The Long-Term Impact of Early-Life Tuberculosis Disease on Child Health: A Prospective Birth Cohort Study.

Rationale: There is growing concern that post-tuberculosis disease (TB) sequelae and morbidity are substantial, but no studies have controlled for preexisting factors before disease. Whether children have post-TB morbidity is not well characterized. Objectives: To assess the effect of a TB diagnosis on wheezing episodes, lung function, and anthropometric measurements among children enrolled in a prospective birth cohort study in South Africa. Methods: We prospectively followed children from birth through 5 years for TB using diagnostic tests including chest radiography and repeated induced sputum sample testing with Xpert MTB/RIF and liquid culture. We longitudinally measured health outcomes including growth, wheezing, and lung function up to 5 years. Mixed-effects linear regression models were used to assess growth and lung function after TB. Poisson regression was used to assess risk of subsequent wheezing. Measurements and Main Results: Among 1,068 participants, 96 TB cases occurred (1,228 cases per 100,000 person-years [95% confidence interval (CI), 1,006-1,500]) occurred over 7,815 child-years of follow-up. TB was associated with lower length-for-age (-0.40 [95% CI, -0.68 to -0.11]), weight-for-age (-0.30 [95% CI, -0.59 to -0.01]), and body mass index (-0.54 [95% CI, -0.83 to -0.25]) z-scores at 5 years. Children developing TB were consistently more likely to wheeze regardless of the timing of TB. Children with diagnoses of TB between 0 and 1 year of age had reduced time to peak tidal expiratory flow over total expiratory time (-2.35% [95% CI, -4.86% to -0.17%]) and higher fractional exhaled nitric oxide (2.88 ppb [95% CI, 0.57-5.19 ppb]) at 5 years. Children with diagnoses of TB between 1 and 4 years of age had impaired Vt (-9.32 ml [95% CI, -14.89 to -3.75 ml]) and time to peak tidal expiratory flow over total expiratory time (-2.73% [95% CI, -5.45% to -0.01%]) at 5 years. Conclusions: Prevention of TB disease in the first few years of life may have substantial long-term benefits through childhood.

Longitudinal Changes in Spirometry in South African Adolescents Perinatally Infected With Human Immunodeficiency Virus Who Are Receiving Antiretroviral Therapy.

BACKGROUND: Despite increased access to highly active antiretroviral therapy (HAART), lung disease remains common in human immunodeficiency virus (HIV)-infected (HIV+) adolescents. There is limited information on changes in lung function over time in perinatally HIV+ adolescents on HAART. The objective was to investigate the progression of spirometry findings over 2 years in HIV+ adolescents on HAART in a prospective cohort, the Cape Town Adolescent Antiretroviral Cohort (CTAAC). METHODS: HIV+ adolescents aged 9-14 years, with at least 6 months of HAART, and a comparator group of healthy HIV-uninfected (HIV-), age-matched controls were enrolled in CTAAC. Spirometry and bronchodilator testing were done at baseline, 12 months, and 24 months. Mixed-effect models were used to compute longitudinal changes in lung function. RESULTS: Five hundred fifteen HIV+ adolescents, mean age 12 (standard deviation [SD], 1.6) years, 50.4% male, and 110 HIV- adolescents, mean age 11.8 (SD, 1.8) years, 45.6% male, were tested at baseline; 477 (93%) HIV+ and 102 (93%) HIV- adolescents at 12 months; and 473 (92%) HIV+ and 97 (88%) HIV- adolescents at 24 months. Only 5.4% of the HIV+ adolescents had HIV viral load >10 000 copies/mL at baseline. Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were lower in the HIV+ compared to the HIV- adolescents and tracked with no deterioration or catch-up over 2 years. Previous pulmonary tuberculosis (PTB) or lower respiratory tract infection (LRTI) was significantly associated with reduced FEV1 and FVC (P < .05 for both). CONCLUSIONS: HIV+ adolescents had lower lung function over 2 years than HIV- adolescents. This study highlights the need for lung function surveillance and prevention of LRTIs and PTB in HIV+ adolescents.

Intra-breath measures of respiratory mechanics in healthy African infants detect risk of respiratory illness in early life.

Lower respiratory tract illness (LRTI) is a leading cause of mortality and morbidity in children. Sensitive and noninvasive infant lung function techniques are needed to measure risk for and impact of LRTI on lung health. The objective of this study was to investigate whether lung function derived from the intra-breath forced oscillation technique (FOT) was able to identify healthy infants at risk of LRTI in the first year of life.Lung function was measured with the novel intra-breath FOT, in 6-week-old infants in a South African birth cohort (Drakenstein Child Health Study). LRTI during the first year was confirmed by study staff. The association between baseline lung function and LRTI was assessed with logistic regression and odds ratios determined using optimal cut-off values.Of the 627 healthy infants with successful lung function testing, 161 (24%) had 238 LRTI episodes subsequently during the first year. Volume dependence of respiratory resistance (ΔR) and reactance (ΔX) was associated with LRTI. The predictive value was stronger if LRTI was recurrent (n=50 (31%): OR 2.5, ΔX), required hospitalisation (n=38 (16%): OR 5.4, ΔR) or was associated with wheeze (n=87 (37%): OR 3.9, ΔX).Intra-breath FOT can identify healthy infants at risk of developing LRTI, wheezing or severe illness in the first year of life.

Lung Function in African Infants in the Drakenstein Child Health Study. Impact of Lower Respiratory Tract Illness.

RATIONALE: Lower respiratory tract illness is a major cause of childhood morbidity and mortality. It is unknown whether infants are predisposed to illness because of impaired lung function or whether respiratory illness reduces lung function. OBJECTIVES: To investigate the impact of early life exposures, including lower respiratory tract illness, on lung function during infancy. METHODS: Infants enrolled in the Drakenstein child health study had lung function at 6 weeks and 1 year. Testing during quiet natural sleep included tidal breathing, exhaled nitric oxide, and multiple breath washout measures. Risk factors for impaired lung health were collected longitudinally. Lower respiratory tract illness surveillance was performed and any episode investigated. MEASUREMENTS AND MAIN RESULTS: Lung function was tested in 648 children at 1 year. One hundred and fifty (29%) infants had a lower respiratory tract illness during the first year of life. Lower respiratory tract illness was independently associated with increased respiratory rate (4%; 95% confidence interval [CI], 1.01-1.08; P = 0.02). Repeat episodes further increased respiratory rate (3%; 95% CI, 1.01-1.05; P = 0.004), decreased tidal volume (-1.7 ml; 95% CI, -3.3 to -0.2; P = 0.03), and increased the lung clearance index (0.13 turnovers; 95% CI, 0.04-0.22; P = 0.006) compared with infants without illness. Tobacco smoke exposure, lung function at 6 weeks, infant growth, and prematurity were other independent predictors of lung function at 1 year. CONCLUSIONS: Early life lower respiratory tract illness impairs lung function at 1 year, independent of baseline lung function. Preventing early life lower respiratory tract illness is important to optimize lung function and promote respiratory health in childhood.

Isoniazid for preventing tuberculosis in HIV-infected children.

BACKGROUND: Tuberculosis (TB) is an important cause of illness and death in HIV-positive children living in areas of high TB prevalence. We know that isoniazid prophylaxis prevents TB in HIV-negative children following TB exposure, but there is uncertainty related to its role in TB preventive treatment in HIV-positive children. OBJECTIVES: To summarise the effects of TB preventive treatment versus placebo in HIV-positive children with no known TB contact on active TB, death, and reported adverse events. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE/PubMed, Embase and two trial registers up to February 2017. SELECTION CRITERIA: We included trials of HIV-positive children with and without known TB exposure, randomized to receive TB preventive treatment or placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently used the study selection criteria, assessed risk of bias, and extracted data. We assessed effects using risk, incidence rate and hazard ratios and assessed the certainty of evidence using GRADE. MAIN RESULTS: We included three trials, involving 991 participants, below the age of 13 years, from South Africa and Botswana. Children were randomized to isoniazid prophylaxis or placebo, given daily or three times weekly. The median length of follow-up ranged from 5.7 to 34 months; some were on antiretroviral therapy (ART).In HIV-positive children not on ART, isoniazid prophylaxis may reduce the risk of active TB (hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.11 to 0.87; 1 trial, 240 participants, low certainty evidence), and death (HR 0.46, 95% CI 0.22 to 0.95; 1 trial, 240 participants, low certainty evidence). One trial (182 participants) reported number of children with laboratory adverse events, which was similar between the isoniazid prophylaxis and placebo groups. No clinical adverse events were reported.In HIV-positive children on ART, we do not know if isoniazid prophylaxis reduces the risk of active TB (risk ratio (RR) 0.76, 95% CI 0.50 to 1.14; 3 trials, 737 participants, very low certainty evidence) or death (RR 1.45, 95% CI 0.78 to 2.72; 3 trials, 737 participants, very low certainty evidence). Two trials (714 participants) reported number of clinical adverse events and three trials (795 participants) reported number of laboratory adverse events; for both categories, the number of adverse events were similar between the isoniazid prophylaxis and placebo groups. AUTHORS' CONCLUSIONS: Isoniazid prophylaxis given to all children diagnosed with HIV may reduce the risk of active TB and death in HIV-positive children not on ART in studies from Africa. For children on ART, no clear benefit was detected. .

Lung function abnormalities in HIV-infected adults and children.

Despite the advent of antiretroviral therapy (ART), the human immunodeficiency virus (HIV) epidemic remains a global health crisis with a high burden of respiratory disease among infected persons. While the early complications of the epidemic were dominated by opportunistic infections, improved survival has led to the emergence of non-infectious conditions that are associated with chronic respiratory symptoms and pulmonary disability. Obstructive ventilatory defects and reduced diffusing capacity are common findings in adults, and the association between HIV and chronic obstructive pulmonary disease is increasingly recognized. There is synergism between viral factors, opportunistic infections, conventional influences like tobacco smoke and biomass fuel exposure, and potentially, the immunological effects of ART on the development of HIV-associated chronic obstructive lung disease. Pulmonary function data for HIV-infected infants and children are scarce, but shows that bronchiectasis and obliterative bronchiolitis with severe airflow limitation are major problems, particularly in the developing world. However, studies from these regions are sorely lacking. There is thus a major unmet need to understand the influences of chronic HIV infection on the lung in both adults and children, and to devise strategies to manage and prevent these diseases in HIV-infected individuals. It is important for clinicians working with HIV-infected individuals to have an appreciation of their effects on measurements of lung function. This review therefore summarizes the lung function abnormalities described in HIV-positive adults and children, with an emphasis on obstructive lung disease, and examines potential pathogenic links between HIV and the development of chronic pulmonary disability.

Optimized algorithm for speed-of-sound-based infant sulfur hexafluoride multiple-breath washout measurements.

INTRODUCTION: Major methodological issues with the existing algorithm (WBreath) used for the analysis of speed-of-sound-based infant sulfur hexafluoride (SF6) multiple-breath washout (MBW) measurements lead to implausible results and complicate the comparison between different age groups and centers. METHODS: We developed OASIS-a novel algorithm to analyze speed-of-sound-based infant SF6 MBW measurements. This algorithm uses known context of the measurements to replace the dependence of WBreath on model input parameters. We validated the functional residual capacity (FRC) measurement accuracy of this new algorithm in vitro, and investigated its use in existing infant MBW data sets from different infant cohorts from Switzerland and South Africa. RESULTS: In vitro, OASIS managed to outperform WBreath at FRC measurement accuracy, lowering mean (SD) absolute error from 5.1 (3.2) % to 2.1 (1.6) % across volumes relevant for the infant age range, in variable temperature, respiratory rate, tidal volume and ventilation inhomogeneity conditions. We showed that changes in the input parameters to WBreath had a major impact on MBW results, a methodological drawback which does not exist in the new algorithm. OASIS produced more plausible results than WBreath in longitudinal tracking of lung clearance index (LCI), provided improved measurement stability in LCI over time, and improved comparability between centers. DISCUSSION: This new algorithm represents a meaningful advance in obtaining results from a legacy system of lung function measurement by allowing a single method to analyze measurements from different age groups and centers.

Chronic respiratory disease in Indigenous peoples: a framework to address inequity and strengthen respiratory health and health care globally.

Indigenous peoples around the world bear a disproportionate burden of chronic respiratory diseases, which are associated with increased risks of morbidity and mortality. Despite the imperative to address global inequity, research focused on strengthening respiratory health in Indigenous peoples is lacking, particularly in low-income and middle-income countries. Drivers of the increased rates and severity of chronic respiratory diseases in Indigenous peoples include a high prevalence of risk factors (eg, prematurity, low birthweight, poor nutrition, air pollution, high burden of infections, and poverty) and poor access to appropriate diagnosis and care, which might be linked to colonisation and historical and current systemic racism. Efforts to tackle this disproportionate burden of chronic respiratory diseases must include both global approaches to address contributing factors, including decolonisation of health care and research, and local approaches, co-designed with Indigenous people, to ensure the provision of culturally strengthened care with more equitable prioritisation of resources. Here, we review evidence on the burden of chronic respiratory diseases in Indigenous peoples globally, summarise factors that underlie health disparities between Indigenous and non-Indigenous people, propose a framework of approaches to improve the respiratory health of Indigenous peoples, and outline future directions for clinical care and research.

Determinants of lung function development from birth to age 5 years: an interrupted time series analysis of a South African birth cohort.

BACKGROUND: Early life is a key period that determines long-term health. Lung development in childhood predicts lung function attained in adulthood and morbidity and mortality across the life course. We aimed to assess the effect of early-life lower respiratory tract infection (LRTI) and associated risk factors on lung development from birth to school age in a South African birth cohort. METHODS: We prospectively followed children enrolled in a population-based cohort from birth (between March 5, 2012 and March 31, 2015) to age 5 years with annual lung function assessment. Data on multiple early-life exposures, including LRTI, were collected. The effect of early-life risk factors on lung function development from birth to age 5 years was assessed using the Generalised Additive Models for Location, Scale and Shape and Interrupted Time Series approach. FINDINGS: 966 children (475 [49·2%] female, 491 [50·8%] male) had lung function measured with oscillometry, tidal flow volume loops, and multiple breath washout. LRTI occurred in 484 (50·1%) children, with a median of 2·0 LRTI episodes (IQR 1·0-3·0) per child. LRTI was independently associated with altered lung function, as evidenced by lower compliance (0·959 [95% CI 0·941-0·978]), higher resistance (1·028 [1·016-1·041]), and higher respiratory rate (1·018 [1·063-1·029]) over 5 years. Additional impact on lung function parameters occurred with each subsequent LRTI. Respiratory syncytial virus (RSV) LRTI was associated with lower expiratory flow ratio (0·97 [0·95-0·99]) compared with non-RSV LRTI. Maternal factors including allergy, smoking, and HIV infection were also associated with altered lung development, as was preterm birth, low birthweight, female sex, and coming from a less wealthy household. INTERPRETATION: Public health interventions targeting LRTI prevention, with RSV a priority, are vital, particularly in low-income and middle-income settings. FUNDING: UK Medical Research Council Grant, The Wellcome Trust, The Bill & Melinda Gates Foundation, US National Institutes of Health Human Heredity and Health in Africa, South African Medical Research Council, Hungarian Scientific Research Fund, and European Respiratory Society.

Home ventilation in low resource settings: Learning to do more, with less.

Long-term ventilation (LTV) in children at home, especially invasive ventilation, is not widely available nor practised in low-resource settings (LRS). Barriers to providing LTV include underdeveloped pediatric critical care services, limited expertise in pediatric LTV, limited capacity to screen for sleep-disordered breathing (SDB) and high cost of LTV equipment and consumables. Additional challenges encountered in LRS may be unreliable electricity supply and difficult socioeconomic conditions. Where LTV at home has been successfully implemented, caregivers and families in LRS must often take full responsibility for their child's care as professional home-based nursing care is scarce. Selecting suitable children and families to offer LTV in LRS may therefore face difficult ethical decisions when families are disempowered or incapable of providing 24-h care at home. Early caregiver participation and hands-on training in tracheostomy care and LTV equipment is key to success, irrespective of the caregiver's level of education. The use of overnight oximetry, mobile phone technology, spirometry, and clinical evaluation are simple tools that can aid recognition and monitoring of children needing LTV. As children survive longer supported by LTV, engaging with adult services at an early stage is important to ensure suitable pathways for transition to adult care are in place. Building capacity and expertise in pediatric LTV in LRS requires targeted training of health professionals in related disciplines and advocacy to policymakers and funders that LTV in appropriately selected circumstances is worthwhile, life-changing, and cost-saving.

Early childhood wheezing phenotypes and determinants in a South African birth cohort: longitudinal analysis of the Drakenstein Child Health Study.

BACKGROUND: Developmental trajectories of childhood wheezing in low-income and middle-income countries (LMICs) have not been well described. We aimed to derive longitudinal wheeze phenotypes from birth to 5 years in a South African birth cohort and compare those with phenotypes derived from a UK cohort. METHODS: We used data from the Drakenstein Child Health Study (DCHS), a longitudinal birth cohort study in a peri-urban area outside Cape Town, South Africa. Pregnant women (aged ≥18 years) were enrolled during their second trimester at two public health clinics. We followed up children from birth to 5 years to derive six multidimensional indicators of wheezing (including duration, temporal sequencing, persistence, and recurrence) and applied Partition Around Medoids clustering to derive wheeze phenotypes. We compared phenotypes with a UK cohort (the Avon Longitudinal Study of Parents and Children [ALSPAC]). We investigated associations of phenotypes with early-life exposures, including all-cause lower respiratory tract infection (LRTI) and virus-specific LRTI (respiratory syncytial virus, rhinovirus, adenovirus, influenza, and parainfluenza virus) up to age 5 years. We investigated the association of phenotypes with lung function at 6 weeks and 5 years. FINDINGS: Between March 5, 2012, and March 31, 2015, we enrolled 1137 mothers and there were 1143 livebirths. Four wheeze phenotypes were identified among 950 children with complete data: never (480 children [50%]), early transient (215 children [23%]), late onset (104 children [11%]), and recurrent (151 children [16%]). Multivariate adjusted analysis indicated that LRTI and respiratory syncytial virus-LRTI, but not other respiratory viruses, were associated with increased risk of recurrent wheeze (odds ratio [OR] 2·79 [95% CI 2·05-3·81] for all LTRIs; OR 2·59 [1·30-5·15] for respiratory syncytial virus-LRTIs). Maternal smoking (1·88 [1·12-3·02]), higher socioeconomic status (2·46 [1·23-4·91]), intimate partner violence (2·01 [1·23-3·29]), and male sex (2·47 [1·50-4·04]) were also associated with recurrent wheeze. LRTI and respiratory syncytial virus-LRTI were also associated with early transient and late onset clusters. Wheezing illness architecture differed between DCHS and ALSPAC; children included in ALSPAC in the early transient cluster wheezed for a longer period before remission and late-onset wheezing started at an older age, and no persistent phenotype was identified in DCHS. At 5 years, airway resistance was higher in children with early or recurrent wheeze compared with children who had never wheezed. Airway resistance increased from 6 weeks to 5 years among children with recurrent wheeze. INTERPRETATION: Effective strategies to reduce maternal smoking and psychosocial stressors and new preventive interventions for respiratory syncytial virus are urgently needed to optimise child health in LMICs. FUNDING: UK Medical Research Council; The Bill & Melinda Gates Foundation; National Institutes of Health Human Heredity and Health in Africa; South African Medical Research Council; Wellcome Trust.

Normal values of respiratory oscillometry in South African children and adolescents.

Introduction: Noninvasive measurement of respiratory impedance by oscillometry can be used in young children aged from 3 years and those unable to perform forced respiratory manoeuvres. It can discriminate between healthy children and those with respiratory disease. However, its clinical application is limited by the lack of reference data for African paediatric populations. The aim of the present study was to develop reference equations for oscillometry outcomes in South African children and adolescents. Methods: Healthy subjects, enrolled in the Drakenstein Child Health Study, HIV-uninfected adolescents in the Cape Town Adolescent Antiretroviral Cohort and healthy children attending surgical outpatient clinics at Red Cross War Memorial Children's Hospital were measured with conventional spectral (6-32 Hz) and intra-breath (10 Hz) oscillometry. Stepwise linear regression was used to assess the relationship between respiratory variables and anthropometric predictors (height, sex, ancestry) to generate reference equations. Results: A total of 692 subjects, 48.4% female, median age of 5.2 years (range: 3-17 years) were included. The median (interquartile range (IQR)) for weight for age z-score and height for age z-score was -0.42 (-1.11-0.35) and -0.65 (-1.43-0.35), respectively. Stepwise regression demonstrated that all the variables were significantly dependent on height only. Comparison to previous reference data indicated slightly higher resistance and lower compliance values in the smallest children. Conclusion: We established the first respiratory oscillometry reference equations for African children and adolescents, which will facilitate use in early identification and management of respiratory disease. Our results suggest differences in oscillometry measures by ancestry but also highlight the lack of standardisation in methodology.

ERS International Congress 2022: highlights from the Paediatrics Assembly.

This review has been prepared by the Early Career Members and Chairs of the European Respiratory Society (ERS) Assembly 7: Paediatrics. We here summarise the highlights of the advances in paediatric respiratory research presented at the ERS International Congress 2022. The eight scientific groups of this Assembly cover a wide range of research areas, including respiratory physiology and sleep, asthma and allergy, cystic fibrosis (CF), respiratory infection and immunology, neonatology and intensive care, respiratory epidemiology, bronchology, and lung and airway developmental biology. Specifically, we report on abstracts presented at the congress on the effect of high altitude on sleep, sleep disorders, the hypoxic challenge test, and measurements of ventilation inhomogeneity. We discuss prevention of preschool wheeze and asthma, and new asthma medications. In children with CF, we describe how to monitor the effect of CF transmembrane conductance regulator modulator therapy. We present respiratory manifestations and chronic lung disease associated with common variable immunodeficiency. Furthermore, we discuss how to monitor respiratory function in neonatal and paediatric intensive care units. In respiratory epidemiology, we present the latest news from population-based and clinical cohort studies. We also focus on innovative and interventional procedures for the paediatric airway, such as cryotherapy. Finally, we stress the importance of better understanding the molecular mechanisms underlying normal and abnormal lung development.

Lung Function in Preschool Children in Low and Middle Income Countries: An Under-Represented Potential Tool to Strengthen Child Health.

Background: The burden of respiratory disease is high in low-middle income countries (LMIC). Pulmonary function tests are useful as an objective measure of lung health and to track progression. Spirometry is the commonest test, but its use is limited in preschool children. Other lung function methods have been developed but their use in LMIC has not been well described. Aim: To review the use of preschool lung function testing in children in LMIC, with particular reference to feasibility and clinical applications. Methods: Electronic databases "PubMed", "Scopus"," Web of Science", and "EBSCO host" were searched for publications in low and middle income countries on preschool lung function testing, including spirometry, fractional exhaled nitric oxide (FeNO), oscillometry, interrupter technique, tidal breathing and multiple breath washout (MBW), from 1 January 2011 to 31 January 2022. Papers in English were included and those including only children ≥6 years were excluded. Result: A total of 61 papers from LMIC in Asia, South America, Africa, Eurasia or the Middle East were included. Of these, 40 included spirometry, 7 FeNO, 15 oscillometry, 2 interrupter technique, and 2 tidal breathing. The papers covered test feasibility (19/61), clinical application (46/61) or epidemiological studies (13/61). Lung function testing was successful in preschool children from LMIC. Spirometry was the most technically demanding and success gradually increased with age. Conclusion: Preschool lung function testing is under-represented in LMIC for the burden of respiratory disease. These tests have the potential to strengthen respiratory care in LMIC, however access needs to be improved.