Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children.

BACKGROUND: Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen. METHODS: We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment. RESULTS: From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups). CONCLUSIONS: Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.).

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.

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.

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.

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.

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.

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.

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.

The Diagnostic Accuracy of Chest Radiographic Features for Pediatric Intrathoracic Tuberculosis.

INTRODUCTION: The chest radiograph (CR) remains a key tool in the diagnosis of pediatric tuberculosis (TB). In children with presumptive intrathoracic TB, we aimed to identify CR features that had high specificity for, and were strongly associated with, bacteriologically confirmed TB. METHODS: We analyzed CR data from children with presumptive intrathoracic TB prospectively enrolled in a cohort study in a high-TB burden setting and who were classified using standard clinical case definitions as "confirmed," "unconfirmed," or "unlikely" TB. We report the CR features and inter-reader agreement between expert readers who interpreted the CRs. We calculated the sensitivity and specificity of the CR features with at least moderate inter-reader agreement and analyzed the relationship between these CR features and the classification of TB in a multivariable regression model. RESULTS: Of features with at least moderate inter-reader agreement, enlargement of perihilar and/or paratracheal lymph nodes, bronchial deviation/compression, cavities, expansile pneumonia, and pleural effusion had a specificity of > 90% for confirmed TB, compared with unlikely TB. Enlargement of perihilar (adjusted odds ratio [aOR]: 6.6; 95% confidence interval [CI], 3.80-11.72) and/or paratracheal lymph nodes (aOR: 5.14; 95% CI, 2.25-12.58), bronchial deviation/compression (aOR: 6.22; 95% CI, 2.70-15.69), pleural effusion (aOR: 2.27; 95% CI, 1.04-4.78), and cavities (aOR: 7.45; 95% CI, 3.38-17.45) were associated with confirmed TB in the multivariate regression model, whereas alveolar opacification (aOR: 1.16; 95% CI, .76-1.77) and expansile pneumonia (aOR: 4.16; 95% CI, .93-22.34) were not. CONCLUSIONS: In children investigated for intrathoracic TB enlargement of perihilar or paratracheal lymph nodes, bronchial compression/deviation, pleural effusion, or cavities on CR strongly support the diagnosis.

Development of a Treatment-decision Algorithm for Human Immunodeficiency Virus-uninfected Children Evaluated for Pulmonary Tuberculosis.

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 antituberculosis treatment in more children. METHODS: We analyzed data from a prospective cohort of children <13 years old 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 baseline chest radiographic and Xpert MTB/RIF assay results to the model to develop an algorithm with ≥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 months); 242 (50.6%) were retrospectively classified with tuberculosis, bacteriologically confirmed in 104 (43.0%). 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 radiographic results increased the proportion to 89.3%. The algorithm was 90.1% sensitive and 52.1% specific, and maintained a sensitivity of >90% among children <2 years old 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.

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.

The Critical Need for Pooled Data on Coronavirus Disease 2019 in African Children: An AFREhealth Call for Action Through Multicountry Research Collaboration.

Globally, there are prevailing knowledge gaps in the epidemiology, clinical manifestations, and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among children and adolescents; and these gaps are especially wide in African countries. The availability of robust age-disaggregated data is a critical first step in improving knowledge on disease burden and manifestations of coronavirus disease 2019 (COVID-19) among children. Furthermore, it is essential to improve understanding of SARS-CoV-2 interactions with comorbidities and coinfections such as human immunodeficiency virus (HIV), tuberculosis, malaria, sickle cell disease, and malnutrition, which are highly prevalent among children in sub-Saharan Africa. The African Forum for Research and Education in Health (AFREhealth) COVID-19 Research Collaboration on Children and Adolescents is conducting studies across Western, Central, Eastern, and Southern Africa to address existing knowledge gaps. This consortium is expected to generate key evidence to inform clinical practice and public health policy-making for COVID-19 while concurrently addressing other major diseases affecting children in African countries.

Post-Tuberculosis Lung Disease: Clinical Review of an Under-Recognised Global Challenge.

An estimated 58 million people have survived tuberculosis since 2000, yet many of them will suffer from post-tuberculosis lung disease (PTLD). PTLD results from a complex interplay between organism, host, and environmental factors and affects long-term respiratory health. PTLD is an overlapping spectrum of disorders that affects large and small airways (bronchiectasis and obstructive lung disease), lung parenchyma, pulmonary vasculature, and pleura and may be complicated by co-infection and haemoptysis. People affected by PTLD have shortened life expectancy and increased risk of recurrent tuberculosis, but predictors of long-term outcomes are not known. No data are available on PTLD in children and on impact throughout the life course. Risk-factors for PTLD include multiple episodes of tuberculosis, drug-resistant tuberculosis, delays in diagnosis, and possibly smoking. Due to a lack of controlled trials in this population, no evidence-based recommendations for the investigation and management of PTLD are currently available. Empirical expert opinion advocates pulmonary rehabilitation, smoking cessation, and vaccinations (pneumococcal and influenza). Exacerbations in PTLD remain both poorly understood and under-recognised. Among people with PTLD, the probability of tuberculosis recurrence must be balanced against other causes of symptom worsening. Unnecessary courses of repeated empiric anti-tuberculosis chemotherapy should be avoided. PTLD is an important contributor to the global burden of chronic lung disease. Advocacy is needed to increase recognition for PTLD and its associated economic, social, and psychological consequences and to better understand how PTLD sequelae could be mitigated. Research is urgently needed to inform policy to guide clinical decision-making and preventative strategies for PTLD.

Stool Culture for Diagnosis of Pulmonary Tuberculosis in Children.

Bacteriological confirmation of Mycobacterium tuberculosis is achieved in the minority of young children with tuberculosis (TB), since specimen collection is resource intensive and respiratory secretions are mostly paucibacillary, leading to limited sensitivity of available diagnostic tests. Although molecular tests are increasingly available globally, mycobacterial culture remains the gold standard for diagnosis and determination of drug susceptibility and is more sensitive than molecular methods for paucibacillary TB. We evaluated stool culture as an alternative to respiratory specimens for the diagnosis of suspected intrathoracic TB in a subgroup of 188 children (median age, 14.4 months; 15.4% HIV infected) enrolled in a TB diagnostic study at two local hospitals in Cape Town, South Africa. One stool culture was compared to overall bacteriological confirmation by stool Xpert and by Xpert and culture of multiple respiratory specimens. After decontamination/digestion with NALC (N-acetyl-l-cysteine)-NaOH (1.25%), concentrated fluorescent smear microscopy, Xpert MTB/RIF, and liquid culture were completed for all specimens. Culture contamination of stool specimens was high at 41.5%. Seven of 90 (7.8%) children initiating TB treatment were stool culture positive for M. tuberculosis Excluding contaminated cultures, the sensitivity of stool culture versus confirmed TB was 6/25 (24.0%; 95% confidence interval [CI] = 9.4 to 45.1%). In addition, stool culture detected TB in 1/93 (1.1%) children with "unconfirmed TB." Testing the same stool by Xpert increased sensitivity to 33.3% (95% CI = 18.0 to 51.8%). In conclusion, stool culture had low sensitivity for M. tuberculosis detection in children with intrathoracic TB. Reducing culture contamination through improved laboratory protocols may enable more reliable estimates of its diagnostic utility.

Novel Homozygous Mutation of the Internal Translation Initiation Start Site of VHL is Exclusively Associated with Erythrocytosis: Indications for Distinct Functional Roles of von Hippel-Lindau Tumor Suppressor Isoforms.

Congenital secondary erythrocytosis is a rare disorder characterized by increased red blood cell production. An important cause involves defects in the oxygen sensing pathway, in particular the PHD2-VHL-HIF axis. Mutations in VHL are also associated with the von Hippel-Lindau tumor predisposition syndrome. The differences in phenotypic expression of VHL mutations are poorly understood. We report on three patients with erythrocytosis, from two unrelated families. All patients show exceptionally high erythropoietin (EPO) levels, and are homozygous for a novel missense mutation in VHL: c.162G>C p.(Met54Ile). The c.162G>C mutation is the most upstream homozygous VHL mutation described so far in patients with erythrocytosis. It abolishes the internal translational start codon, which directs expression of VHLp19, resulting in the production of only VHLp30. The exceptionally high EPO levels and the absence of VHL-associated tumors in the patients suggest that VHLp19 has a role for regulating EPO levels that VHLp30 does not have, whereas VHLp30 is really the tumor suppressor isoform.

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.

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.

Designing a Smartphone-Based Pulse Oximeter for Children in South Africa (Phefumla Project): Qualitative Analysis of Human-Centered Design Workshops With Health Care Workers.

Background: Pulse oximeters noninvasively measure blood oxygen levels, but these devices have rarely been designed for low-resource settings and are inconsistently available at outpatient clinics. Objective: The Phefumla project aims to develop and validate a pediatric smartphone-based pulse oximeter designed specifically for this context. We present the process of human-centered oximeter design with health care workers in South Africa. Methods: We purposively sampled 19 health care workers from 5 clinics in Khayelitsha, Cape Town. Using a human-centered design approach, we conducted participatory workshops with four activities with health care workers: (1) they received 3D-printed prototypes of potential oximeter designs to provide feedback; (2) we demonstrated on dolls how they would use the novel oximeter; (3) they used pile sorting to rank design features and suggest additional features they desired; and (4) they designed their preferred user interface using a whiteboard, marker, and magnetized features that could be repositioned. We audio recorded the workshops, photographed outputs, and took detailed field notes. Analysis involved iterative review of these data to describe preferences, identify key design updates, and provide modifications. Results: Participants expressed a positive sentiment toward the idea of a smartphone pulse oximeter and suggested that a pediatric device would address an important gap in outpatient care. Specifically, participants expressed a preference for the prototype that they felt enabled more diversity in the way it could be used. There was a strong tendency to prioritize pragmatic design features, such as robustness, which was largely dictated by health care worker context. They also added features that would allow the oximeter device to serve other clinical functions in addition to oxygen saturation measurement, such as temperature and respiratory rate measurements. Conclusions: Our end user-centered rapid participatory approach led to tangible design changes and prompted design discussions that the team had not previously considered. Overall, health care workers prioritized pragmatism for pediatric pulse oximeter device design.

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.