Characterization of bacterial and viral pathogens in the respiratory tract of children with HIV-associated chronic lung disease: a case-control study.

INTRODUCTION: Chronic lung disease is a major cause of morbidity in African children with HIV infection; however, the microbial determinants of HIV-associated chronic lung disease (HCLD) remain poorly understood. We conducted a case-control study to investigate the prevalence and densities of respiratory microbes among pneumococcal conjugate vaccine (PCV)-naive children with (HCLD +) and without HCLD (HCLD-) established on antiretroviral treatment (ART). METHODS: Nasopharyngeal swabs collected from HCLD + (defined as forced-expiratory-volume/second < -1.0 without reversibility postbronchodilation) and age-, site-, and duration-of-ART-matched HCLD- participants aged between 6-19 years enrolled in Zimbabwe and Malawi (BREATHE trial-NCT02426112) were tested for 94 pneumococcal serotypes together with twelve bacteria, including Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI), Moraxella catarrhalis (MC), and eight viruses, including human rhinovirus (HRV), respiratory syncytial virus A or B, and human metapneumovirus, using nanofluidic qPCR (Standard BioTools formerly known as Fluidigm). Fisher's exact test and logistic regression analysis were used for between-group comparisons and risk factors associated with common respiratory microbes, respectively. RESULTS: A total of 345 participants (287 HCLD + , 58 HCLD-; median age, 15.5 years [IQR = 12.8-18], females, 52%) were included in the final analysis. The prevalence of SP (40%[116/287] vs. 21%[12/58], p = 0.005) and HRV (7%[21/287] vs. 0%[0/58], p = 0.032) were higher in HCLD + participants compared to HCLD- participants. Of the participants positive for SP (116 HCLD + & 12 HCLD-), 66% [85/128] had non-PCV-13 serotypes detected. Overall, PCV-13 serotypes (4, 19A, 19F: 16% [7/43] each) and NVT 13 and 21 (9% [8/85] each) predominated. The densities of HI (2 × 104 genomic equivalents [GE/ml] vs. 3 × 102 GE/ml, p = 0.006) and MC (1 × 104 GE/ml vs. 1 × 103 GE/ml, p = 0.031) were higher in HCLD + compared to HCLD-. Bacterial codetection (≥ any 2 bacteria) was higher in the HCLD + group (36% [114/287] vs. (19% [11/58]), (p = 0.014), with SP and HI codetection (HCLD + : 30% [86/287] vs. HCLD-: 12% [7/58], p = 0.005) predominating. Viruses (predominantly HRV) were detected only in HCLD + participants. Lastly, participants with a history of previous tuberculosis treatment were more likely to carry SP (adjusted odds ratio (aOR): 1.9 [1.1 -3.2], p = 0.021) or HI (aOR: 2.0 [1.2 - 3.3], p = 0.011), while those who used ART for ≥ 2 years were less likely to carry HI (aOR: 0.3 [0.1 - 0.8], p = 0.005) and MC (aOR: 0.4 [0.1 - 0.9], p = 0.039). CONCLUSION: Children with HCLD + were more likely to be colonized by SP and HRV and had higher HI and MC bacterial loads in their nasopharynx. The role of SP, HI, and HRV in the pathogenesis of CLD, including how they influence the risk of acute exacerbations, should be studied further. TRIAL REGISTRATION: The BREATHE trial (ClinicalTrials.gov Identifier: NCT02426112 , registered date: 24 April 2015).

Sputum bacterial load and bacterial composition correlate with lung function and are altered by long-term azithromycin treatment in children with HIV-associated chronic lung disease.

BACKGROUND: Long-term azithromycin (AZM) treatment reduces the frequency of acute respiratory exacerbation in children and adolescents with HIV-associated chronic lung disease (HCLD). However, the impact of this treatment on the respiratory bacteriome is unknown. METHOD: African children with HCLD (defined as forced expiratory volume in 1 s z-score (FEV1z) less than - 1.0 with no reversibility) were enrolled in a placebo-controlled trial of once-weekly AZM given for 48-weeks (BREATHE trial). Sputum samples were collected at baseline, 48 weeks (end of treatment) and 72 weeks (6 months post-intervention in participants who reached this timepoint before trial conclusion). Sputum bacterial load and bacteriome profiles were determined using 16S rRNA gene qPCR and V4 region amplicon sequencing, respectively. The primary outcomes were within-participant and within-arm (AZM vs placebo) changes in the sputum bacteriome measured across baseline, 48 weeks and 72 weeks. Associations between clinical or socio-demographic factors and bacteriome profiles were also assessed using linear regression. RESULTS: In total, 347 participants (median age: 15.3 years, interquartile range [12.7-17.7]) were enrolled and randomised to AZM (173) or placebo (174). After 48 weeks, participants in the AZM arm had reduced sputum bacterial load vs placebo arm (16S rRNA copies/µl in log10, mean difference and 95% confidence interval [CI] of AZM vs placebo - 0.54 [- 0.71; - 0.36]). Shannon alpha diversity remained stable in the AZM arm but declined in the placebo arm between baseline and 48 weeks (3.03 vs. 2.80, p = 0.04, Wilcoxon paired test). Bacterial community structure changed in the AZM arm at 48 weeks compared with baseline (PERMANOVA test p = 0.003) but resolved at 72 weeks. The relative abundances of genera previously associated with HCLD decreased in the AZM arm at 48 weeks compared with baseline, including Haemophilus (17.9% vs. 25.8%, p < 0.05, ANCOM ω = 32) and Moraxella (1% vs. 1.9%, p < 0.05, ANCOM ω = 47). This reduction was sustained at 72 weeks relative to baseline. Lung function (FEV1z) was negatively associated with bacterial load (coefficient, [CI]: - 0.09 [- 0.16; - 0.02]) and positively associated with Shannon diversity (0.19 [0.12; 0.27]). The relative abundance of Neisseria (coefficient, [standard error]: (2.85, [0.7], q = 0.01), and Haemophilus (- 6.1, [1.2], q < 0.001) were positively and negatively associated with FEV1z, respectively. An increase in the relative abundance of Streptococcus from baseline to 48 weeks was associated with improvement in FEV1z (3.2 [1.11], q = 0.01) whilst an increase in Moraxella was associated with decline in FEV1z (-2.74 [0.74], q = 0.002). CONCLUSIONS: AZM treatment preserved sputum bacterial diversity and reduced the relative abundances of the HCLD-associated genera Haemophilus and Moraxella. These bacteriological effects were associated with improvement in lung function and may account for reduced respiratory exacerbations associated with AZM treatment of children with HCLD. Video Abstract.

Risk factors for sustained virological non-suppression among children and adolescents living with HIV in Zimbabwe and Malawi: a secondary data analysis.

BACKGROUND: We investigated risk factors for sustained virological non-suppression (viral load ≥ 1000 copies/ml on two tests 48 weeks apart) among children and adolescents accessing HIV care in public sector clinics in Harare, Zimbabwe and Blantyre, Malawi. METHODS: Participants were enrolled between 2016 and 2019, were aged 6-19 years, living with HIV, had chronic lung disease (FEV z-score < -1) and had taken antiretroviral therapy (ART) for at least six months. We used multivariate logistic regression to identify risk factors for virological non-suppression after 48 weeks, among participants who were non-suppressed at enrolment. RESULTS: At enrolment 258 participants (64.6%) were on first-line ART and 152/347 (43.8%) had virological non-suppression. After 48 weeks 114/313 (36.4%) were non-suppressed. Participants non-suppressed at baseline had almost ten times higher odds of non-suppression at follow-up (OR = 9.9, 95%CI 5.3-18.4, p < 0.001). Of those who were non-suppressed at enrolment, 87/136 (64.0%) were still non-suppressed at 48 weeks. Among this group non-suppression at 48 weeks was associated with not switching ART regimen (adjusted OR = 5.55; 95%CI 1.41-21.83); p = 0.014) and with older age. Twelve participants switched regimen in Zimbabwe and none in Malawi. CONCLUSIONS: Viral non-suppression was high among this group and many with high viral load were not switched to a new regimen, resulting in continued non-suppression after 48 weeks. Further research could determine whether improved adherence counselling and training clinicians on regimen switches can improve viral suppression rates in this population. TRIAL REGISTRATION: Secondary cohort analysis of data from BREATHE trial (Clinicaltrials.gov NCT02426112 ).

Adherence to additional medication for management of HIV-associated comorbidities among older children and adolescents taking antiretroviral therapy.

BACKGROUND: Management of co-morbidities among persons living with HIV is an emerging priority, which may require additional medication over and above life-long antiretroviral therapy (ART). We explored factors associated with adherence to the trial drug among children and adolescents with perinatally acquired HIV taking antiretroviral therapy (ART) in the Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-Infected Children (BREATHE) trial. METHODS: The BREATHE trial recruited 6-19 year olds with perinatally acquired HIV and co-morbid chronic lung disease as measured by FEV1. This two-site trial was individually randomised (1:1), double-blind and placebo-controlled. Participants received a once-weekly weight-based dose of 1-5 tablets of azithromycin (AZM: 250mg) or placebo, taken orally. We used pharmacy dispensing records and count of returned pills to measure adherence to study medication. Logistic regression was used to explore factors associated with adherence coverage. Poisson regression with Lexis expansion for time was used to explore whether adherence modified the effect of azithromycin on the incidence of acute respiratory exacerbation, a secondary outcome of the trial. Trial registration: ClinicalTrials.gov NCT02426112. RESULTS: The 347 participants (median age 15.3, 51% male) consumed 14,622 doses of study medication over 16,220 person-weeks under study. Adherence was higher for those randomised to AZM (73.4%) than placebo (68.4%) and declined over the 48 weeks of the study (Score test for trend <0.02). Those with unsuppressed HIV viral load at baseline had 2.08 (95% CI: 1.19, 3.63) times the odds of non-adherence than those with viral suppression. Differences were also observed between trial sites. CONCLUSION: The majority of children and adolescents tolerated the addition of a once-weekly dose of medication to their pill burden. Barriers in adhering to treatment for co-morbid conditions are likely common to barriers in adhering to ART. Control of co-morbidities will therefore present additional challenges in HIV care.

Retrospective assessment of occupational disease trends in Russian Arctic apatite miners.

For many years in Russia, apatite ore mining has been associated with high levels of occupational morbidity. The aim of the study was to retrospectively assess occupational disease trends in Russian Arctic apatite miners. We analysed data from routine health screening of 2 649 underground apatite miners in 2007 and data of social-hygienic monitoring "Working conditions and occupational morbidity" in 2008-2020. In 2007, according to the results of routine health screening, 6 778 chronic diseases were diagnosed in 2 649 miners, the most prevalent being musculoskeletal (34.4%) and eye (16.0%) diseases. In the next 13 years, 572 occupational diseases were first diagnosed in 300 (11.3%) miners, most prevalent being musculoskeletal diseases (47.2%). The risk of developing occupational diseases in tunnellers exceeded that in all other miners, including timber-men (RR = 1.56; CI 1.06-2.30), vibration-loading machine operators (RR = 1.67; CI 0.99-2.80), drillers (RR = 1.51; CI 1.08-2.11) and blasters (RR = 2.12; CI 1.55-2.84). We conclude that ongoing modernisation of ore mining processes and medical preventive measures should include more effective health-improving interventions for underground apatite miners. Findings from the analysis of data can be used by health professionals and policy makers to address these problems.

The impact of long-term azithromycin on antibiotic resistance in HIV-associated chronic lung disease.

Selection for resistance to azithromycin (AZM) and other antibiotics such as tetracyclines and lincosamides remains a concern with long-term AZM use for treatment of chronic lung diseases (CLD). We investigated the impact of 48 weeks of AZM on the carriage and antibiotic resistance of common respiratory bacteria among children with HIV-associated CLD. Nasopharyngeal (NP) swabs and sputa were collected at baseline, 48 and 72 weeks from participants with HIV-associated CLD randomised to receive weekly AZM or placebo for 48 weeks and followed post-intervention until 72 weeks. The primary outcomes were prevalence and antibiotic resistance of Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI) and Moraxella catarrhalis (MC) at these timepoints. Mixed-effects logistic regression and Fisher's exact test were used to compare carriage and resistance, respectively. Of 347 (174 AZM, 173 placebo) participants (median age 15 years (IQR 13-18), female 49%), NP carriage was significantly lower in the AZM (n=159) compared to placebo (n=153) arm for SP (18% versus 41%, p<0.001), HI (7% versus 16%, p=0.01) and MC (4% versus 11%, p=0.02); SP resistance to AZM (62% (18 out of 29) versus 13% (8 out of 63), p<0.0001) or tetracycline (60% (18 out of 29) versus 21% (13 out of 63), p<0.0001) was higher in the AZM arm. Carriage of SA resistant to AZM (91% (31 out of 34) versus 3% (1 out of 31), p<0.0001), tetracycline (35% (12 out of 34) versus 13% (4 out of 31), p=0.05) and clindamycin (79% (27 out of 34) versus 3% (1 out of 31), p<0.0001) was also significantly higher in the AZM arm and persisted at 72 weeks. Similar findings were observed for sputa. The persistence of antibiotic resistance and its clinical relevance for future infectious episodes requiring treatment needs further investigation.

The effect of azithromycin for management of HIV-associated chronic lung disease on right heart function: Results from the BREATHE trial.

BACKGROUND: Right heart abnormalities and pulmonary hypertension (PH) may be secondary to chronic lung disease. Chronic lung disease is common in children with HIV. In the BREATHE trial ( Trial registration: NCT02426112), azithromycin (AZM) reduced the risk of acute respiratory exacerbations in children aged 6-19 years with HIV-associated chronic lung disease (HCLD) taking antiretroviral therapy. We assessed the possible effect of AZM on right heart dysfunction and/or PH in the trial. METHODS: A standardised transthoracic echocardiogram using M-mode, two-dimensional and Doppler was performed, at baseline and at completion of weight-based AZM given weekly for 48 weeks. Linear regression was used to compare trial arms. RESULTS: A total of 169 participants (82 AZM arm; 87 placebo arm) were included. Participants in the placebo arm were older, median age 16.2 (13.0-18.2) vs 15.3 (12.9-17.4) years, p = 0.184 in the AZM arm. At baseline, right heart abnormalities (right ventricular systolic dysfunction (RVSD), dilatation, or PH) were observed in 7(4%). Following treatment, there was no difference in prevalence of RVSD between arms (p = 0.761). There was one incident case of suspected PH, and overall, no difference in pulmonary pressures. CONCLUSION: In children with HCLD, there was evidence of secondary cardiac effects, but AZM had no effect on right heart function. Long-term follow-up in children with HIV should be part of future research to understand the clinical implications of right heart abnormalities.

Effect of azithromycin on incidence of acute respiratory exacerbations in children with HIV taking antiretroviral therapy and co-morbid chronic lung disease: a secondary analysis of the BREATHE trial.

BACKGROUND: In the BREATHE trial weekly azithromycin decreased the rate of acute respiratory exacerbations (AREs) compared to placebo among children and adolescents with HIV-associated chronic lung disease (CLD) taking antiretroviral therapy (ART). The aim of this analysis was to identify risk factors associated with AREs and mediators of the effect of azithromycin on AREs. METHODS: The primary outcome of this analysis was the rate of AREs by study arm up to 49 weeks. We analysed rates using Poisson regression with random intercepts. Interaction terms were fitted for potential effect modifiers. Participants were recruited from Zimbabwe and Malawi between15 June 2016 and 4 September 2018. FINDINGS: We analysed data from 345 participants (171 allocated to azithromycin and 174 allocated to placebo). Rates of AREs were higher among those with an abnormally high respiratory rate at baseline (adjusted rate ratio (aRR) 2.08 95% CI 1.10-3.95 p-value 0.02) and among those with a CD4 cell count <200 cells/mm3 (aRR 2.71; 95% CI 1.27-5.76; p-value 0.008). We found some evidence for variation in the effect of azithromycin by sex (p-value for interaction=0.07); males had a greater reduction in the rate of ARE with azithromycin treatment than females. We found that azithromycin had a greater impact on reducing AREs in participants with chronic respiratory symptoms at baseline, those on 1st line ART, with a FEV1 score >-2 and participants without baseline resistance to azithromycin. However, there was no statistical evidence for interaction due to low statistical power. INTERPRETATION: These may represent subgroups who may benefit the most from treatment with weekly azithromycin, which could help guide targeted treatment. FUNDING: There was no funding source for this post hoc analysis.

MercuNorth - monitoring mercury in pregnant women from the Arctic as a baseline to assess the effectiveness of the Minamata Convention.

Exposure to mercury (Hg) is a global concern, particularly among Arctic populations that rely on the consumption of marine mammals and fish which are the main route of Hg exposure for Arctic populations.The MercuNorth project was created to establish baseline Hg levels across several Arctic regions during the period preceding the Minamata Convention. Blood samples were collected from 669 pregnant women, aged 18-44 years, between 2010 and 2016 from sites across the circumpolar Arctic including Alaska (USA), Nunavik (Canada), Greenland, Iceland, Norway, Sweden, Northern Lapland (Finland) and Murmansk Oblast (Russia). Descriptive statistics were calculated, multiple pairwise comparisons were made between regions, and unadjusted linear trend analyses were performed.Geometric mean concentrations of total Hg were highest in Nunavik (5.20 µg/L)  and Greenland (3.79 µg/L), followed by Alaska (2.13 µg/L), with much lower concentrations observed in the other regions (ranged between 0.48 and 1.29 µg/L). In Nunavik, Alaska and Greenland, blood Hg concentrations have decreased significantly since 1992, 2000 and 2010 respectively with % annual decreases of 4.7%, 7.5% and 2.7%, respectively.These circumpolar data combined with fish and marine mammal consumption data can be used for assessing long-term Hg trends and the effectiveness of the Minamata Convention.

Per- and Polyfluoroalkyl Substances in Human Serum Samples of Selected Populations from Ghana.

The aims of this study were to assess serum concentrations of per- and polyfluoroalkyl substances (PFASs) in selected populations from Ghana, including workers engaged in the repair of electronic equipment (ERWs), and to elucidate PFAS concentrations in relation to blood mercury concentrations (B-Hg) as a biomarker of seafood consumption. In all, 219 participants were recruited into the study, of which 26 were women and 64 were ERWs. Overall, the PFAS concentrations were low. The most abundant components were perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonic acid (PFHxS). Women had generally lower PFAS concentration than men. The ERWs had statistically significantly higher concentrations of perfluorooctanoate (PFOA), which was associated with the concentration of tin in urine. This could indicate exposure during soldering. The concentration of B-Hg was associated with several of the PFASs such as PFOA, PFOS and perfluoroheptane sulfonate (PFHpS). Additionally, the concentrations of perfluorodecanoic acid (PFDA) and perfluoroundecanoate (PFUnDA) were highly associated with the concentrations of B-Hg. It is noteworthy that the linear isomer of PFHxS was strongly associated with B-Hg while the branched isomers of PFHxS were not. In conclusion, the PFAS concentrations observed in the present study are low compared to other populations previously investigated, which also reflects a lower PFAS exposure within the Ghanaian cohorts. ERWs had significantly higher PFOA concentrations than the other participants. Several PFASs were associated with B-Hg, indicating that seafood consumption may be a source of PFAS exposure.

Prevalence and antimicrobial resistance profiles of respiratory microbial flora in African children with HIV-associated chronic lung disease.

BACKGROUND: HIV-associated chronic lung disease (CLD) is common among children living with HIV (CLWH) in sub-Saharan Africa, including those on antiretroviral therapy (ART). However, the pathogenesis of CLD and its possible association with microbial determinants remain poorly understood. We investigated the prevalence, and antibiotic susceptibility of Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI), and Moraxella catarrhalis (MC) among CLWH (established on ART) who had CLD (CLD+), or not (CLD-) in Zimbabwe and Malawi. METHODS: Nasopharyngeal swabs (NP) and sputa were collected from CLD+ CLWH (defined as forced-expiratory volume per second z-score < - 1 without reversibility post-bronchodilation with salbutamol), at enrolment as part of a randomised, placebo-controlled trial of azithromycin (BREATHE trial - NCT02426112 ), and from age- and sex-matched CLD- CLWH. Samples were cultured, and antibiotic susceptibility testing was conducted using disk diffusion. Risk factors for bacterial carriage were identified using questionnaires and analysed using multivariate logistic regression. RESULTS: A total of 410 participants (336 CLD+, 74 CLD-) were enrolled (median age, 15 years [IQR = 13-18]). SP and MC carriage in NP were higher in CLD+ than in CLD- children: 46% (154/336) vs. 26% (19/74), p = 0.008; and 14% (49/336) vs. 3% (2/74), p = 0.012, respectively. SP isolates from the NP of CLD+ children were more likely to be non-susceptible to penicillin than those from CLD- children (36% [53/144] vs 11% [2/18], p = 0.036). Methicillin-resistant SA was uncommon [4% (7/195)]. In multivariate analysis, key factors associated with NP bacterial carriage included having CLD (SP: adjusted odds ratio (aOR) 2 [95% CI 1.1-3.9]), younger age (SP: aOR 3.2 [1.8-5.8]), viral load suppression (SP: aOR 0.6 [0.4-1.0], SA: 0.5 [0.3-0.9]), stunting (SP: aOR 1.6 [1.1-2.6]) and male sex (SA: aOR 1.7 [1.0-2.9]). Sputum bacterial carriage was similar in both groups (50%) and was associated with Zimbabwean site (SP: aOR 3.1 [1.4-7.3], SA: 2.1 [1.1-4.2]), being on ART for a longer period (SP: aOR 0.3 [0.1-0.8]), and hot compared to rainy season (SP: aOR 2.3 [1.2-4.4]). CONCLUSIONS: CLD+ CLWH were more likely to be colonised by MC and SP, including penicillin-non-susceptible SP strains, than CLD- CLWH. The role of these bacteria in CLD pathogenesis, including the risk of acute exacerbations, should be further studied.

Effect of Once-Weekly Azithromycin vs Placebo in Children With HIV-Associated Chronic Lung Disease: The BREATHE Randomized Clinical Trial.

Importance: HIV-associated chronic lung disease (HCLD) in children is associated with small airways disease, is common despite antiretroviral therapy (ART), and is associated with substantial morbidity. Azithromycin has antibiotic and immunomodulatory activity and may be effective in treating HCLD through reducing respiratory tract infections and inflammation. Objective: To determine whether prophylactic azithromycin is effective in preventing worsening of lung function and in reducing acute respiratory exacerbations (AREs) in children with HCLD taking ART. Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial (BREATHE) was conducted between 2016 and 2019, including 12 months of follow-up, at outpatient HIV clinics in 2 public sector hospitals in Malawi and Zimbabwe. Participants were randomized 1:1 to intervention or placebo, and participants and study personnel were blinded to treatment allocation. Participants included children aged 6 to 19 years with perinatally acquired HIV and HCLD (defined as forced expiratory volume in 1 second [FEV1] z score < -1) who were taking ART for 6 months or longer. Data analysis was performed from September 2019 to April 2020. Intervention: Once-weekly oral azithromycin with weight-based dosing, for 48 weeks. Main Outcomes and Measures: All outcomes were prespecified. The primary outcome was the mean difference in FEV1 z score using intention-to-treat analysis for participants seen at end line. Secondary outcomes included AREs, all-cause hospitalizations, mortality, and weight-for-age z score. Results: A total of 347 individuals (median [interquartile range] age, 15.3 [12.7-17.7] years; 177 boys [51.0%]) were randomized, 174 to the azithromycin group and 173 to the placebo group; 162 participants in the azithromycin group and 146 placebo group participants had a primary outcome available and were analyzed. The mean difference in FEV1 z score was 0.06 (95% CI, -0.10 to 0.21; P = .48) higher in the azithromycin group than in the placebo group, a nonsignificant difference. The rate of AREs was 12.1 events per 100 person-years in the azithromycin group and 24.7 events per 100 person-years in the placebo groups (hazard ratio, 0.50; 95% CI, 0.27 to 0.93; P = .03). The hospitalization rate was 1.3 events per 100 person-years in the azithromycin group and 7.1 events per 100 person-years in the placebo groups, but the difference was not significant (hazard ratio, 0.24; 95% CI, 0.06 to 1.07; P = .06). Three deaths occurred, all in the placebo group. The mean weight-for-age z score was 0.03 (95% CI, -0.08 to 0.14; P = .56) higher in the azithromycin group than in the placebo group, although the difference was not significant. There were no drug-related severe adverse events. Conclusions and Relevance: In this randomized clinical trial specifically addressing childhood HCLD, once-weekly azithromycin did not improve lung function or growth but was associated with reduced AREs; the number of hospitalizations was also lower in the azithromycin group but the difference was not significant. Future research should identify patient groups who would benefit most from this intervention and optimum treatment length, to maximize benefits while reducing the risk of antimicrobial resistance. Trial Registration: ClinicalTrials.gov Identifier: NCT02426112.

In Utero Exposure to Aluminium and Other Neurotoxic Elements in Urban Coastal South African Women at Delivery: An Emerging Concern.

Aluminium (Al) is a non-essential neurotoxicant and there is limited information regarding exposure to Al in utero. This study sought to evaluate the in utero exposure to Al in urban South African women, its effects on birth outcomes and possible synergistic effects between Al, essential and neurotoxic elements such as lead (Pb), mercury (Hg) and arsenic (As), as well as a a potential sex-dependent response to these elements in neonates. This study has found elevated levels of Al in urban women at delivery. The Spearman's rank correlation coefficients (p-value) of the association between maternal serum Al and birth outcomes (gestational age and parity), and between maternal serum Al and Cu, Zn and Se, were statistically significant. However, in the general and the stratified models, no association was found between any of the birth outcomes and maternal serum Al. The association between maternal serum Al and neurotoxic elements at delivery showed a significant positive correlation for Pb only (rho = 0.361; p < 0.001) which was found to be sex-dependent in neonates (males, rho = 0.285; p < 0.004 and females, rho = 0.444, p < 0.001). Our preliminary findings indicate that in utero exposure to Al is an emerging concern requiring further research and directives from public health authorities.

Composition of Gut Microbiota of Children and Adolescents With Perinatal Human Immunodeficiency Virus Infection Taking Antiretroviral Therapy in Zimbabwe.

BACKGROUND: Human immunodeficiency virus (HIV) infection causes impairment of the gastrointestinal barrier, with substantial depletion of CD4+ T cells in the gut. Antiretroviral therapy (ART) restores CD4+ counts and may have beneficial effects on gut microbiota in adults. Little is known about effect of long-term ART on gut microbiome in HIV-infected children. We investigated composition of gut microbiota in HIV-infected and -uninfected children and assessed associations between gut microbiota and patient characteristics. METHODS: In a cross-sectional study, rectal swabs were collected from 177 HIV-infected and 103 HIV-uninfected controls. Gut microbial composition was explored using 16S ribosomal ribonucleic acid sequencing. RESULTS: Human immunodeficiency virus-infected children had significantly lower alpha-diversity and higher beta-diversity compared to HIV-uninfected. No association was observed between microbiome diversity and CD4+ T-cell count, HIV viral load, or HIV-associated chronic lung disease. We found enriched levels of Corynebacterium (P < .01), Finegoldia (P < .01), and Anaerococcus (P < .01) in HIV-infected participants and enrichment of Enterobacteriaceae (P = .02) in participants with low CD4+ counts (<400 cells/mm3). Prolonged ART-treatment (≥10 years) was significantly associated with a richer gut microbiota by alpha diversity. CONCLUSIONS: Human immunodeficiency virus-infected children have altered gut microbiota. Prolonged ART may restore the richness of the microbiota closer to that of HIV-uninfected children.

Incidence and Progression of Echocardiographic Abnormalities in Older Children with Human Immunodeficiency Virus and Adolescents Taking Antiretroviral Therapy: A Prospective Cohort Study.

BACKGROUND: A high prevalence of cardiac abnormalities has been reported in children with human immunodeficiency virus (HIV) taking antiretroviral therapy (ART) in sub-Saharan Africa. We investigated the incidence and progression of cardiac abnormalities among children taking ART in Zimbabwe. METHODS: A prospective cohort study was conducted at a pediatric HIV clinic from 2014 to 2017. Children with HIV aged between 6 and 16 years and taking ART ≥6 months were enrolled. Transthoracic echocardiography was performed at baseline and after 18 months. RESULTS: Of 197 participants recruited at baseline, 175 (89%; 48% female; median age 12 years, interquartile range 10-14 years) were followed up. The incidences of left and right heart abnormalities were 3.52 and 5.64 per 100 person-years, respectively. Stunting was associated with the development of any cardiac abnormality (adjusted odds ratio 2.59, 95% confidence interval 1.03-6.49; P = .043). Right ventricular (RV) dilatation persisted at follow-up in 92% of participants and left ventricular (LV) diastolic dysfunction in 88%. Cardiac abnormalities present at baseline reverted to normal over the follow-up period in 11 (6%). There was an overall increase in mean z scores for LV, left atrium (LA), RV, interventricular septum, and LV posterior wall diameters at 18 months (P < .001). CONCLUSIONS: Despite ART, children with HIV have a high incidence of cardiac abnormalities, with only a minority being transient. Mean z scores for LV, LA, RV, interventricular septum, and LV posterior wall diameters increased over a relatively short follow-up period, suggesting the potential for progression of cardiac abnormalities. Longer follow-up is required to understand the clinical implications of these abnormalities.

Health Risk Modifiers of Exposure to Persistent Pollutants among Indigenous Peoples of Chukotka.

The aim of the study was to assess temporal trends in health risks related to most common persistent contaminants, including polychlorinated biphenyls (PCBs), dichloro-diphenyl-trichloroethanes (DDTs), lead (Pb), as well as mercury (Hg) among indigenous peoples living in coastal areas of Chukotka in Arctic Russia. This is examined in relation to exposure pathways and a range of social and behavioral factors capable of modifying the exposure to these contaminants, including place of residence, income, traditional subsistence, alcohol consumption, and awareness of risk prevention. The primary exposure pathway for PCBs is shown to be the intake of traditional foods, which explained as much as 90% of the total health risk calculated employing established risk guidelines. Nearly 50% of past DDT-related health risks also appear to have been contributed by contaminated indoor surfaces involving commonly used DDT-containing insecticides. Individuals who practiced traditional activities are shown to have experienced a 4.4-fold higher risk of exposure to PCBs and a 1.3-fold higher risk for DDTs, Pb, and Hg. Low income, high consumption of marine mammal fat, alcohol consumption, and lack of awareness of health risk prevention are attributed to a further 2- to 6-fold increase in the risk of PCBs exposure. Low socioeconomic status enhances the health risks associated with exposure to the persistent contaminants examined.

History of tuberculosis is associated with lower exhaled nitric oxide levels in HIV-infected children.

OBJECTIVE: HIV disrupts host defense mechanisms and maintains chronic inflammation in the lung. Nitric oxide is a marker of lung inflammation and can be measured in the exhaled air. We investigated the relationship between exhaled nitric oxide (eNO), HIV status and airway abnormalities in perinatally HIV-infected children aged 6-19 years. DESIGN: A cross-sectional study. METHODS: HIV-infected individuals on antiretroviral therapy and HIV-uninfected children with no active tuberculosis (TB) or acute respiratory tract infection were recruited from a public hospital in Harare, Zimbabwe. Clinical history was collected and eNO testing and spirometry was performed. The association between eNO and explanatory variables (HIV, FEV1 z-score, CD4 cell count, viral load, history of TB) was investigated using linear regression analysis adjusted for age, sex and time of eNO testing. RESULTS: In total, 222 HIV-infected and 97 HIV-uninfected participants were included. Among HIV-infected participants, 57 (25.7%) had a history of past TB; 56 (25.2%) had airway obstruction, but no prior TB. HIV status was associated with lower eNO level [mean ratio 0.79 (95% confidence interval, 95% CI 0.65-0.97), P = 0.03]. Within the HIV-infected group, history of past TB was associated with lower eNO levels after controlling for age, sex and time of eNO testing [0.79 (95% CI 0.67-0.94), P = 0.007]. CONCLUSION: HIV infection and history of TB were associated with lower eNO levels. eNO levels may be a marker of HIV and TB-induced alteration in pulmonary physiology; further studies focused on potential causes for lower eNO levels in HIV and TB are warranted.

The atherogenic index (ATH index) as a potential predictive marker of idiopathic sudden sensorineural hearing loss: a case control study.

BACKGROUND: The importance of blood lipids in the pathogenesis of sudden sensorineural hearing loss (SSNHL) is widely discussed in the literature. However, the published results that hyperlipidaemia causes hearing problems are contradictory. The objective of this study was to establish whether increased lipid levels affect the risk of idiopathic SSNHL. METHODS: A case-controlled study was conducted of 27 patients with idiopathic SSNHL and 24 healthy control subjects. All of the subjects underwent complete audiological examination. The plasma levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), apolipoprotein (apo) A-I, apoB and apoE were measured with commercially available kits (Chronolab Systems, Spain). Several clinical ratios and indices of lipid metabolism were calculated. RESULTS: Detailed analysis of lipid metabolism in patients with idiopathic SSNHL has shown that disturbances in auditory function are associated with increased atherogenicity of the lipid profile. However, there were no significant differences in the conventional parameters of lipid metabolism (TC, TG and HDL-C) between patients with idiopathic SSNHL and subjects in the control group. Higher values of the apoB/apoA-I ratio, atherogenic index of plasma (AIP) and atherogenic index (ATH index) in patients with SSNHL indicated increased atherogenicity of the lipid profile. Binary logistic regression analysis showed that of these three indices, only higher values of the ATH index were significantly associated with an increased risk of idiopathic SSNHL. CONCLUSIONS: The ATH index can be used as a marker indicating the risk of idiopathic SSNHL when the conventional lipid indices are still normal.

High prevalence of echocardiographic abnormalities in older HIV-infected children taking antiretroviral therapy.

BACKGROUND: Antiretroviral therapy (ART) has decreased mortality so that increasing numbers of children with HIV are reaching adolescence. However, longstanding HIV infection and/or its treatment in children is associated with noninfectious complications including cardiac disease. We investigated the prevalence, spectrum and risk factors for echocardiographic abnormalities among children established on ART. METHODS: HIV-infected children aged 6-16 years, on ART at least 6 months were enrolled into a cross-sectional study from a public-sector paediatric HIV clinic in Harare, Zimbabwe. A standardized examination including transthoracic echocardiography was performed. Local echocardiographic reference ranges were used to define cardiac abnormalities. Logistic regression was used to examine the association between cardiac abnormalities and risk factors. RESULTS: Of the 201participants recruited, 92 (46%) were girls and median age was 11 (IQR 9-12) years; CD4+ cell count was 727 cells/µl (IQR 473-935) and 154 (78%) had viral load less than 400 copies/ml. Echocardiographic abnormalities were found in 83 (42%); left ventricular (LV) diastolic dysfunction was the most common abnormality 45 (23%) and LV hypertrophy in 22 (11%). LV and left atrial dilatation were found in 9 (5%) and 16 (8%), respectively. Right ventricular dilatation and systolic dysfunction were found in 13 (7%) and 4 (2%), respectively, of whom 60% had concurrent left heart abnormalities. Current use of nevirapine was associated with LVH [aOR 3.14 (1.13-8.72; P = 0.03)] and hypertension was associated with LV diastolic dysfunction [aOR 3.12 (1.48-6.57; P < 0.01)]. CONCLUSION: HIV-infected children established on ART have a high burden of echocardiographic abnormalities. Right heart disease was predominantly associated with left heart abnormalities and may be part of a global cardiomyopathic process. Further studies are needed to investigate the natural history, aetiology, and pathogenesis of these abnormalities, so that appropriate monitoring and treatment strategies can be developed.

High HIV and active tuberculosis prevalence and increased mortality risk in adults with symptoms of TB: a systematic review and meta-analyses.

INTRODUCTION: HIV and tuberculosis (TB) remain leading causes of preventable death in low- and middle-income countries (LMICs). The World Health Organization (WHO) recommends HIV testing for all individuals with TB symptoms, but implementation has been suboptimal. We conducted a systematic literature review and meta-analyses to estimate HIV and TB prevalence, and short-term (two to six months) mortality, among adults with TB symptoms at community- and facility level. METHODS: We searched Embase, Global Health and MEDLINE databases, and reviewed conference abstracts for studies reporting simultaneous HIV and TB screening of adults in LMICs published between January 2003 and December 2017. Meta-analyses were performed to estimate prevalence of HIV, undiagnosed TB and mortality risk at different health system levels. RESULTS: Sixty-two studies including 260,792 symptomatic adults were identified, mostly from Africa and Asia. Median HIV prevalence was 19.2% (IQR: 8.3% to 40.4%) at community level, 55.7% (IQR: 20.9% to 71.2%) at primary care level and 80.7% (IQR: 73.8% to 84.6%) at hospital level. Median TB prevalence was 6.9% (IQR: 3.3% to 8.4%) at community, 20.5% (IQR: 11.7% to 46.4%) at primary care and 36.4% (IQR: 22.9% to 40.9%) at hospital level. Median short-term mortality was 22.6% (IQR: 15.6% to 27.7%) among inpatients, 3.1% (IQR: 1.2% to 4.2%) at primary care and 1.6% (95% CI: 0.45 to 4.13, n = 1 study) at community level. CONCLUSIONS: Adults with TB symptoms have extremely high prevalence of HIV infection, even when identified through community surveys. TB prevalence and mortality increased substantially at primary care and inpatient level respectively. Strategies to expand symptom-based TB screening combined with HIV and TB testing for all symptomatic individuals should be of the highest priority for both disease programmes in LMICs with generalized HIV epidemics. Interventions to reduce short-term mortality are urgently needed.