Clinical outcomes in children living with HIV treated for non-severe tuberculosis in the SHINE Trial.

BACKGROUND: Children living with HIV(CLWH) are at high risk of tuberculosis(TB) and face poor outcomes, despite antiretroviral treatment(ART). We evaluated outcomes in CLWH and HIV-uninfected children treated for non-severe TB in the SHINE trial. METHODS: SHINE was a randomized trial that enrolled children aged <16 years with smear-negative, non-severe TB who were randomized to receive 4 vs 6 months of TB treatment and followed for 72 weeks. We assessed TB relapse/recurrence, mortality, hospitalizations, grade ≥3 adverse events by HIV status, and HIV virological suppression in CLWH. RESULTS: Of 1204 enrolled, 127(11%) were CLWH, of similar age (median(IQR) 3.6(1.2, 10.3) vs. 3.5(1.5, 6.9)years, p= 0.07), but more underweight (WAZ; -2.3(-3.3, -0.8) vs -1.0(-1.8, -0.2), p<0.01) and anemic (hemoglobin 9.5(8.7, 10.9) vs 11.5(10.4, 12.3)g/dl, p<0.01) compared to HIV-uninfected children. 68(54%) CLWH were ART-naïve; baseline median CD4 count 719(241-1134) cells/mm3, CD4% 16(10-26)%). CLWH were more likely to be hospitalized (aOR=2.4(1.3-4.6)) and die (aHR(95%CI) 2.6(1.2,5.8)). HIV status, age <3 years (aHR 6.3(1.5,27.3)), malnutrition (aHR 6.2(2.4,15.9)) and hemoglobin <7g/dl(aHR 3.8(1.3,11.5) independently predicted mortality. Among children with available VL, 45% and 61% CLWH had VL<1000copies/ml at weeks 24 and 48, respectively. There was no difference in the effect of randomized treatment duration (4 vs 6 months) on TB treatment outcomes by HIV status (p for interaction=0.42). CONCLUSIONS: We found no evidence of a difference in TB outcomes between 4 and 6 months of treatment for CLWH treated for non-severe TB. Irrespective of TB treatment duration, CLWH had higher rates of mortality and hospitalization than HIV-uninfected counterparts.

We compared outcomes between children with and without HIV treated for non-severe TB. Regardless of treatment duration (4 or 6 months), children with HIV had similar TB outcomes but had higher mortality and hospitalization rates than their HIV-uninfected counterparts.

The socioeconomic impact of the COVID-19 lockdown on families affected by childhood respiratory illnesses in Cape Town, South Africa.

The COVID-19 pandemic impacted families globally, directly and indirectly. Children presenting with respiratory illnesses are affected by emerging health systems and socioeconomic changes in the COVID-19 era. We explored the socioeconomic impacts of the COVID-19 lockdown on families with a respiratory illness diagnosed in their child in Cape Town, South Africa. This study was nested in a prospective observational cohort of children presenting with respiratory symptoms presumptive of COVID-19. We conducted 21 semi-structured interviews to explore the socioeconomic impact of the COVID-19 pandemic on families with a child affected by respiratory illnesses. We used case descriptive analysis and thematically organised common and divergent experiences. We found that socioeconomic challenges in low-income communities were exacerbated: 1) loss of pre-COVID sources of income (loss of income, employment and working hours), 2) shrinking employment opportunities due to business closures and strict preventative measures, 3) family network dependence to cope with financial pressures, 4) impact on education, implicating additional pressures due to lack of resources for adequate home schooling and 5) caregivers' mental health and wellbeing being impacted, causing stress and anxiety due to loss of income. This study shows that the COVID-19 lockdown impacted the socioeconomic aspects of families caring for a child with a respiratory illness. Care became more complicated and adversely impacted the family's emotional well-being and health-seeking behaviour. These impacts should be more carefully considered in order to strengthen health services and global health messaging in future pandemics.

Respiratory adenovirus infections in children: a focus on Africa.

PURPOSE OF REVIEW: Lower respiratory tract infections (LRTIs) are an important cause of child morbidity and mortality globally, especially in children under the age of 5 years in Africa. Respiratory viruses, including human adenoviruses (HAdVs), are common causes of LRTIs in children. This review aims to shed light on the epidemiology, clinical manifestations, sequelae, and treatment options specific to adenovirus respiratory infections in African children. RECENT FINDINGS: Recent evidence has challenged the perception that adenovirus is a negligible cause of LRTIs. Studies show HAdV emerging as the third most common viral pathogen in fatal pneumonias among under-5 children in low-income and middle-income African countries, contributing to 5.5% of all pneumonia deaths and ranking second in hospital-associated viral pneumonia deaths. Predominant HAdV serotypes associated with disease differ by country and region, and have changed over time. Risk factors for increased disease severity and long-term respiratory sequelae in previously healthy African children with HAdV LRTIs are not well established. SUMMARY: Although respiratory viruses, including HAdV, are recognized contributors to LRTIs, the prevalence and impact of adenovirus infections have been under-recognized and understated. Available data suggests that African children, particularly those under 5 years old, are at risk of severe sequelae from respiratory HAdV infections. Long-term sequelae, including bronchiectasis and postinfectious bronchiolitis obliterans, further underscore the significant impact of HAdV infections. However, the scarcity of comprehensive data hampers our understanding of the extent of the impact of HAdV infections on child lung health in Africa. We recommend scaled-up HAdV surveillance, ensuring its consistent inclusion in population-level LRTI assessments, and expanded and equitable access to diagnostics for early recognition of African children at risk of developing chronic sequelae and death. Enhanced understanding of adenovirus epidemiology and clinical outcomes and the availability of therapeutic options are essential for informed public health strategies and clinical care.

How does post COVID differ from other post-viral conditions in childhood and adolescence (0-20 years old)? A systematic review.

Background: Post Coronavirus disease (COVID) and other post-viral infection syndromes present an overlap of pathogenesis, onset, progression, and symptom profile. We aimed to systematically describe studies on post-viral conditions and determine the entity of post COVID compared to other post-viral conditions in children. Methods: We conducted a systematic search of the Embase, MEDLINE, Cochrane Library, and GoogleScholar databases (January 1946-3 November 2023), according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The main outcomes were differences in condition duration, symptom type, and development of chronic symptoms. This systematic review was registered on PROSPERO (CRD42023401789). Findings: 35/5051 studies were included, with 42,934 children, adolescents and young adults (0-20 years old) overall. Twenty-eight studies focused on post COVID symptoms, followed by five papers on Respiratory Syncytial Virus (RSV) and Rhinovirus, one study on Epstein-Barr Virus (EBV), and one on gastrointestinal viruses. Studies on post COVID mainly reported data on older children/adolescents, describing long-lasting symptoms, including fatigue, neurologic, cardiorespiratory, musculoskeletal, mental health, and gastrointestinal symptoms. The maximum described symptoms duration was eighteen months, with an average follow-up of seven months. The development of chronic symptoms was reported by 30 studies (93.8%) for 10,473/28,474 patients (36.8%). Recovery was achieved in 18,001/28,474 cases (63.2%). The study on EBV reported persistent fatigue in adolescents for a similar duration (6 months, 46% chronic). Studies on RSV and Rhinovirus were mainly done in children under three years, with development of recurrent wheezing (up to 3 years). Interpretation: Post-viral fatigue was a shared feature between post COVID and post EBV conditions. A better understanding of post COVID as a unique condition, sharing features with other post-viral syndromes, is needed. The healthcare burden and socio-economic consequences for children and their families warrant further investigation and development of appropriate healthcare management plans. The foremost requirement is the establishment of consistent and shareable definitions, as well as a consensus on outcomes, to effectively evaluate follow-up and quantify the burden of different viral infections. Funding: EU Horizon, EDCTP, NIH.

Impaired lung function in adolescents with pulmonary tuberculosis during treatment and following treatment completion.

Background: Little is known about post-tuberculosis lung disease in adolescents. We prospectively assessed lung function in adolescents with microbiologically confirmed pulmonary tuberculosis during treatment and after treatment completion. Methods: In a prospective study, we enrolled adolescents diagnosed with microbiologically confirmed tuberculosis and healthy tuberculosis-exposed household controls, between October 2020 and July 2021 in Cape Town, South Africa. Spirometry, plethysmography, diffusion capacity lung function tests and 6-min walking test (6MWT) were completed according to international guidelines 2 months into treatment and following treatment completion. Abnormal lung function was defined as abnormal spirometry (z-score < -1.64 for forced expiratory volume in 1 s (FEV1) and/or forced vital capacity (FVC) and/or FEV1/FVC), plethysmography (total lung capacity (TLC) < 80% of predicted, residual volume over TLC of >45%) and/or diffusion capacity (DLCO z-score < -1.64). Findings: One-hundred adolescents were enrolled; 50 (50%) with tuberculosis and 50 (50%) healthy tuberculosis-exposed controls. Of the 50 adolescents with tuberculosis, ten had multidrug-resistant tuberculosis. Mean age of the group was 14.9 years (SD 2.7), 6 (6.0%) were living with HIV and 9 (9.0%) were previously treated for tuberculosis. Lung function improved over time; during treatment abnormal lung function was found in 76% of adolescents with tuberculosis, compared to 65% after treatment completion. Spirometry indices were lower in adolescents with tuberculosis compared to controls, both at 2 months and after treatment completion. Plethysmography in adolescents with tuberculosis showed that air-trapping was more common during treatment than in controls (12% vs 0%, respectively, p = 0.017); which improved following treatment completion. Adolescents with tuberculosis both during and after treatment completion walked a shorter distance than controls. Interpretation: Adolescents with tuberculosis have impaired lung function even after treatment completion. It is crucial to include adolescents in trials on the prevention and treatment of tuberculosis-associated respiratory morbidity. Funding: EDCTP, National Institute of Health, Medical Research Council, BMBF.

COVID-19 and MIS-C treatment in children-results from an international survey.

Children have been mostly excluded from COVID-19 clinical trials, and, as a result, most medicines approved for COVID-19 have no pediatric indication. In addition, access to COVID-19 therapeutics remains limited. Collecting physicians' experiences with off-label use of therapeutics is important to inform global prioritization processes and better target pediatric research and development. A standardized questionnaire was designed to explore the use of therapeutics used to treat COVID-19 and multisystem inflammatory syndrome in children (MIS-C) in pediatric patients globally. Seventy-three physicians from 29 countries participated. For COVID-19, steroids were used by 75.6% of respondents; remdesivir and monoclonal antibodies were prescribed by 48.6% and 27.1% of respondents, respectively. For MIS-C, steroids were prescribed by 79.1% of respondents and intravenous immunoglobulins by 69.6%. The use of these products depended on their pediatric approval and the limited availability of antivirals and most monoclonal antibodies in Africa, South America, Southeast Asia, and Eastern Europe. Off-label prescription resulted widespread due to the paucity of clinical trials in young children at the time of the survey; though, based on our survey results, it was generally safe and led to clinical benefits.  Conclusion: This survey provides a snapshot of current practice for treating pediatric COVID-19 worldwide, informing global prioritization efforts to better target pediatric research and development for COVID-19 therapeutics. Off-label use of such medicines is widespread for the paucity of clinical trials under 12 years and 40 kg, though appears to be safe and generally results in clinical benefits, even in young children. However, access to care, including medicine availability, differs widely globally. Clinical development of COVID-19 antivirals and monoclonal antibodies requires acceleration to ensure pediatric indication and allow worldwide availability of therapeutics that will enable more equitable access to COVID-19 treatment. What is Known: • Children have been mostly excluded from COVID-19 clinical trials, and, as a result, most medicines approved for COVID-19 have no pediatric indication. • Access to care differs widely globally, so because of the diversity of national healthcare systems; the unequal availability of medicines for COVID-19 treatment represents an obstacle to the pediatric population's universal right to health care. What is New: • Off-label COVID-19 drug prescription is widespread due to the lack of clinical trials in children younger than 12 years and weighing less than 40 kg, but relatively safe and generally leading to clinical benefit. • The application of the GAP-f framework to COVID-19 medicines is crucial, ensuring widespread access to all safe and effective drugs, enabling the rapid development of age-appropriate formulations, and developing specific access plans (including stability, storage, packaging, and labeling) for distribution in low- and middle-income countries (LMICs). Antivirals and monoclonal antibodies may benefit from the acceleration to reach widespread and equal diffusion.

Quantitation of Circulating Mycobacterium tuberculosis Antigens by Nanopore Biosensing in Children Evaluated for Pulmonary Tuberculosis in South Africa.

Nanopore sensing of proteomic biomarkers lacks accuracy due to the ultralow abundance of targets, a wide variety of interferents in clinical samples, and the mismatch between pore and analyte sizes. By converting antigens to DNA probes via click chemistry and quantifying their characteristic signals, we show a nanopore assay with several amplification mechanisms to achieve an attomolar level limit of detection that enables quantitation of the circulating Mycobacterium tuberculosis (Mtb) antigen ESAT-6/CFP-10 complex in human serum. The assay's nonsputum-based feature and low-volume sample requirements make it particularly well-suited for detecting pediatric tuberculosis (TB) disease, where establishing an accurate diagnosis is greatly complicated by the paucibacillary nature of respiratory secretions, nonspecific symptoms, and challenges with sample collection. In the clinical assessment, the assay was applied to analyze ESAT-6/CFP-10 levels in serum samples collected during baseline investigation for TB in 75 children, aged 0-12 years, enrolled in a diagnostic study conducted in Cape Town, South Africa. This nanopore assay showed superior sensitivity in children with confirmed TB (94.4%) compared to clinical "gold standard" diagnostic technologies (Xpert MTB/RIF 44.4% and Mtb culture 72.2%) and filled the diagnostic gap for children with unconfirmed TB, where these traditional technologies fell short. We envision that, in combination with automated sample processing and portable nanopore devices, this methodology will offer a powerful tool to support the diagnosis of pulmonary TB in children.

Lung function tracking in children with perinatally acquired HIV following early antiretroviral therapy initiation.

INTRODUCTION: Lung disease remains a frequent complication in children with perinatal HIV infection (CHIV) and exposure without infection (CHEU), resulting in diminished lung function. In CHIV, early antiretroviral therapy (ART) initiation improves survival and extrapulmonary outcomes. However, it is unknown if there is benefit to lung function. METHODS: Cohorts of CHIV (ART initiated at median 4.0 months), CHEU and HIV-unexposed children (CHU) prospectively performed pulmonary function testing (PFT) consisting of spirometry, plethysmography and diffusing capacity from 2013 to 2020. We determined lung function trajectories for PFT outcomes comparing CHIV to CHU and CHEU to CHU, using linear mixed effects models with multiple imputation. Potential confounders included sex, age, height, weight, body mass index z-score, urine cotinine and Tanner stage. RESULTS: 328 participants (122 CHIV, 126 CHEU, 80 CHU) performed PFT (ages 6.6-15.6 years). Spirometry (forced expiratory volume in 1 s, FEV1, forced vital capacity (FVC), FEV1/FVC) outcomes were similar between groups. In plethysmography, the mean residual volume (RV) z-score was 17% greater in CHIV than CHU (95% CI 1% to 33%, p=0.042). There was no difference in total lung capacity (TLC) or RV/TLC z-scores between groups. Diffusing capacity for carbon monoxide was similar in all groups, while alveolar volume (VA) differed between HIV groups by sex. CONCLUSION: Our study indicates that early ART initiation can mitigate the loss of lung function in CHIV with lasting benefit through childhood; however, there remains concern of small airway disease. CHEU does not appear to disrupt childhood lung function trajectory.

SARS-CoV-2 infection and pulmonary tuberculosis in children and adolescents: a case-control study.

BACKGROUND: The Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pandemic has had an impact on the global tuberculosis (TB) epidemic but evidence on the possible interaction between SARS-CoV-2 and TB, especially in children and adolescents, remains limited. We aimed to evaluate the relationship between previous infection with SARS-CoV-2 and the risk of TB in children and adolescents. METHODS: An unmatched case-control study was conducted using SARS-CoV-2 unvaccinated children and adolescents recruited into two observational TB studies (Teen TB and Umoya), between November 2020 and November 2021, in Cape Town, South Africa. Sixty-four individuals with pulmonary TB (aged < 20 years) and 99 individuals without pulmonary TB (aged < 20 years) were included. Demographics and clinical data were obtained. Serum samples collected at enrolment underwent quantitative SARS-CoV-2 anti-spike immunoglobulin G (IgG) testing using the Abbott SARS-CoV-2 IgG II Quant assay. Odds ratios (ORs) for TB were estimated using unconditional logistic regression. RESULTS: There was no statistically significant difference in the odds of having pulmonary TB between those who were SARS-CoV-2 IgG seropositive and those who were seronegative (adjusted OR 0.51; 95% CI: 0.23-1.11; n = 163; p = 0.09). Of those with positive SARS-CoV-2 serology indicating prior infection, baseline IgG titres were higher in individuals with TB compared to those without TB (p = 0.04) and individuals with IgG titres in the highest tertile were more likely to have pulmonary TB compared to those with IgG levels in the lowest tertile (OR: 4.00; 95%CI: 1.13- 14.21; p = 0.03). CONCLUSIONS: Our study did not find convincing evidence that SARS-CoV-2 seropositivity was associated with subsequent pulmonary TB disease; however, the association between magnitude of SARS-CoV-2 IgG response and pulmonary TB warrants further investigation. Future prospective studies, evaluating the effects of sex, age and puberty on host immune responses to M. tuberculosis and SARS-CoV-2, will also provide more clarity on the interplay between these two infections.

Clinical Presentation and Outcome of Acute Respiratory Illnesses in South African Children During the COVID-19 Pandemic.

BACKGROUND: Data from low- and middle-income countries (LMICs) show higher morbidity and mortality in children with acute respiratory illness (ARI) from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, whether SARS-CoV-2 infection is distinct from other causes of ARI in this regard is unclear. We describe clinical characteristics and outcomes of South African children with SARS-CoV-2 and non-SARS-CoV-2 ARIs. METHODS: We performed a cross-sectional study including 0-13 years old children admitted to Tygerberg Hospital between May and December 2020 with an ARI. Routine clinical data were collected by the attending clinicians. All children underwent SARS-CoV-2 polymerase chain reaction testing. For severity of disease, the need for respiratory support and duration of support was considered. Multivariable logistic regression models were built to determine the factors associated with SARS-CoV-2 infection and severity. RESULTS: Data for 176 children were available, 38 (22%) children were SARS-CoV-2 polymerase chain reaction positive and 138 (78%) were negative. SARS-CoV-2 positive children were more likely to be female (OR: 2.68, 95% CI: 1.18-6.07), had lower weight-for-age Z score (OR: 0.76, 95% CI: 0.63-0.93), presented more frequently with fever (OR: 3.56, 95% CI: 1.54-8.24) and less often with cough (OR: 0.27, 95% CI: 0.11-0.66). SARS-CoV-2 infection was associated with significantly longer duration of oxygen treatment (median 8 vs. 3 days; OR: 1.1, 95% CI: 1.01-1.20). Overall, 66% of children had viral coinfection, with no significant difference between the groups. In total, 18% of SARS-CoV-2 positive children were readmitted within 3 months for a respiratory reason, compared with 15% SARS-CoV-2 negative children ( P = 0.64). CONCLUSIONS: Our data show that ARIs from SARS-CoV-2 cannot be easily differentiated, but were associated with a higher morbidity compared with ARIs from other causes. Overall outcomes were good. The long-term implications of severe SARS-CoV-2 pneumonia in young children in low- and middle-income countries require further study.

Short-term outcomes of South African children with multisystem inflammatory syndrome in children: a prospective cohort study.

BACKGROUND: Despite the life-threatening presentation of multisystem inflammatory syndrome in children (MIS-C), the overall prognosis is favourable in centres with access to appropriate supportive care. In this study, we investigate the short-term outcomes in children with MIS-C in Cape Town, South Africa. METHODS: This prospective observational cohort study included children <13 years who fulfilled the WHO case definition of MIS-C and were admitted to Tygerberg Hospital in Cape Town, South Africa between 1 June 2020 and 31 October 2021. Clinical features were recorded at baseline and at follow-up at the 6-week cardiology and 3-month rheumatology-immunology clinics, respectively. FINDINGS: Fifty-three children with a median age of 7.4 years (IQR 4.2-9.9) were included. There was a slight male predominance (30/53; 56.6%) and the majority was of mixed ancestry (28/53; 52.83%) or black African ancestry (24/53; 45.3%). Fourteen children (14/53; 26.4%) had comorbid disease. The median length of hospital stay was 8 days (IQR 6-10). All children had an echocardiogram performed at baseline of which 39 were abnormal (39/53; 73.6%). All children were discharged alive. The median days from discharge to cardiology follow-up was 39 days (IQR 33.5-41.5) and for rheumatology-immunology clinic was 70.5 days (IQR 59.5-85.0). Eleven children (11/41; 26.8%) had a persistently abnormal echocardiogram at cardiology follow-up. Systemic inflammation and organ dysfunction resolved in most. INTERPRETATION: Although the short-term outcomes of MIS-C in our cohort were generally good, the cardiac morbidity needs further characterisation and follow-up.

Chronic lung disease in children due to SARS-CoV-2 pneumonia: Case series.

The reported prevalence of chronic lung disease (CLD) due to coronavirus 2 (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2)]) pneumonia with the severe acute respiratory syndrome in children is unknown and rarely reported in English literature. In contrast to most other respiratory viruses, children generally have less severe symptoms when infected with SARS-CoV-2. Although only a minority of children with SARS-CoV-2 infection require hospitalization, severe cases have been reported. More severe SARS-CoV-2 respiratory disease in infants has been reported in low- and middle-income countries (LMICs) compared to high-income countries (HICs). We describe our experience of five cases of CLD in children due to SARS-CoV-2 collected between April 2020 and August 2022. We included children who had a history of a positive SARS-CoV-2 polymerase chain reaction (PCR) or antigen test or a positive antibody test in the serum. Three patterns of CLD related to SARS-CoV-2 were identified: (1) CLD in infants postventilation for severe pneumonia (n = 3); (2) small airway disease with bronchiolitis obliterans picture (n = 1) and (3) adolescent with adult-like post-SARS-CoV-2 disease (n = 1). Chest computerized tomography scans showed airspace disease and ground-glass opacities involving both lungs with the development of coarse interstitial markings seen in four patients, reflecting the long-term fibrotic consequences of diffuse alveolar damage that occur in children post-SARS-CoV-2 infection. Children with SARS-CoV-2 infection mostly have mild symptoms with little to no long-term sequelae, but the severe long-term respiratory disease can develop.

Optimising computer aided detection to identify intra-thoracic tuberculosis on chest x-ray in South African children.

Diagnostic tools for paediatric tuberculosis remain limited, with heavy reliance on clinical algorithms which include chest x-ray. Computer aided detection (CAD) for tuberculosis on chest x-ray has shown promise in adults. We aimed to measure and optimise the performance of an adult CAD system, CAD4TB, to identify tuberculosis on chest x-rays from children with presumptive tuberculosis. Chest x-rays from 620 children <13 years enrolled in a prospective observational diagnostic study in South Africa, were evaluated. All chest x-rays were read by a panel of expert readers who attributed each with a radiological reference of either 'tuberculosis' or 'not tuberculosis'. Of the 525 chest x-rays included in this analysis, 80 (40 with a reference of 'tuberculosis' and 40 with 'not tuberculosis') were allocated to an independent test set. The remainder made up the training set. The performance of CAD4TB to identify 'tuberculosis' versus 'not tuberculosis' on chest x-ray against the radiological reference read was calculated. The CAD4TB software was then fine-tuned using the paediatric training set. We compared the performance of the fine-tuned model to the original model. Our findings were that the area under the receiver operating characteristic curve (AUC) of the original CAD4TB model, prior to fine-tuning, was 0.58. After fine-tuning there was an improvement in the AUC to 0.72 (p = 0.0016). In this first-ever description of the use of CAD to identify tuberculosis on chest x-ray in children, we demonstrate a significant improvement in the performance of CAD4TB after fine-tuning with a set of well-characterised paediatric chest x-rays. CAD has the potential to be a useful additional diagnostic tool for paediatric tuberculosis. We recommend replicating the methods we describe using a larger chest x-ray dataset from a more diverse population and evaluating the potential role of CAD to replace a human-read chest x-ray within treatment-decision algorithms for paediatric tuberculosis.

Recurrent Tuberculosis Treatment Episodes in Children Presenting With Presumptive Pulmonary Tuberculosis in Cape Town, South Africa.

BACKGROUND: Limited data are available on tuberculosis (TB) recurrence in children. The aim of this study was to explore the burden of and risk factors for recurrent TB treatment in children. METHODS: A prospective, observational cohort study of children (0-13 years) presenting with presumptive pulmonary TB in Cape Town, South Africa from March 2012 to March 2017. Recurrent TB was defined as more than 1 episode of TB treatment (microbiologically confirmed and unconfirmed). RESULTS: Of 620 children enrolled with presumptive pulmonary TB, data of 608 children were reviewed for TB recurrence after exclusions. The median age was 16.7 [interquartile range (IQR) 9.5-33.3] months, 324 (53.3%) were male and 72 (11.8%) children living with HIV (CLHIV). TB was diagnosed in 297 of 608 (48.8%), of whom 26 had previously received TB treatment, giving a prevalence of 8.8% recurrence: 22 (84.6%) had 1 and 4 (15.4%) had 2 prior TB treatment episodes. The median age of children with recurrent TB was 47.5 (IQR: 20.8-82.5) months at the current episode: 19 of 26 (73.1%) were CLHIV, of whom 12 of 19 (63.2%) were on antiretroviral therapy for a median 43.1 months and all 12 for longer than 6 months. None of the 9 children on antiretroviral treatment with available viral load (VL) data were virally suppressed (median VL, 22,983 copies/ml). Three of 26 (11.6%) children had documented microbiologically confirmed TB at 2 episodes. Four children (15.4%) received drug-resistant TB treatment at recurrence. CONCLUSIONS: There was a high rate of recurrent treatment for TB in this cohort of young children, with CLHIV at the highest risk.

Development of treatment-decision algorithms for children evaluated for pulmonary tuberculosis: an individual participant data meta-analysis.

BACKGROUND: Many children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies so far have been small and localised, with limited generalisability. We aimed to evaluate the performance of currently used diagnostic algorithms and to use prediction modelling to develop evidence-based algorithms to assist in tuberculosis treatment decision making for children presenting to primary health-care centres. METHODS: For this meta-analysis, we identified individual participant data from a WHO public call for data on the management of tuberculosis in children and adolescents and referral from childhood tuberculosis experts. We included studies that prospectively recruited consecutive participants younger than 10 years attending health-care centres in countries with a high tuberculosis incidence for clinical evaluation of pulmonary tuberculosis. We collated individual participant data including clinical, bacteriological, and radiological information and a standardised reference classification of pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing treatment-decision algorithms. We then used the data to develop two multivariable prediction models that included features used in clinical evaluation of pulmonary tuberculosis-one with chest x-ray features and one without-and we investigated each model's generalisability using internal-external cross-validation. The parameter coefficient estimates of the two models were scaled into two scoring systems to classify tuberculosis with a prespecified sensitivity target. The two scoring systems were used to develop two pragmatic, treatment-decision algorithms for use in primary health-care settings. FINDINGS: Of 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having pulmonary tuberculosis: 541 (29·9%) bacteriologically confirmed and 1270 (70·1%) unconfirmed. Existing treatment-decision algorithms had highly variable diagnostic performance. The scoring system derived from the prediction model that included clinical features and features from chest x-ray had a combined sensitivity of 0·86 [95% CI 0·68-0·94] and specificity of 0·37 [0·15-0·66] against a composite reference standard. The scoring system derived from the model that included only clinical features had a combined sensitivity of 0·84 [95% CI 0·66-0·93] and specificity of 0·30 [0·13-0·56] against a composite reference standard. The scoring system from each model was placed after triage steps, including assessment of illness acuity and risk of poor tuberculosis-related outcomes, to develop treatment-decision algorithms. INTERPRETATION: We adopted an evidence-based approach to develop pragmatic algorithms to guide tuberculosis treatment decisions in children, irrespective of the resources locally available. This approach will empower health workers in primary health-care settings with high tuberculosis incidence and limited resources to initiate tuberculosis treatment in children to improve access to care and reduce tuberculosis-related mortality. These algorithms have been included in the operational handbook accompanying the latest WHO guidelines on the management of tuberculosis in children and adolescents. Future prospective evaluation of algorithms, including those developed in this work, is necessary to investigate clinical performance. FUNDING: WHO, US National Institutes of Health.

UMOYA: a prospective longitudinal cohort study to evaluate novel diagnostic tools and to assess long-term impact on lung health in South African children with presumptive pulmonary TB-a study protocol.

BACKGROUND: Despite a high paediatric tuberculosis (TB) burden globally, sensitive and specific diagnostic tools are lacking. In addition, no data exist on the impact of pulmonary TB on long-term child lung health in low- and middle-income countries. The prospective observational UMOYA study aims (1) to build a state-of-the-art clinical, radiological, and biological repository of well-characterised children with presumptive pulmonary TB as a platform for future studies to explore new emerging diagnostic tools and biomarkers for early diagnosis and treatment response; and (2) to investigate the short and long-term impact of pulmonary TB on lung health and quality of life in children. METHODS: We will recruit up to 600 children (0-13 years) with presumptive pulmonary TB and 100 healthy controls. Recruitment started in November 2017 and is expected to continue until May 2023. Sputum and non-sputum-based samples are collected at enrolment and during follow-up in TB cases and symptomatic controls. TB treatment is started by routine care services. Intensive follow-up for 6 months will allow for TB cases to retrospectively be classified according to international consensus clinical case definitions for TB. Long-term follow-up, including imaging, comprehensive assessment of lung function and quality of life questionnaires, are done yearly up to 4 years after recruitment. DISCUSSION: The UMOYA study will provide a unique platform to evaluate new emerging diagnostic tools and biomarkers for early diagnosis and treatment response and to investigate long-term outcomes of pulmonary TB and other respiratory events on lung health in children.

A systematic review of risk factors for mortality among tuberculosis patients in South Africa.

BACKGROUND: Tuberculosis (TB)-associated mortality in South Africa remains high. This review aimed to systematically assess risk factors associated with death during TB treatment in South African patients. METHODS: We conducted a systematic review of TB research articles published between 2010 and 2018. We searched BioMed Central (BMC), PubMed®, EBSCOhost, Cochrane, and SCOPUS for publications between January 2010 and December 2018. Searches were conducted between August 2019 and October 2019. We included randomised control trials (RCTs), case control, cross sectional, retrospective, and prospective cohort studies where TB mortality was a primary endpoint and effect measure estimates were provided for risk factors for TB mortality during TB treatment. Due to heterogeneity in effect measures and risk factors evaluated, a formal meta-analysis of risk factors for TB mortality was not appropriate. A random effects meta-analysis was used to estimate case fatality ratios (CFRs) for all studies and for specific subgroups so that these could be compared. Quality assessments were performed using the Newcastle-Ottawa scale or the Cochrane Risk of Bias Tool. RESULTS: We identified 1995 titles for screening, 24 publications met our inclusion criteria (one cross-sectional study, 2 RCTs, and 21 cohort studies). Twenty-two studies reported on adults (n = 12561) and two were restricted to children < 15 years of age (n = 696). The CFR estimated for all studies was 26.4% (CI 18.1-34.7, n = 13257 ); 37.5% (CI 24.8-50.3, n = 5149) for drug-resistant (DR) TB; 12.5% (CI 1.1-23.9, n = 1935) for drug-susceptible (DS) TB; 15.6% (CI 8.1-23.2, n = 6173) for studies in which drug susceptibility was mixed or not specified; 21.3% (CI 15.3-27.3, n = 7375) for people living with HIV/AIDS (PLHIV); 19.2% (CI 7.7-30.7, n = 1691) in HIV-negative TB patients; and 6.8% (CI 4.9-8.7, n = 696) in paediatric studies. The main risk factors associated with TB mortality were HIV infection, prior TB treatment, DR-TB, and lower body weight at TB diagnosis. CONCLUSIONS: In South Africa, overall mortality during TB treatment remains high, people with DR-TB have an elevated risk of mortality during TB treatment and interventions to mitigate high mortality are needed. In addition, better prospective data on TB mortality are needed, especially amongst vulnerable sub-populations including young children, adolescents, pregnant women, and people with co-morbidities other than HIV. Limitations included a lack of prospective studies and RCTs and a high degree of heterogeneity in risk factors and comparator variables. SYSTEMATIC REVIEW REGISTRATION: The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42018108622. This study was funded by the Bill and Melinda Gates Foundation (Investment ID OPP1173131) via the South African TB Think Tank.

Pediatric coronavirus disease 2019 in Africa.

PURPOSE OF REVIEW: Three years into the coronavirus disease 2019 (COVID-19) pandemic, data on pediatric COVID-19 from African settings is limited. Understanding the impact of the pandemic in this setting with a high burden of communicable and noncommunicable diseases is critical to implementing effective interventions in public health programs. RECENT FINDINGS: More severe COVID-19 has been reported in African settings, with especially infants and children with underlying comorbidities at highest risk for more severe disease. Data on the role of tuberculosis and HIV remain sparse. Compared to better resourced settings more children with multisystem inflammatory disease (MISC) are younger than 5 years and there is higher morbidity in all settings and increased mortality in some settings. Several reports suggest decreasing prevalence and severity of MIS-C disease with subsequent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variant waves. Whether this decrease continues remains to be determined. Thus far, data on long-COVID in African settings is lacking and urgently needed considering the severity of the disease seen in the African population. SUMMARY: Considering the differences seen in the severity of disease and short-term outcomes, there is an urgent need to establish long-term outcomes in children with COVID-19 and MIS-C in African children, including lung health assessment.