Pharmacokinetics and cardiac safety of clofazimine in children with rifampicin-resistant tuberculosis.

Clofazimine is recommended for the treatment of rifampicin-resistant tuberculosis (RR-TB), but there is currently no verified dosing guideline for its use in children. There is only limited safety and no pharmacokinetic (PK) data available for children. We aimed to characterize clofazimine PK and its relationship with QT-interval prolongation in children. An observational cohort study of South African children <18 years old routinely treated for RR-TB with a clofazimine-containing regimen was analyzed. Clofazimine 100 mg gelatin capsules were given orally once daily (≥20 kg body weight), every second day (10 to <20 kg), or thrice weekly (<10 kg). PK sampling and electrocardiograms were completed pre-dose and at 1, 4, and 10 hours post-dose, and the population PK and Fridericia-corrected QT (QTcF) interval prolongation were characterized. Fifty-four children contributed both PK and QTcF data, with a median age (2.5th-97.5th centiles) of 3.3 (0.5-15.6) years; five children were living with HIV. Weekly area under the time-concentration curve at steady state was 79.1 (15.0-271) mg.h/L compared to an adult target of 60.9 (56.0-66.6) mg.h/L. Children living with HIV had four times higher clearance compared to those without. No child had a QTcF ≥500 ms. A linear concentration-QTcF relationship was found, with a drug effect of 0.05 (0.027, 0.075) ms/µg/L. In some of the first PK data in children, we found clofazimine exposure using an off-label dosing strategy was higher in children versus adults. Clofazimine concentrations were associated with an increase in QTcF, but severe prolongation was not observed. More data are required to inform dosing strategies in children.

QT Interval Prolongation with One or More QT-Prolonging Agents Used as Part of a Multidrug Regimen for Rifampicin-Resistant Tuberculosis Treatment: Findings from Two Pediatric Studies.

Rifampicin-resistant tuberculosis (RR-TB) involves treatment with many drugs that can prolong the QT interval; this risk may increase when multiple QT-prolonging drugs are used together. We assessed QT interval prolongation in children with RR-TB receiving one or more QT-prolonging drugs. Data were obtained from two prospective observational studies in Cape Town, South Africa. Electrocardiograms were performed before and after drug administration of clofazimine (CFZ), levofloxacin (LFX), moxifloxacin (MFX), bedaquiline (BDQ), and delamanid. The change in Fridericia-corrected QT (QTcF) was modeled. Drug and other covariate effects were quantified. A total of 88 children with a median (2.5th-to-97.5th range) age of 3.9 (0.5 to 15.7) years were included, of whom 55 (62.5%) were under 5 years of age. A QTcF interval of >450 ms was observed in 7 patient-visits: regimens were CFZ+MFX (n = 3), CFZ+BDQ+LFX (n = 2), CFZ alone (n = 1), and MFX alone (n = 1). There were no events with a QTcF interval of >500 ms. In a multivariate analysis, CFZ+MFX was associated with a 13.0-ms increase in change in QTcF (P < 0.001) and in maximum QTcF (P = 0.0166) compared to those when other MFX- or LFX-based regimens were used. In conclusion, we found a low risk of QTcF interval prolongation in children with RR-TB who received at least one QT-prolonging drug. Greater increases in maximum QTcF and ΔQTcF were observed when MFX and CFZ were used together. Future studies characterizing exposure-QTcF responses in children will be helpful to ensure safety with higher doses if required for effective treatment of RR-TB.

The impact of COVID-19 on a South African pediatric cardiac service: implications and insights into service capacity.

Background and Objectives: The Western Cape public pediatric cardiac service is under-resourced. COVID-19 regulations are likely to have long-term effects on patient care but may provide insight into service capacity requirements. As such, we aimed to quantify the impact of COVID-19 regulations on this service. Methods: An uncontrolled retrospective pre-post study of all presenting patients over two, one-year periods; the pre-COVID-19 period (01/03/2019-29/02/2020) and the peri-COVID-19 period (01/03/2020-28/02/2021). Results: Admissions decreased by 39% (624 to 378) and cardiac surgeries decreased by 29% (293 to 208) in the peri-COVID-19 period, with an increase in urgent cases (PR:5.99, 95%CI:3.58-10.02, p < 0.001). Age at surgery was lower in the peri-COVID-19 period, 7.2 (2.4-20.4) vs. 10.8 (4.8-49.2) months (p < 0.05), likewise, age at surgery for transposition of the great arteries (TGA) was lower peri-COVID-19, 15 (IQR:11.2-25.5) vs. 46 (IQR:11-62.5) days (p < 0.05). Length of stay 6 (IQR:2-14) vs. 3 days (IQR:1-9) (p < 0.001), complications (PR:1.21, 95%CI:1.01-1.43, p < 0.05), and age-adjusted delayed-sternal-closure rates (PR:3.20, 95%CI:1.09-9.33, p < 0.05) increased peri-COVID-19. Conclusion: Cardiac procedures were significantly reduced in the peri-COVID-19 period which will have implications on an overburdened service and ultimately, patient outcomes. COVID-19 restrictions on elective procedures freed capacity for urgent cases, demonstrated by the absolute increase in urgent cases and significant decrease in age at TGA-surgery. This facilitated intervention at the point of physiological need, albeit at the expense of elective procedures, and also revealed insights into capacity requirements of the Western Cape. These data emphasize the need for an informed strategy to increase capacity and reduce backlog whilst ensuring minimal morbidity and mortality.Graphical Abstract.

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.

Investigation of Copy Number Variation in South African Patients With Congenital Heart Defects.

BACKGROUND: Congenital heart disease (CHD) is a leading non-infectious cause of pediatric morbidity and mortality worldwide. Although the etiology of CHD is poorly understood, genetic factors including copy number variants (CNVs) contribute to the risk of CHD in individuals of European ancestry. The presence of rare CNVs in African CHD populations is unknown. This study aimed to identify pathogenic and likely pathogenic CNVs in South African patients with CHD. METHODS: Genotyping was performed on 90 patients with nonsyndromic CHD using the Affymetrix CytoScan HD platform. These data were used to identify large, rare CNVs in known CHD-associated genes and candidate genes. RESULTS: We identified eight CNVs overlapping known CHD-associated genes (GATA4, CRKL, TBX1, FLT4, B3GAT3, NSD1) in six patients. The analysis also revealed CNVs encompassing five candidate genes likely to play a role in the development of CHD (DGCR8, KDM2A, JARID2, FSTL1, CYFIP1) in five patients. One patient was found to have 47, XXY karyotype. We report a total discovery yield of 6.7%, with 5.6% of the cohort carrying pathogenic or likely pathogenic CNVs expected to cause the observed phenotypes. CONCLUSIONS: In this study, we show that chromosomal microarray is an effective technique for identifying CNVs in African patients diagnosed with CHD and have demonstrated results similar to previous CHD genetic studies in Europeans. Novel potential CHD genes were also identified, indicating the value of genetic studies of CHD in ancestrally diverse populations.

Tuberculous bronchial stenosis: Diagnosis and role of interventional bronchoscopy.

The reported prevalence of tuberculous bronchial stenosis in children is unknown and rarely reported in English-speaking literature. In adult patients with pulmonary tuberculosis, it varies from 40% in an autopsied series in the preantibiotic era to 10% in patients who have undergone routine bronchofibroscopy in modern times. We describe our experience of four cases of confirmed bronchial stenosis due to MTB collected between January 2000 and June 2021 in this case series descriptive study. The diagnosis of bronchial stenosis due to TB was made on flexible bronchoscopy. A TB diagnosis was made if MTB was cultured from respiratory secretions, when Ziehl-Neelsen smear or GeneXpert MTB/RIF test was positive, or if a chest radiograph revealed radiographic features typical of MTB. Bronchial stenosis due to TB is rare even if airway compression is frequently seen. Although an early diagnosis of bronchial stenosis due to TB is difficult on chest X-rays, all children in this series demonstrated parenchymal changes distal to the stenosis ranging from hyperinflation and lobar collaps to bronchiectasis. If bronchial stenosis resulting from TB disease is diagnosed early, balloon dilatation as described in this report, may be an effective and safe intervention, preventing long-term complications such as irreversible lung destruction, that may require pneumonectomy.

Pharmacokinetics and Safety of Bedaquiline in Human Immunodeficiency Virus (HIV)-Positive and Negative Older Children and Adolescents With Rifampicin-Resistant Tuberculosis.

BACKGROUND: Pharmacokinetic data for bedaquiline in children are limited. We described the pharmacokinetics and safety of bedaquiline in South African children and adolescents receiving treatment for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in routine care. METHODS: In this observational cohort study, children aged 6-17 years receiving bedaquiline at recommended doses as part of MDR/RR-TB treatment underwent semi-intensive pharmacokinetic sampling. Bedaquiline and the M2 metabolite plasma concentrations were quantified, and nonlinear mixed-effects modeling performed. Pediatric data were described using a pre-established model of bedaquiline pharmacokinetics in adults. The exposure reference was 187 µg ⋅ h/mL, the median weekly area under the curve (AUC) of adults at week 24 of treatment with bedaquiline. Safety was assessed through monthly clinical, blood and electrocardiogram monitoring, and treatment outcomes described. RESULTS: Fifteen children (3 human immunodeficiency virus [HIV]-positive) with median age 13.3 years (range 6.5-16.3) were included. A bedaquiline pharmacokinetic model was adapted to be allometrically scaled in clearance and volume, centered in the median child population weight. Bedaquiline bioavailability was 57% of that in adults. Overall bedaquiline exposures were below target, and AUC reference attainment was achieved in only 3 (20%) children. Ten children experienced 27 adverse events at least possibly related to bedaquiline; no adverse events led to bedaquiline withdrawal. Two adverse events (arthritis and arthralgia) were considered severe, and 2 children had mild QT interval corrected for heart rate using Fridericia's formula (QT) prolongation. CONCLUSIONS: The evaluated doses of bedaquiline in children ≥ 6 years of age were safe but achieved slightly lower plasma concentrations compared to adults receiving the recommended dose, possibly due to delayed food intake relative to bedaquiline administration.

Moxifloxacin Pharmacokinetics, Cardiac Safety, and Dosing for the Treatment of Rifampicin-Resistant Tuberculosis in Children.

BACKGROUND: Moxifloxacin is a 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 and QT interval prolongation and evaluate optimal dosing in children with RR-TB. METHODS: Pharmacokinetic data were pooled from 2 observational studies in South African children 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 aged <2 years, and 8 (9%) were living with human immunodeficiency virus (HIV). 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 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 (interindividual 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 coadministered with other QT-prolonging agents.

PROTEA, A Southern African Multicenter Congenital Heart Disease Registry and Biorepository: Rationale, Design, and Initial Results.

Objectives: The PartneRships in cOngeniTal hEart disease (PROTEA) project aims to establish a densely phenotyped and genotyped Congenital Heart Disease (CHD) cohort for southern Africa. This will facilitate research into the epidemiology and genetic determinants of CHD in the region. This paper introduces the PROTEA project, characterizes its initial cohort, from the Western Cape Province of South Africa, and compares the proportion or "cohort-prevalences" of CHD-subtypes with international findings. Methods: PROTEA is a prospective multicenter CHD registry and biorepository. The initial cohort was recruited from seven hospitals in the Western Cape Province of South Africa from 1 April 2017 to 31 March 2019. All patients with structural CHD were eligible for inclusion. Descriptive data for the preliminary cohort are presented. In addition, cohort-prevalences (i.e., the proportion of patients within the cohort with a specific CHD-subtype) of 26 CHD-subtypes in PROTEA's pediatric cohort were compared with the cohort-prevalences of CHD-subtypes in two global birth-prevalence studies. Results: The study enrolled 1,473 participants over 2 years, median age was 1.9 (IQR 0.4-7.1) years. Predominant subtypes included ventricular septal defect (VSD) (339, 20%), atrial septal defect (ASD) (174, 11%), patent ductus arteriosus (185, 11%), atrioventricular septal defect (AVSD) (124, 7%), and tetralogy of Fallot (121, 7%). VSDs were 1.8 (95% CI, 1.6-2.0) times and ASDs 1.4 (95% CI, 1.2-1.6) times more common in global prevalence estimates than in PROTEA's pediatric cohort. AVSDs were 2.1 (95% CI, 1.7-2.5) times more common in PROTEA and pulmonary stenosis and double outlet right ventricle were also significantly more common compared to global estimates. Median maternal age at delivery was 28 (IQR 23-34) years. Eighty-two percent (347/425) of mothers used no pre-conception supplementation and 42% (105/250) used no first trimester supplements. Conclusions: The cohort-prevalence of certain mild CHD subtypes is lower than for international estimates and the cohort-prevalence of certain severe subtypes is higher. PROTEA is not a prevalence study, and these inconsistencies are unlikely the result of true differences in prevalence. However, these findings may indicate under-diagnosis of mild to moderate CHD and differences in CHD management and outcomes. This reemphasizes the need for robust CHD epidemiological research in the region.

Rationale and design of the African Cardiomyopathy and Myocarditis Registry Program: The IMHOTEP study.

BACKGROUND: Heart failure (HF), the dominant form of cardiovascular disease in Africans, is mainly due to hypertension, rheumatic heart disease and cardiomyopathy. Cardiomyopathies pose a great challenge because of poor prognosis and high prevalence in low- and middle-income countries (LMICs). Little is known about the etiology and outcome of cardiomyopathy in Africa. Specifically, the role of myocarditis and the genetic causes of cardiomyopathy are largely unidentified in Africans. METHOD: The African Cardiomyopathy and Myocarditis Registry Program (the IMHOTEP study) is a pan-African multi-centre, hospital-based cohort study, designed with the primary aim of describing the clinical characteristics, genetic causes, prevalence, management and outcome of cardiomyopathy and myocarditis in children and adults. The secondary aim is to identify barriers to the implementation of evidence-based care and provide a platform for trials and other intervention studies to reduce morbidity and mortality in cardiomyopathy. The registry consists of a prospective cohort of newly diagnosed (i.e., incident) cases and a retrospective (i.e., prevalent) cohort of existing cases from participating centres. Patients with cardiomyopathy and myocarditis will be subjected to a standardized 3-stage diagnostic process. To date, 750 patients have been recruited into the multi-centre pilot phase of the study. CONCLUSION: The IMHOTEP study will provide comprehensive and novel data on clinical features, genetic causes, prevalence and outcome of African children and adults with all forms of cardiomyopathy and myocarditis in Africa. Based on these findings, appropriate strategies for management and prevention of the cardiomyopathies in LMICs are likely to emerge.

Clinical Experience With Severe Acute Respiratory Syndrome Coronavirus 2-Related Illness in Children: Hospital Experience in Cape Town, South Africa.

BACKGROUND: Children seem relatively protected from serious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease, but little is known about children living in settings with high tuberculosis and human immunodeficiency virus (HIV) burden. This study reflects clinical data on South African children with SARS-CoV-2. METHODS: We collected clinical data of children aged <13 years with laboratory-confirmed SARS-CoV-2 presenting to Tygerberg Hospital, Cape Town, between 17 April and 24 July 2020. RESULTS: One hundred fifty-nine children (median age, 48.0 months [interquartile range {IQR}, 12.0-106.0 months]) were included. Hospitalized children (n = 62), with a median age of 13.5 months (IQR, 1.8-43.5 months) were younger than children not admitted (n = 97; median age, 81.0 months [IQR, 34.5-120.5 months]; P < .01.). Thirty-three of 159 (20.8%) children had preexisting medical conditions. Fifty-one of 62 (82.3%) hospitalized children were symptomatic; lower respiratory tract infection was diagnosed in 21 of 51 (41.2%) children, and in 11 of 16 (68.8%) children <3 months of age. Respiratory support was required in 25 of 51 (49.0%) children; 13 of these (52.0%) were <3 months of age. One child was HIV infected and 11 of 51 (21.2%) were HIV exposed but uninfected, and 7 of 51 (13.7%) children had a recent or new diagnosis of tuberculosis. CONCLUSIONS: Children <1 year of age hospitalized with SARS-CoV-2 in Cape Town frequently required respiratory support. Access to oxygen may be limited in some low- and middle-income countries, which could potentially drive morbidity and mortality. HIV infection was uncommon but a relationship between HIV exposure, tuberculosis, and SARS-CoV-2 should be explored.

A Patient-Specific CFD Pipeline Using Doppler Echocardiography for Application in Coarctation of the Aorta in a Limited Resource Clinical Context.

Congenital heart disease (CHD) is the most common birth defect globally and coarctation of the aorta (CoA) is one of the commoner CHD conditions, affecting around 1/1800 live births. CoA is considered a CHD of critical severity. Unfortunately, the prognosis for a child born in a low and lower-middle income country (LLMICs) with CoA is far worse than in a high-income country. Reduced diagnostic and interventional capacities of specialists in these regions lead to delayed diagnosis and treatment, which in turn lead to more cases presenting at an advanced stage. Computational fluid dynamics (CFD) is an important tool in this context since it can provide additional diagnostic data in the form of hemodynamic parameters. It also provides an in silico framework, both to test potential procedures and to assess the risk of further complications arising post-repair. Although this concept is already in practice in high income countries, the clinical infrastructure in LLMICs can be sparse, and access to advanced imaging modalities such as phase contrast magnetic resonance imaging (PC-MRI) is limited, if not impossible. In this study, a pipeline was developed in conjunction with clinicians at the Red Cross War Memorial Children's Hospital, Cape Town and was applied to perform a patient-specific CFD study of CoA. The pipeline uses data acquired from CT angiography and Doppler transthoracic echocardiography (both much more clinically available than MRI in LLMICs), while segmentation is conducted via SimVascular and simulation is realized using OpenFOAM. The reduction in cost through use of open-source software and the use of broadly available imaging modalities makes the methodology clinically feasible and repeatable within resource-constrained environments. The project identifies the key role of Doppler echocardiography, despite its disadvantages, as an intrinsic component of the pipeline if it is to be used routinely in LLMICs.

Congenital Heart Disease in Low- and Lower-Middle-Income Countries: Current Status and New Opportunities.

PURPOSE OF REVIEW: The paper summarises the most recent data on congenital heart disease (CHD) in low- and lower-middle-income countries (LLMICs). In addition, we present an approach to diagnosis, management and interventions in these regions and present innovations, research priorities and opportunities to improve outcomes and develop new programs. RECENT FINDINGS: The reported birth prevalence of CHD in LLMICs is increasing, with clear evidence of the impact of surgical intervention on the burden of disease. New methods of teaching and training are demonstrating improved outcomes. Local capacity building remains the key. There is a significant gap in epidemiological and outcomes data in CHD in LLMICs. Although the global agenda still does not address the needs of children with CHD adequately, regional initiatives are focusing on quality improvement and context-specific interventions. Future research should focus on epidemiology and the use of innovative thinking and partnerships to provide low-cost, high-impact solutions.

Acquired neonatal bronchial stenosis after selective intubation: Successful managed with balloon dilatation.

Premature babies are prone to airway-related complications. Selective intubation for the management of pulmonary interstitial emphysema may cause acquired bronchial stenosis. Balloon dilatation under fluoroscopy is a safe minimal invasive and successful intervention for acquired bronchial stenosis. Follow-up bronchoscopy is needed due to risk of restenosis.

Infective endocarditis in infants and children in the Western Cape, South Africa: a retrospective analysis.

Infective endocarditis is a microbial infection of the endothelial surface of the heart, predominantly the heart valves, that is associated with high mortality and morbidity. Few contemporary data exist regarding affected children in our context. AIMS AND OBJECTIVES: We aimed to describe the profile and treatment outcomes of infant and childhood endocarditis at our facilities. METHODS: This is a retrospective analysis of infants and children with endocarditis at two public sector hospitals in the Western Cape Province of South Africa over a 5-year period. Patients with "definite" and "possible" endocarditis according to Modified Duke Criteria were included in the review. RESULTS: Forty-nine patients were identified for inclusion; 29 had congenital heart disease as a predisposing condition; 64% of patients met "definite" and 36% "possible" criteria. The in-hospital mortality rate was 20%; 53% of patients underwent surgery with a post-operative mortality rate of 7.7%. The median interval from diagnosis to surgery was 20 days (interquartile range, 9-47 days). Valve replacement occurred in 28% and valve repair in 58%. There was a significant reduction in valvular dysfunction in patients undergoing surgery and only a marginal improvement in patients treated medically. Overall, 43% of patients had some degree of residual valvular dysfunction. CONCLUSION: Endocarditis is a serious disease with a high in-hospital mortality and presents challenges in making an accurate diagnosis. Despite a significant reduction in valvular dysfunction, a portion of patients had residual valvular dysfunction. Early surgery is associated with a lower mortality rate, but a higher rate of valve replacement compared with delayed surgery.

Clinical and Cardiac Safety of Long-term Levofloxacin in Children Treated for Multidrug-resistant Tuberculosis.

Safety concerns persist for long-term pediatric fluoroquinolone use. Seventy children (median age, 2.1 years) treated with levofloxacin 10-20 mg/kg once daily for multidrug-resistant tuberculosis (median observation time, 11.8 months) had few musculoskeletal events, no levofloxacin-attributed serious adverse events, and no Fridericia-corrected QT interval >450 ms. Long-term levofloxacin was safe and well tolerated.