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.

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.

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.

Impact of HIV and antiretroviral drug exposure on lung growth and function over 2 years in an African Birth Cohort.

OBJECTIVE: To assess the impact of HIV and antiretroviral exposure without infection on lung growth and function over the first 2 years of life. DESIGN: Prospective observational study of an African birth cohort, Drakenstein Child Health Study. METHOD: Infants enrolled antenatally had lung function measured at 6 weeks, 1 and 2 years. HIV-infected women received antiretroviral therapy (ART) as per local guidelines. The association between HIV and antiretroviral exposure with lung function was assessed using mixed effects modelling. RESULTS: Of 1143 infants born, two HIV-infected infants were excluded from analysis; 909 (80%) infants had lung function collected at 6 weeks [190 (21%) were HIV-exposed uninfected (HEU)]; 782 (69%) at 1 year and 741 (65%) at 2 years. At 6 weeks HEU infants had larger tidal volume compared with HIV-unexposed infants (1.13 ml, confidence interval: 0.02-2.23, P = 0.045). High maternal viral load was associated with a 17% lower expiratory flow over 2 years (0.17, confidence interval 0.00-0.34, P = 0.046). First-line ART initiated during pregnancy was associated with lower infant tidal volume at 6 weeks compared with those who initiated ART before pregnancy (-2.7 ml, -5.31 to -0.10, P = 0.042), and low maternal CD4 cell counts associated with lower infant tidal over 2 years (-11.1 ml, -18.58-3.58, P = 0.004). CONCLUSION: HIV exposure is associated with altered lung function in early life, with a vulnerable HEU subgroup based on maternal disease severity, immunological compromise and ART exposure. These data highlight the importance of ongoing surveillance of respiratory health in HEU children.

Expression of UCP2 in Wistar rats varies according to age and the severity of obesity

Obesity, a complex metabolic disorder, is characterized by mitochondrial dysfunction and oxidative stress. Increased expression of uncoupling protein 2 (UCP2) during obesity is an adaptive response to suppress the production of reactive oxygen species. The aims of this study were to compare the expression of UCP2 in diet-induced obese Wistar rats that differed according to age and their severity of obesity, and to compare UCP2 expression in the liver and muscle of these rats. UCP2 messenger RNA and protein expression was increased 4.6-fold (p < 0.0001) and 3.0-fold (p < 0.05), respectively, in the liver of the older and heavier rats. In contrast, UCP2 expression was decreased twofold (p < 0.005) in the muscle of these rats, while UCP3 messenger RNA (mRNA) was increased twofold (p < 0.01). Peroxisome proliferator-activated receptor alpha (PPARα) was similarly increased (3.0-fold, p < 0.05) in the liver of the older and more severe obese rats. Total protein content was increased (2.3-fold, p < 0.0001), while 5' adenosine monophosphate-activated protein kinase (AMPK) activity was decreased (1.3-fold, p = 0.05) in the liver of the older, heavier rats. No difference in total protein content and AMPK expression was observed in the muscle of these rats. This study showed that the expression of UCP2 varies according to age and the severity of obesity and supports the widely held notion that increased UCP2 expression is an adaptive response to increased fatty acid β-oxidation and reactive oxygen species production that occurs during obesity. An understanding of metabolic adaptation is imperative to gain insight into the underlying causes of disease, thus facilitating intervention strategies to combat disease progression (AU)

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Expression of UCP2 in Wistar rats varies according to age and the severity of obesity.

Obesity, a complex metabolic disorder, is characterized by mitochondrial dysfunction and oxidative stress. Increased expression of uncoupling protein 2 (UCP2) during obesity is an adaptive response to suppress the production of reactive oxygen species. The aims of this study were to compare the expression of UCP2 in diet-induced obese Wistar rats that differed according to age and their severity of obesity, and to compare UCP2 expression in the liver and muscle of these rats. UCP2 messenger RNA and protein expression was increased 4.6-fold (p < 0.0001) and 3.0-fold (p < 0.05), respectively, in the liver of the older and heavier rats. In contrast, UCP2 expression was decreased twofold (p < 0.005) in the muscle of these rats, while UCP3 messenger RNA (mRNA) was increased twofold (p < 0.01). Peroxisome proliferator-activated receptor alpha (PPARα) was similarly increased (3.0-fold, p < 0.05) in the liver of the older and more severe obese rats. Total protein content was increased (2.3-fold, p < 0.0001), while 5' adenosine monophosphate-activated protein kinase (AMPK) activity was decreased (1.3-fold, p = 0.05) in the liver of the older, heavier rats. No difference in total protein content and AMPK expression was observed in the muscle of these rats. This study showed that the expression of UCP2 varies according to age and the severity of obesity and supports the widely held notion that increased UCP2 expression is an adaptive response to increased fatty acid ß-oxidation and reactive oxygen species production that occurs during obesity. An understanding of metabolic adaptation is imperative to gain insight into the underlying causes of disease, thus facilitating intervention strategies to combat disease progression.