for multidrug-resistant tuberculosis, while the DATiC study contributed data for 9 children treated for drug-susceptible tuberculosis. The median age of the children in the studies combined was 2.6 years (range, 0.23 to 15 years), and the median weight was 12.5 kg (range, 2.5 to 66 kg). A one-compartment, transit absorption model with first-order elimination best described ethionamide pharmacokinetics in children. Allometric scaling of clearance (typical value, 8.88 liters/h), the volume of distribution (typical value, 21.4 liters), and maturation of clearance and absorption improved the model fit. HIV coinfection decreased the ethionamide bioavailability by 22%, rifampin coadministration increased clearance by 16%, and ethionamide administration by use of a nasogastric tube increased the rate, but the not extent, of absorption. The developed model was used to predict pediatric doses achieving the same drug exposure achieved in 50- to 70-kg adults receiving 750-mg once-daily dosing. Based on model predictions, we recommend a weight-banded pediatric dosing scheme using scored 125-mg tablets.
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http://dx.doi.org/10.1128/AAC.01984-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038277PMC
February 2020

Inclusion of key populations in clinical trials of new antituberculosis treatments: Current barriers and recommendations for pregnant and lactating women, children, and HIV-infected persons.

PLoS Med 2019 08 15;16(8):e1002882. Epub 2019 Aug 15.

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.

Amita Gupta and colleagues discuss priorities in clinical research aimed at improving tuberculosis prevention and treatment in pregnant women, children, and people with HIV.
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http://dx.doi.org/10.1371/journal.pmed.1002882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695091PMC
August 2019

Alternative dosing guidelines to improve outcomes in childhood tuberculosis: a mathematical modelling study.

Lancet Child Adolesc Health 2019 09 16;3(9):636-645. Epub 2019 Jul 16.

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA. Electronic address:

Background: Malnourished and young children are particularly susceptible to severe forms of tuberculosis and poor treatment response. WHO dosing guidelines for drugs for tuberculosis treatment are based only on weight, which might lead to systematic underdosing and poor outcomes in these children. We aimed to assess and quantify the population effect of WHO guidelines for drug-susceptible tuberculosis in children in the 20 countries with the highest disease burden.

Methods: We used an integrated model that linked country-specific demographic data at the individual level from the 20 countries with the highest disease burden to pharmacokinetic, outcome, and epidemiological models. We estimated tuberculosis treatment outcomes in children younger than 5 years following WHO guidelines (children are dosed by weight bands corresponding to the number of fixed-dose combination tablets [75 mg rifampicin, 50 mg isoniazid, 150 mg pyrazinamide]) and two alternative dosing strategies: one based on a proposed algorithm that uses age, weight, and available formulations, in which underweight children would receive the same drug doses as would normal weight children of the same age; and another based on an individualised algorithm without dose limitations, in which derived doses results in target exposure attainment for the typical child.

Findings: We estimated that 57 234 (43%) of 133 302 children younger than 5 years who were treated for tuberculosis in 2017 were underdosed with WHO dosing and only 47% of children would reach the rifampicin exposure target. Underdosing and subtherapeutic exposures were more common among malnourished children than among age-matched healthy children. The proposed dosing approach improved estimated rifampicin target exposure attainment to 62% and equalised outcomes by nutritional status. An estimated third of unfavourable treatment outcomes might be resolved with this dosing strategy, saving the lives of a minimum of 2423 children in these countries annually. With individualised dosing approaches, almost all children could achieve adequate exposure for cure.

Interpretation: This work shows that a simple change in dosing procedure to include age and nutritional status, requiring no additional measurements or new drug formulations, is one approach to improve tuberculosis treatment outcomes in children, especially malnourished children who are at high risk of mortality.

Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development and UK Medical Research Council.
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http://dx.doi.org/10.1016/S2352-4642(19)30196-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605863PMC
September 2019

The evolving research agenda for paediatric tuberculosis infection.

Lancet Infect Dis 2019 09 17;19(9):e322-e329. Epub 2019 Jun 17.

The Indus Hospital, Karachi, Pakistan.

Following exposure to tuberculosis and subsequent infection, children often progress to tuberculosis disease more rapidly than adults. And yet the natural history of tuberculosis in children, as a continuum from exposure to infection and then to disease, is poorly understood. Children are rarely diagnosed with tuberculosis infection in routine care in international settings and few receive tuberculosis infection treatment. In this Personal View, we review the most up-to-date knowledge in three areas of childhood tuberculosis infection-namely, pathophysiology, diagnosis, and treatment. We then outline what is missing in each of these three areas to generate a priority research agenda. Finally, we suggest potential study designs that might answer these questions. Understanding of pathophysiology could be improved through animal models, laboratory studies assessing the immunological responses of blood or respiratory samples to Mycobacterium spp in vitro, as well as investigating immune responses in children exposed to tuberculosis. Identification of children with sub-clinical disease and at high risk of progression to clinically overt disease, would allow treatment to be targeted at those most likely to benefit. Optimisation and discovery of novel treatments for tuberculosis infection in children should account for mechanisms of action of tuberculosis drugs, as well as child-specific factors including pharmacokinetics and appropriate formulations. To conduct these studies, a change in mindset is required, with a recognition that the diagnosis and treatment of tuberculosis infection in children is a necessary component in addressing the overall tuberculosis epidemic. Collaboration between stakeholders will be required and funding will need to increase, both for research and implementation. The consequences of inaction, however, will lead to further decades of children suffering from what should increasingly be recognised as a preventable disease.
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http://dx.doi.org/10.1016/S1473-3099(18)30787-4DOI Listing
September 2019

Morbidity and mortality up to 5 years post tuberculosis treatment in South Africa: A pilot study.

Int J Infect Dis 2019 Aug 24;85:57-63. Epub 2019 May 24.

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; DST-NRF South African Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Stellenbosch University, Stellenbosch, South Africa.

Background: A high risk of tuberculosis (TB), chronic lung disease, and mortality have been reported among people with a history of previous TB treatment, but data from high-incidence settings remain limited. The aim of this study was to characterize general morbidity and mortality among adults who had successfully completed TB treatment in the past 5 years in a high-incidence setting in South Africa.

Methods: Adults (≥18 years) who had completed treatment for pulmonary TB between 2013 and 2017 were randomly selected from TB treatment registers. Household visits were conducted to locate and interview former TB (FTB) patients, and bacteriological testing for TB was offered. Additional data sources were used to ascertain the vitality status of FTB patients who could not be located.

Results: Addresses were located for 200 of the 223 FTB patients sampled and 89 FTB patients were contacted of whom 51 agreed to be interviewed. Approximately half reported persistent respiratory symptoms, such as shortness of breath and wheezing, and repeated lung infections. One (3.6%) of 28 patients who provided a sputum sample had culture-positive TB and another two were currently on re-treatment for TB. Fifteen deaths post treatment were ascertained, resulting in a standardized mortality ratio of 3.8 (95% confidence interval 2.3-6.3) after successful TB treatment relative to the general population.

Conclusions: In this high-incidence setting, locating and interviewing FTB patients was challenging. The study findings are consistent with a high rate of respiratory disease, including recurrent TB, and substantially elevated mortality among FTB patients.
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http://dx.doi.org/10.1016/j.ijid.2019.05.024DOI Listing
August 2019

Pharmacokinetics, optimal dosing, and safety of linezolid in children with multidrug-resistant tuberculosis: Combined data from two prospective observational studies.

PLoS Med 2019 04 30;16(4):e1002789. Epub 2019 Apr 30.

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America.

Background: Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB.

Methods And Findings: Children routinely treated for MDR-TB in 2 observational studies (2011-2015, 2016-2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data.

Conclusions: Linezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated.
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http://dx.doi.org/10.1371/journal.pmed.1002789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490911PMC
April 2019

Feasibility of Identifying Household Contacts of Rifampin-and Multidrug-resistant Tuberculosis Cases at High Risk of Progression to Tuberculosis Disease.

Clin Infect Dis 2020 01;70(3):425-435

Aurum Institute, Parktown, South Africa.

Background: We assessed multidrug-resistant tuberculosis (MDR-TB) cases and their household contacts (HHCs) to inform the development of an interventional clinical trial.

Methods: We conducted a cross-sectional study of adult MDR-TB cases and their HHCs in 8 countries with high TB burdens. HHCs underwent symptom screenings, chest radiographies, sputum TB bacteriologies, TB infection (TBI) testing (tuberculin skin test [TST] and interferon gamma release assay [IGRA]), and human immunodeficiency virus (HIV) testing.

Results: From October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were enrolled. At diagnosis, 69% of MDR-TB cases were positive for acid-fast bacilli sputum smears and 43% had cavitary disease; at study entry, 35% remained smear positive after a median MDR-TB treatment duration of 8.8 weeks. There were 9 HHCs that were diagnosed with TB prior to entry and excluded. Of the remaining 1007 HHCs, 41% were male and the median age was 25 years. There were 121 (12%) HHCs that had new cases of TB identified: 17 (2%) were confirmed, 33 (3%) probable, and 71 (7%) possible TB cases. The TBI prevalence (defined as either TST or IGRA positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775 (77%) were considered high-risk per these mutually exclusive groups: 102 (10%) were aged <5 years; 63 (6%) were aged ≥5 and were infected with HIV; and 610 (61%) were aged ≥5 years, were negative for HIV or had an unknown HIV status, and were TBI positive. Only 21 (2%) HHCs were on preventive therapy.

Conclusions: The majority of HHCs in these high-burden countries were at high risk of TB disease and infection, yet few were receiving routine preventive therapy. Trials of novel, preventive therapies are urgently needed to inform treatment policy and practice.
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http://dx.doi.org/10.1093/cid/ciz235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188224PMC
January 2020

Treatment Outcomes in Global Systematic Review and Patient Meta-Analysis of Children with Extensively Drug-Resistant Tuberculosis.

Emerg Infect Dis 2019 03;25(3):441-450

Extensively drug-resistant tuberculosis (XDR TB) has extremely poor treatment outcomes in adults. Limited data are available for children. We report on clinical manifestations, treatment, and outcomes for 37 children (<15 years of age) with bacteriologically confirmed XDR TB in 11 countries. These patients were managed during 1999-2013. For the 37 children, median age was 11 years, 32 (87%) had pulmonary TB, and 29 had a recorded HIV status; 7 (24%) were infected with HIV. Median treatment duration was 7.0 months for the intensive phase and 12.2 months for the continuation phase. Thirty (81%) children had favorable treatment outcomes. Four (11%) died, 1 (3%) failed treatment, and 2 (5%) did not complete treatment. We found a high proportion of favorable treatment outcomes among children, with mortality rates markedly lower than for adults. Regimens and duration of treatment varied considerably. Evaluation of new regimens in children is required.
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http://dx.doi.org/10.3201/eid2503.180852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390755PMC
March 2019

Pharmacokinetics, Safety, and Dosing of Novel Pediatric Levofloxacin Dispersible Tablets in Children with Multidrug-Resistant Tuberculosis Exposure.

Antimicrob Agents Chemother 2019 04 27;63(4). Epub 2019 Mar 27.

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.

This study characterized the pharmacokinetics of novel 100-mg levofloxacin dispersible tablets in 24 children aged <5 years who had household multidrug-resistant tuberculosus (MDR-TB) exposure. The current data were pooled with previously published data from children ( = 109) with MDR-TB receiving adult (250-mg) levofloxacin tablets, using nonlinear mixed-effects modelling. The adult tablets had 41% lower bioavailability than the novel dispersible tablets, resulting in much higher exposures with the dispersible tablets with the same dose.
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http://dx.doi.org/10.1128/AAC.01865-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437514PMC
April 2019
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