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.

Quantitative CT analysis for bronchiolitis obliterans in perinatally HIV-infected adolescents-comparison with controls and lung function data.

OBJECTIVE: To compare quantitative chest CT parameters in perinatally HIV-infected adolescents with and without bronchiolitis obliterans compared with HIV-uninfected controls and their association with lung function measurements. MATERIALS AND METHODS: Seventy-eight (41 girls) HIV-infected adolescents with a mean age of 13.8 ± 1.65 years and abnormal pulmonary function tests in the prospective Cape Town Adolescent Antiretroviral Cohort underwent contrast-enhanced chest CT on inspiration and expiration. Sixteen age-, sex-, and height-matched non-infected controls were identified retrospectively. Fifty-one HIV-infected adolescents (28 girls) displayed mosaic attenuation on expiration suggesting bronchiolitis obliterans. Pulmonary function tests were collected. The following parameters were obtained: low- and high-attenuation areas, mean lung density, kurtosis, skewness, ventilation heterogeneity, lung mass, and volume. RESULTS: HIV-infected adolescents showed a significantly higher mean lung density, ventilation heterogeneity, mass, and high- and low-attenuation areas compared with non-infected individuals. Kurtosis and skewness were significantly lower as well. HIV-infected adolescents with bronchiolitis obliterans had a significantly lower kurtosis and skewness compared with those without bronchiolitis obliterans. Lung mass and volume showed the strongest correlations with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and alveolar volume. Low-attenuation areas below - 950 HU and ventilation heterogeneity showed the strongest correlation with FEV1/FVC (range, - 0.51 to - 0.34) and forced expiratory flow between 25 and 75% of FVC (range, - 0.50 to - 0.35). CONCLUSION: Quantitative chest CT on inspiration is a feasible technique to differentiate perinatally HIV-infected adolescents with and without bronchiolitis obliterans. Quantitative CT parameters correlate with spirometric measurements of small-airway disease. KEY POINTS: • Perinatally HIV-infected adolescents showed a more heterogeneous attenuation of the lung parenchyma with a higher percentage of low- and high-attenuation areas compared with non-infected patients. • Kurtosis and skewness are able to differentiate between HIV-infected adolescents with and without bronchiolitis obliterans using an inspiratory chest CT. • Quantitative CT parameters of the chest correlate significantly with pulmonary function test. Low-attenuation areas and ventilation heterogeneity are particularly associated with spirometric parameters related to airway obstruction.

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.

Respiratory Complications in Children and Adolescents with Human Immunodeficiency Virus.

Respiratory complications comprise a large proportion of the burden of mortality and morbidity in children with human immunodeficiency virus (HIV). HIV-associated lower respiratory tract infection (LRTI) has declined in incidence with early diagnosis and use of antiretroviral therapy (ART) but is widespread in areas with limited access to ART. HIV-exposed uninfected infants have a higher risk of LRTI early in life than unexposed infants. Pulmonary tuberculosis (PTB) presenting as acute or chronic disease is common in highly TB endemic areas. Chronic lung disease is common; preceding LRTI, PTB or late initiation of ART are risk factors.

Tuberculosis infection and disease in South African adolescents with perinatally acquired HIV on antiretroviral therapy: a cohort study.

INTRODUCTION: There are limited data on Tuberculosis (TB) in adolescents with perinatally acquired HIV (APHIV). We examined the incidence and determinants of TB infection and disease in the Cape Town Adolescent Antiretroviral Cohort (CTAAC). METHODS: Youth between nine and fourteen years on antiretroviral therapy (ART) for more than six months in public sector care, and age-matched HIV-negative adolescents, were enrolled between July 2013 through March 2015 and followed six-monthly. Data were censored on 31 October 2018. Symptom screening, chest radiograph, viral load, CD4 count, QuantiFERON (QFT) and sputum for Xpert MTB/RIF, microscopy, culture and sensitivity were performed annually. TB infection was defined by a QFT of >0.35 IU/mL. TB diagnosis was defined as confirmed (culture or Xpert MTB/RIF positive) or unconfirmed (clinical diagnosis and started on TB treatment). Analyses examined the incidence and determinants of TB infection and disease. RESULTS: Overall 496 HIV+ and 103 HIV-negative participants (median age at enrolment 12 years (interquartile range, IQR 10.6 to 13.3) were followed for a median of 3.1 years (IQR 3.0 to 3.4); 50% (298/599) were male. APHIV initiated ART at median age 4.4 years (IQR 2.1 to 7.6). At enrolment, 376/496 (76%) had HIV viral load <40 copies/mL, median CD4 count was 713 cells/mm3 and 179/559 (32%) were QFT+, with no difference by HIV status (APHIV 154/468, 33%; HIV negative 25/91, 27%; p = 0.31). The cumulative QFT+ prevalence was similar (APHIV 225/492, 46%; 95%CI 41% to 50%; HIV negative 44/98, 45%; 95% CI 35% to 55%; p = 0.88). APHIV had a higher incidence of all TB disease than HIV-negative adolescents (2.2/100PY, 95% CI 1.6 to 3.1 vs. 0.3/100PY, 95% CI 0.04 to 2.2; IRR 7.36, 95% CI 1.01 to 53.55). The rate of bacteriologically confirmed TB in APHIV was 1.3/100 PY compared to 0.3/100PY for HIV-negative adolescents, suggesting a fourfold increased risk of developing TB disease in APHIV despite access to ART. In addition, a positive QFT at enrolment was not predictive of TB in this population. CONCLUSIONS: High incidence rates of TB disease occur in APHIV despite similar QFT conversion rates to HIV-negative adolescents. Strategies to prevent TB in this vulnerable group must be strengthened.

COVID-19 and Pediatric Lung Disease: A South African Tertiary Center Experience.

The COVID-19 pandemic led to rapid global spread with far-reaching impacts on health-care systems. Whilst pediatric data consistently shown a milder disease course, chronic lung disease has been identified as a risk factor for hospitalization and severe disease. In Africa, comprised predominantly of low middle-income countries (LMIC), the additional burden of HIV, tuberculosis, malnutrition and overcrowding is high and further impacts health risk. This paper reviewed the literature on COVID-19 and chronic lung disease in children and provides our experience from an African pediatric pulmonary center in Cape Town, South Africa. South African epidemiological data confirms a low burden of severe disease with children <18 years comprising 8% of all diagnosed cases and 3% of all COVID-19 admissions. A decrease in hospital admission for other viral lower respiratory tract infections was found. While the pulmonology service manages children with a wide range of chronic respiratory conditions including bronchiectasis, cystic fibrosis, asthma, interstitial lung disease and children with tracheostomies, no significant increase in COVID-19 admissions were noted and in those who developed COVID-19, the disease course was not severe. Current evidence suggests that pre-existing respiratory disease in children does not appear to be a significant risk factor for severe COVID-19. Longitudinal data are still needed to assess risk in children with immunosuppression and interstitial lung diseases. The indirect impacts of the pandemic response on child respiratory health are notable and still likely to be fully realized and quantified. Ensuring children have access to full preventive and care services during this time is priority.

Cardiopulmonary dysfunction in perinatally HIV-infected South African adolescents on antiretroviral therapy: baseline findings from the Cape Town Adolescent Antiretroviral Cohort.

INTRODUCTION: Antiretroviral therapy (ART) has reduced morbidity and mortality in sub-Saharan Africa, but the burden of coexistent cardiopulmonary disease in perinatally HIV-positive adolescents on antiretroviral therapy (ART) has not been well described. The aim of this study was to investigate the prevalence and associations of cardiopulmonary dysfunction in adolescents with perinatally acquired HIV on ART. METHODS: For this cross-sectional analysis, 515 perinatally HIV-positive adolescents ages 9 to 14 years on ART for at least six months, and a comparator group of 110 age-matched HIV-uninfected adolescents were tested between August 2013 and April 2015 using echocardiography, six-minute walk test (6MWT) and spirometry. Those with either abnormal spirometry or abnormal 6MWT and any right or left systolic or diastolic dysfunction or abnormal mean pulmonary arterial pressure were considered as having impaired cardiopulmonary function. Logistic regression was used to investigate determinants of impaired cardiopulmonary function. RESULTS: Overall, 474 adolescents with perinatally acquired HIV (mean [SD] age, 12 [1.6] years; median [IQR] ART duration, 7 [4.6 to 9.3] years; median [IQR] CD4 count, 712 [571 to 959] cell/mm3 ) and 109 HIV-uninfected adolescents mean (SD) age 11.8 (1.8) years, had successful cardiac and lung function testing. Impaired cardiopulmonary function was detected in 13% of adolescents with perinatally acquired HIV and 8% of HIV-uninfected adolescents, p = 0.136. Among adolescents with perinatally acquired HIV, those with low tricuspid annular plane systolic excursion (TAPSE) had significantly lower mean FEV1 , 1.5 L versus 1.6 L, p = 0.011. Height (OR 0.7, 95%CI 0.5 to 0.9), body mass index (OR 0.7, 95%CI 0.5 to 0.9) and past pulmonary tuberculosis (OR 2.3, 95%CI 1.2 to 4.4) were significantly associated with a low cardiopulmonary function. CONCLUSIONS: Despite being on ART, cardiopulmonary dysfunction occurs in an appreciable proportion of perinatally HIV-infected adolescents but no significant difference to uninfected controls. This finding requires further exploration. Factors associated with dysfunction may be amenable to public health interventions to reduce cardiopulmonary disease in this population.

Multisystem impairment in South African adolescents with Perinatally acquired HIV on antiretroviral therapy (ART).

INTRODUCTION: Adolescents with perinatally acquired HIV (PHIV) are at risk of chronic disease due to long-standing immune suppression, HIV disease and antiretroviral therapy (ART) exposure. However, there are few data on multisystem disease in this population. We investigated the overlapping burden of neurocognitive, cardiovascular, respiratory and/or renal impairment among PHIV positive (PHIV+) adolescents. METHODS: In this cross-sectional analysis, participants aged 9 to 14 years on ART for >6 months were recruited from seven sites across Cape Town from July 2013 through March 2015, together with age-matched HIV-negative (HIV-) adolescents. Impairment at enrolment was assessed across neurocognitive functioning (using the youth-International HIV Dementia Scale); cardiac function (echocardiogram abnormality); respiratory function (abnormal spirometry) and renal function (abnormal glomerular filtration rate). RESULTS AND DISCUSSION: Overall, 384 PHIV+ and 95 HIV- adolescents were included (mean age, 11.9 years; 49% female). Median age of ART initiation was 4.2 years (IQR: 1.7 to 7.6) and median CD4 count was 709 (IQR: 556 to 944) with 302 (79%) of PHIV+ adolescents virologically suppressed. Abacavir and Zidovudine were the most commonly used nucleoside reverse transcriptase inhibitors (NRTIs) with 60% of adolescents on non-nucleoside reverse transcriptase inhibitors (NNRTI) and 38% on a protease inhibitor (PI). Among PHIV+ adolescents, 167 (43.5%) had single system impairment only, 110 (28.6%) had two systems involved, and 39 (10.2%) had three or four systems involved. PHIV+ participants had more 2-system and 3-system impairment than HIV-, 110 (28.6%) versus 17 (17.9%), p = 0.03 and 39 (10.2%) versus 3 (4.3%), p = 0.03. PHIV+ participants who had failed a year of school (73.8% vs. 46.4%, p = 0.00) and with a viral load >1000 copies/mL at enrolment (16.8% vs. 8.1%, p = 0.03) were more likely to have dual or multisystem impairment. Of those with cardiac impairment, 86.7% had an additional system impaired. Similarly, in those with neurocognitive impairment, almost 60% had additional systems impaired and of those with respiratory impairment, 74% had additional systems impaired. CONCLUSIONS: Despite relatively early ART initiation, there is a substantial burden of multisystem chronic impairment among PHIV+ adolescents. This phenomenon needs to be further explored as this population ages and begins to engage in adult lifestyle factors that may compound these impairments.

Lung function in HIV-infected children and adolescents.

BACKGROUND: The advent of antiretroviral therapy has led to the improved survival of human immunodeficiency virus (HIV)-infected children to adulthood and to HIV becoming a chronic disease in older children and adolescents. Chronic lung disease is common among HIV-infected adolescents. Lung function measurement may help to delineate the spectrum, pathophysiology and guide therapy for HIV-related chronic lung disease. AIM: The aim of this study was to review the available data on the spectrum and determinants of lung function abnormalities and the impact of antiretroviral therapy on lung function in perinatally HIV-infected children and adolescents. METHODS: Electronic databases "PUBMED", "African wide" and "CINAHL" via EBSCO Host, using the MeSH terms "Respiratory function" AND "HIV" OR "Acquired Immunodeficiency Syndrome" AND "Children" OR "Adolescents", were searched for relevant articles on lung function in HIV-infected children and adolescents. The search was limited to English language articles published between January 1984 and September 2017. RESULTS: Eighteen articles were identified, which included studies from Africa, the United States of America (USA) and Italy, representing 2051 HIV-infected children and adolescents, 68% on antiretroviral therapy, aged from 50 days to 24 years. Lung function abnormalities showed HIV-infected participants had increased irreversible lower airway expiratory obstruction and reduced functional aerobic impairment on exercise, compared to HIV-uninfected participants. Mosaic attenuation, extent of bronchiectasis, history of previous pulmonary tuberculosis or previous lower respiratory tract infection and cough for more than 1 month were associated with low lung function. Pulmonary function tests in children established on antiretroviral therapy did not show aerobic impairment and had less severe airway obstruction. CONCLUSION: There is increasing evidence that HIV-infected children and adolescents have high prevalence of lung function impairment, predominantly irreversible lower airway obstruction and reduced aerobic function.

Lung Function in South African Adolescents Infected Perinatally with HIV and Treated Long-Term with Antiretroviral Therapy.

RATIONALE: Lung disease is a common cause of mortality and morbidity in HIV-infected adolescents, but there is limited information on the spectrum of lung function impairment in adolescents on antiretroviral therapy. OBJECTIVES: To investigate lung function in HIV-infected adolescents on antiretroviral therapy in the Cape Town Adolescent Antiretroviral Cohort (Cape Town, South Africa). METHODS: A total of 515 South African adolescents, aged 9-14 years, stable on antiretroviral therapy for at least 6 months, underwent baseline lung function testing. Measures included spirometry, nitrogen multiple-breath washout, forced oscillation technique, 6-minute walk test, single-breath carbon monoxide diffusion testing, and bronchodilator response testing. A comparator group of 110 age- and ethnicity-matched HIV-uninfected adolescents was also tested. RESULTS: For the HIV-infected adolescents (mean [SD] age 12 [1.6] years, 52% male), the median (interquartile range) duration of antiretroviral therapy was 7.6 (4.6-9.2) years. The median (interquartile range) nadir CD4 was 510.5 (274-903) cells/mm3. HIV-infected adolescents had significantly lower FEV1, FVC, FEV1/FVC, diffusing capacity of carbon monoxide, respiratory system compliance, and functional residual capacity than HIV-uninfected adolescents (P < 0.05 for all associations). HIV-infected adolescents had higher airway resistance and lung clearance index than HIV-uninfected adolescents (P < 0.05 for all associations). Although generally small in magnitude, these differences remained significant after adjusting for age, sex, and height. In addition, age, sex, height, and history of past lower respiratory tract infection or pulmonary tuberculosis were associated with reduced lung function. CONCLUSIONS: Perinatally infected South African HIV-infected adolescents on antiretroviral therapy have lower lung function than uninfected adolescents. Prior lower respiratory tract infection or pulmonary tuberculosis is associated with lower lung function.

Listening panel agreement and characteristics of lung sounds digitally recorded from children aged 1-59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) case-control study.

INTRODUCTION: Paediatric lung sound recordings can be systematically assessed, but methodological feasibility and validity is unknown, especially from developing countries. We examined the performance of acoustically interpreting recorded paediatric lung sounds and compared sound characteristics between cases and controls. METHODS: Pneumonia Etiology Research for Child Health staff in six African and Asian sites recorded lung sounds with a digital stethoscope in cases and controls. Cases aged 1-59 months had WHO severe or very severe pneumonia; age-matched community controls did not. A listening panel assigned examination results of normal, crackle, wheeze, crackle and wheeze or uninterpretable, with adjudication of discordant interpretations. Classifications were recategorised into any crackle, any wheeze or abnormal (any crackle or wheeze) and primary listener agreement (first two listeners) was analysed among interpretable examinations using the prevalence-adjusted, bias-adjusted kappa (PABAK). We examined predictors of disagreement with logistic regression and compared case and control lung sounds with descriptive statistics. RESULTS: Primary listeners considered 89.5% of 792 case and 92.4% of 301 control recordings interpretable. Among interpretable recordings, listeners agreed on the presence or absence of any abnormality in 74.9% (PABAK 0.50) of cases and 69.8% (PABAK 0.40) of controls, presence/absence of crackles in 70.6% (PABAK 0.41) of cases and 82.4% (PABAK 0.65) of controls and presence/absence of wheeze in 72.6% (PABAK 0.45) of cases and 73.8% (PABAK 0.48) of controls. Controls, tachypnoea, >3 uninterpretable chest positions, crying, upper airway noises and study site predicted listener disagreement. Among all interpretable examinations, 38.0% of cases and 84.9% of controls were normal (p<0.0001); wheezing was the most common sound (49.9%) in cases. CONCLUSIONS: Listening panel and case-control data suggests our methodology is feasible, likely valid and that small airway inflammation is common in WHO pneumonia. Digital auscultation may be an important future pneumonia diagnostic in developing countries.