The availability, cost, and affordability of essential medicines for asthma and COPD in low-income and middle-income countries: a systematic review.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) cause a considerable burden of morbidity and mortality in low-income and middle-income countries (LMICs). Access to safe, effective, quality-assured, and affordable essential medicines is variable. We aimed to review the existing literature relating to the availability, cost, and affordability of WHO's essential medicines for asthma and COPD in LMICs. METHODS: A systematic review of the literature was done by searching seven databases to identify research articles published between Jan 1, 2010, and June 30, 2022. Studies on named essential medicines for asthma and COPD in LMICs were included and review articles were excluded. Two authors (MS and HT) screened and extracted data independently, and assessed bias using Joanna Briggs Institute appraisal tools. The main outcome measures were availability (WHO target of 80%), cost (compared with median price ratio [MPR]), and affordability (number of days of work of the lowest paid government worker). The study was registered with PROSPERO, CRD42021281069. FINDINGS: Of 4742 studies identified, 29 met the inclusion criteria providing data from 60 LMICs. All studies had a low risk of bias. Six of 58 countries met the 80% availability target for short-acting beta-agonists (SABAs), three of 48 countries for inhaled corticosteroids (ICSs), and zero of four for inhaled corticosteroid-long-acting beta-agonist (ICS-LABA) combination inhalers. Costs were reported by 12 studies: the range of MPRs was 1·1-351 for SABAs, 2·6-340 for ICSs, and 24 for ICS-LABAs in the single study reporting this. Affordability was calculated in ten studies: SABA inhalers typically cost around 1-4 days' wages, ICSs 2-7 days, and ICS-LABAs at least 6 days. The included studies showed heterogeneity. INTERPRETATION: Essential medicines for treating asthma and COPD were largely unavailable and unaffordable in LMICs. This was particularly true for inhalers containing corticosteroids. FUNDING: WHO and Wellcome Trust.

Most Early-Treated Children With Perinatally Acquired HIV Have Preserved Lung Function at School Age.

BACKGROUND: Impaired lung function is common among older children with perinatally acquired HIV (PHIV) who initiated antiretroviral therapy (ART) late in childhood. We determined the prevalence of abnormal spirometry and cofactors for impaired lung function among school-age children with PHIV who initiated ART when aged 12 months or younger. SETTING: Children who received early ART in the Optimizing Pediatric HIV-1 Therapy study in Kenya and underwent spirometry at school age. METHODS: Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured. Abnormal spirometry was defined as follows: obstructive (FEV1/FVC <1.64 z score [zFEV1/FVC]) and restricted (zFVC <1.64 with zFEV1/FVC ≥1.64). Characteristics, including anthropometric and HIV-related data, were ascertained in infancy and at school age. Caregiver carbon monoxide exposure served as a proxy for school-age child exposure. Linear regression determined associations of cofactors with lung function. RESULTS: Among 40 children, the median age was 5 months at ART initiation and 8.5 years at spirometry. The mean zFEV1, zFVC, and zFEV1/FVC (SD) were 0.21 (1.35), 0.31 (1.22), and -0.24 (0.82), respectively. Five (13%) children had abnormal spirometry. Spirometry z scores were significantly lower among children with pre-ART pneumonia, WHO HIV stage 3/4, higher HIV RNA at 6 months after ART initiation, low anthropometric z scores, and higher carbon monoxide exposure. CONCLUSIONS: Most of the children with PHIV who initiated ART at age 12 months or younger had normal spirometry, suggesting that ART in infancy preserved lung function. However, 13% had abnormal spirometry despite early ART. Modifiable factors were associated with impaired lung function, providing potential targets for interventions to prevent chronic lung disease.

Respiratory symptoms and lung function in patients treated for pulmonary tuberculosis in Malawi: a prospective cohort study.

RATIONALE: Pulmonary tuberculosis (PTB) can cause post-TB lung disease (PTLD) associated with respiratory symptoms, spirometric and radiological abnormalities. Understanding of the predictors and natural history of PTLD is limited. OBJECTIVES: To describe the symptoms and lung function of Malawian adults up to 3 years following PTB-treatment completion, and to determine the evolution of PTLD over this period. METHODS: Adults successfully completing PTB treatment in Blantyre, Malawi were followed up for 3 years and assessed using questionnaires, post-bronchodilator spirometry, 6 min walk tests, chest X-ray and high-resolution CT. Predictors of lung function at 3 years were identified by mixed effects regression modelling. MEASUREMENT AND MAIN RESULTS: We recruited 405 participants of whom 301 completed 3 years follow-up (mean (SD) age 35 years (10.2); 66.6% males; 60.4% HIV-positive). At 3 years, 59/301 (19.6%) reported respiratory symptoms and 76/272 (27.9%) had abnormal spirometry. The proportions with low FVC fell from 57/285 (20.0%) at TB treatment completion to 33/272 (12.1%), while obstruction increased from and 41/285 (14.4%) to 43/272 (15.8%) at 3 years. Absolute FEV1 and FVC increased by mean 0.03 L and 0.1 L over this period, but FEV1 decline of more than 0.1 L was seen in 73/246 (29.7%). Higher spirometry values at 3 years were associated with higher body mass index and HIV coinfection at TB-treatment completion. CONCLUSION: Spirometric measures improved over the 3 years following treatment, mostly in the first year. However, a third of PTB survivors experienced ongoing respiratory symptoms and abnormal spirometry (with accelerated FEV1 decline). Effective interventions are needed to improve the care of this group of patients.

Changing lung function and associated health-related quality-of-life: A five-year cohort study of Malawian adults.

BACKGROUND: In Sub-Saharan Africa cross-sectional studies report a high prevalence of abnormal lung function indicative of chronic respiratory disease. The natural history and health impact of this abnormal lung function in low-and middle-income countries is largely unknown. METHODS: A cohort of 1481 adults representative of rural Chikwawa in Malawi were recruited in 2014 and followed-up in 2019. Respiratory symptoms and health-related quality of life (HRQoL) were quantified. Lung function was measured by spirometry. FINDINGS: 1232 (83%) adults participated; spirometry was available for 1082 (73%). Mean (SD) age 49.5 (17.0) years, 278(23%) had ever smoked, and 724 (59%) were women. Forced expiratory volume in one second (FEV1) declined by 53.4 ml/year (95% CI: 49.0, 57.8) and forced vital capacity (FVC) by 45.2 ml/year (95% CI: 39.2, 50.5) . Chronic airflow obstruction increased from 9.5% (7.6, 11.6%) in 2014 to 17.5% (15.3, 19.9%) in 2019. There was no change in diagnosed asthma or in spirometry consistent with asthma or restriction. Rate of FEV1 decline was not associated with diagnosed Chronic obstructive pulmonary disease (COPD), asthma, or spirometry consistent with asthma, COPD, or restriction. HRQoL was adversely associated with respiratory symptoms (dyspnoea, wheeze, cough), previous tuberculosis, declining FEV1 and spirometry consistent with asthma or restriction. These differences exceeded the minimally important difference. INTERPRETATION: In this cohort, the increasing prevalence of COPD is associated with the high rate of FEV1 decline and lung function deficits present before recruitment. Respiratory symptoms and sub-optimal lung function are independently associated with reduced HRQoL.

Challenges in the Implementation of Chronic Obstructive Pulmonary Disease Guidelines in Low- and Middle-Income Countries: An Official American Thoracic Society Workshop Report.

There is a substantial burden of chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), in low- and middle-income countries (LMICs). LMICs have particular challenges in delivering cost-effective prevention, diagnosis, and management of COPD. Optimal care can be supported by effective implementation of guidelines. This American Thoracic Society workshop considered challenges to implementation of COPD guidelines in LMICs. We make 10 specific recommendations: 1) relevant organizations should provide LMIC-specific COPD management guidance; 2) patient and professional organizations must persuade policy-makers of the importance of lung function testing programs in LMICs; 3) healthcare education and training should emphasize the early-life origins of COPD; 4) urgent action is required by governments to reduce airborne exposures, including exposures to tobacco smoke and indoor and outdoor air pollution; 5) guidance for COPD in LMICs should explicitly link across Essential Medicine Lists and the World Health Organization package of essential noncommunicable disease interventions for primary health care in low-resource settings and should consider availability, affordability, sustainability, and cost-effective use of medicines; 6) the pharmaceutical industry should work to make effective COPD and tobacco-dependence medicines globally accessible and affordable; 7) implementation of locally adapted, cost-effective pulmonary rehabilitation programs should be an international priority; 8) the World Health Organization Global Action Plan for the Prevention and Control of Noncommunicable Diseases should specify how improvements in respiratory health will be achieved; 9) research funders should increase the proportion of funding allocated to COPD in LMICs; and 10) the respiratory community should leverage the skills and enthusiasm of earlier-career clinicians and researchers to improve global respiratory health.

Task-shifting to improve asthma education for Malawian children: a qualitative analysis.

BACKGROUND: Asthma education, a key component of long-term asthma management, is challenging in resource-limited settings with shortages of clinical staff. Task-shifting educational roles to lay (non-clinical) staff is a potential solution. We conducted a randomised controlled trial of an enhanced asthma care intervention for children in Malawi, which included reallocation of asthma education tasks to lay-educators. In this qualitative sub-study, we explored the experiences of asthmatic children, their families and lay-educators, to assess the acceptability, facilitators and barriers, and perceived value of the task-shifting asthma education intervention. METHODS: We conducted six focus group discussions, including 15 children and 28 carers, and individual interviews with four lay-educators and a senior nurse. Translated transcripts were coded independently by three researchers and key themes identified. RESULTS: Prior to the intervention, participants reported challenges in asthma care including the busy and sometimes hostile clinical environment, lack of access to information and the erratic supply of medication. The education sessions were well received: participants reported greater understanding of asthma and their treatment and confidence to manage symptoms. The lay-educators appreciated pre-intervention training, written guidelines, and access to clinical support. Low education levels among carers presented challenges, requiring an open, non-critical and individualised approach. DISCUSSION: Asthma education can be successfully delivered by lay-educators with adequate training, supervision and support, with benefits to the patients, their families and the community. Wider implementation could help address human resource shortages and support progress towards Universal Health Coverage. Trial registration The RCT was registered in the Pan African Clinical Trials Registry: PACTR201807211617031.

Mentoring upcoming researchers for non-communicable diseases' research and practice in Malawi.

The Malawi College of Medicine and its partners are building non-communicable diseases' (NCDs') research capacity through a grant from the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health. Several strategies are being implemented including research mentorship for junior researchers interested to build careers in NCDs' research. In this article, we present the rationale for and our experiences with this mentorship program over its 2 years of implementation. Lessons learned and the challenges are also shared.

An enhanced care package to improve asthma management in Malawian children: a randomised controlled trial.

BACKGROUND: Shortages of clinical staff make chronic asthma care challenging in low-income countries. We evaluated an outpatient asthma care package for children, including task-shifting of asthma management roles. METHODS: We conducted a non-blinded individually randomised controlled trial at a tertiary-level government hospital in Blantyre, Malawi. Children aged 6-15 years diagnosed with asthma were recruited from outpatient clinic, stratified by Childhood Asthma Control Test (cACT) score and allocated 1:1 from a concealed file, accessed during electronic questionnaire completion. The intervention, delivered by non-physicians, comprised clinical assessment, optimisation of inhaled treatment, individualised asthma education. The control group received standard care from outpatient physicians. Primary outcome for intention-to-treat analysis was change in cACT score at 3 months. Secondary outcomes included asthma exacerbations requiring emergency healthcare and school absence. FINDINGS: Between September 2018 and December 2019, 120 children (59 intervention; 61 control) were recruited; 65.8% males, with mean (SD) age 9.8 (2.8) years, mean (SD) baseline cACT 20.3 (2.6). At 3 months, intervention children (n=56) had a greater mean (SD) change in cACT score from baseline (2.7 (2.8) vs 0.6 (2.8)) compared with standard care participants (n=59); a difference of 2.1 points (95% CI: 1.1 to 3.1, p<0.001). Fewer intervention children attended emergency healthcare (7.3% vs 25.4%, p=0.02) and missed school (20.0% vs 62.7%, p<0.001) compared with standard care children. INTERPRETATION: The intervention resulted in decreased asthma symptoms and exacerbations. Wider scale-up could present substantial benefits for asthmatic patients in resource-limited settings. TRIAL REGISTRATION NUMBER: PACTR201807211617031.

Cohort profile: The Chikwawa lung health cohort; a population-based observational non-communicable respiratory disease study of adults in Malawi.

PURPOSE: The aim of this article is to provide a detailed description of the Chikwawa lung health cohort which was established in rural Malawi to prospectively determine the prevalence and causes of lung disease amongst the general population of adults living in a low-income rural setting in Sub-Saharan Africa. PARTICIPANTS: A total of 1481 participants were randomly identified and recruited in 2014 for the baseline study. We collected data on demographic, socio-economic status, respiratory symptoms and potentially relevant exposures such as smoking, household fuels, environmental exposures, occupational history/exposures, dietary intake, healthcare utilization, cost (medication, outpatient visits and inpatient admissions) and productivity losses. Spirometry was performed to assess lung function. At baseline, 56.9% of the participants were female, mean age was 43.8 (SD:17.8) and mean body mass index (BMI) was 21.6 Kg/m2 (SD: 3.46). FINDINGS TO DATE: The cohort has reported the prevalence of chronic respiratory symptoms (13.6%, 95% confidence interval [CI], 11.9-15.4), spirometric obstruction (8.7%, 95% CI, 7.0-10.7), and spirometric restriction (34.8%, 95% CI, 31.7-38.0). Additionally, an annual decline in forced expiratory volume in one second [FEV1] of 30.9mL/year (95% CI: 21.6 to 40.1) and forced vital capacity [FVC] by 38.3 mL/year (95% CI: 28.5 to 48.1) has been reported. FUTURE PLANS: The ongoing phases of follow-up will determine the annual rate of decline in lung function as measured through spirometry and the development of airflow obstruction and restriction, and relate these to morbidity, mortality and economic cost of airflow obstruction and restriction. Population-based mathematical models will be developed driven by the empirical data from the cohort and national population data for Malawi to assess the effects of interventions and programmes to address the lung burden in Malawi. The present follow-up study started in 2019.

Achieving Control of Asthma in Children in Africa (ACACIA): protocol of an observational study of children's lung health in six sub-Saharan African countries.

INTRODUCTION: Little is known about asthma control in the rising number of African children who suffer from this condition. The Achieving Control of Asthma in Children in Africa (ACACIA) study is an observational study collecting evidence about paediatric asthma in urban areas of Ghana, Malawi, Nigeria, South Africa, Uganda and Zimbabwe. The primary objectives are: (1) to identify 3000 children aged between 12 years and 14 years with asthma symptoms; and (2) to assess their asthma control, current treatment, knowledge of and attitudes to asthma and barriers to achieving good control. Secondary objective is to develop interventions addressing identified barriers to good symptom control. METHODS AND ANALYSIS: Each centre will undertake screening to identify 500 school children with asthma symptoms using questions from the Global Asthma Network's questionnaire. Children identified to have asthma symptoms will fill in a digital survey, including: Asthma Control Test, questions on medication usage and adherence, medical care, the Brief-Illness Perception questionnaire and environmental factors. Exhaled nitric oxide testing and prebronchodilator and postbronchodilator spirometry will be performed. A subgroup of children will participate in focus group discussions. Results will be analysed using descriptive statistics and comparative analysis. Informed by these results, we will assess the feasibility of potential interventions, including the adaption of a UK-based theatre performance about asthma attitudes and digital solutions to improve asthma management. ETHICS AND DISSEMINATION: The ACACIA study has been reviewed by the Queen Mary University of London Ethics of Research Committee in the UK. All African centres have received local ethical approval for this study. Study results will be published in academic journals and at conferences. Study outputs will be communicated to the public via newsfeeds on the ACACIA website and Twitter, and through news media outlets and other local dissemination. TRIAL REGISTRATION NUMBER: 269211.

Non-communicable respiratory disease and air pollution exposure in Malawi: a prospective cohort study.

RATIONALE: There are no population-based studies from sub-Saharan Africa describing longitudinal lung function in adults. OBJECTIVES: To explore the lung function trajectories and their determinants, including the effects of air pollution exposures and the cleaner-burning biomass-fuelled cookstove intervention of the Cooking and Pneumonia Study (CAPS), in adults living in rural Malawi. METHODS: We assessed respiratory symptoms and exposures, spirometry and measured 48-hour personal exposure to fine particulate matter (PM2.5) and carbon monoxide (CO), on three occasions over 3 years. Longitudinal data were analysed using mixed-effects modelling by maximum likelihood estimation. MEASUREMENTS AND MAIN RESULTS: We recruited 1481 adults, mean (SD) age 43.8 (17.8) years, including 523 participants from CAPS households (271 intervention; 252 controls), and collected multiple spirometry and air pollution measurements for 654 (44%) and 929 (63%), respectively. Compared with Global Lung Function Initiative African-American reference ranges, mean (SD) FEV1 (forced expiratory volume in 1 s) and FVC (forced vital capacity) z-scores were -0.38 (1.14) and -0.19 (1.09). FEV1 and FVC were determined by age, sex, height, previous TB and body mass index, with FEV1 declining by 30.9 mL/year (95% CI: 21.6 to 40.1) and FVC by 38.3 mL/year (95% CI: 28.5 to 48.1). There was decreased exposure to PM2.5 in those with access to a cookstove but no effect on lung function. CONCLUSIONS: We did not observe accelerated lung function decline in this cohort of Malawian adults, compared with that reported in healthy, non-smoking populations from high-income countries; this suggests that the lung function deficits we measured in adulthood may have origins in early life.

Non-communicable respiratory disease in Malawi: a systematic review and meta-analysis.

BACKGROUND: Non-communicable respiratory diseases are important contributors to morbidity and mortality in sub-Saharan African countries such as Malawi. AIM: To conduct a systematic review of the available literature relating to chronic respiratory disease in Malawi. METHODS: We conducted a systematic protocol-driven literature search of key scientific databases including Scopus and Medline. Papers were independently assessed for eligibility by two authors and included if they reported objective measures (including self-reported standard symptoms) of chronic respiratory disease and were conducted in Malawi. A meta-analysis of available estimates was then conducted. We re-analysed data from three of these studies in a secondary data analysis to allow for between-study comparisons. RESULTS: Our search identified 393 papers of which 17 (5 involving children and 12 involving adults) met the inclusion criteria. Wheeze was the symptom most frequently reported in children in the community (12.1%), hospital (11.2%) and HIV clinic (8.1%) settings. Cough was the symptom most frequently reported by adults in the community (3-18%). Spirometric abnormalities varied substantially between studies. For example, in adults, airflow obstruction varied between 2.3% and 20% and low forced vital capacity (FVC) varied between 2.7% and 52.8%. CONCLUSION: We identified a high burden of chronic respiratory symptoms and abnormal spirometry (particularly low FVC) within paediatric and adult populations in Malawi. The estimates for country-wide burden related to this disease were limited by the heterogeneity of the methods used to assess symptoms and spirometry. There is an urgent need to develop a better understanding of the determinants and natural history of non-communicable respiratory disease across the life-course in Malawi.

Lung health and exposure to air pollution in Malawian children (CAPS): a cross-sectional study.

BACKGROUND: Non-communicable lung disease and exposure to air pollution are major problems in sub-Saharan Africa. A high burden of chronic respiratory symptoms, spirometric abnormalities and air pollution exposures has been found in Malawian adults; whether the same would be true in children is unknown. METHODS: This cross-sectional study of children aged 6-8 years, in rural Malawi, included households from communities participating in the Cooking and Pneumonia Study (CAPS), a trial of cleaner-burning biomass-fuelled cookstoves. We assessed; chronic respiratory symptoms, anthropometry, spirometric abnormalities (using Global Lung Initiative equations) and personal carbon monoxide (CO) exposure. Prevalence estimates were calculated, and multivariable analyses were done. RESULTS: We recruited 804 children (mean age 7.1 years, 51.9% female), including 476 (260 intervention; 216 control) from CAPS households. Chronic respiratory symptoms (mainly cough (8.0%) and wheeze (7.1%)) were reported by 16.6% of children. Average height-for-age and weight-for-age z-scores were -1.04 and -1.10, respectively. Spirometric abnormalities (7.1% low forced vital capacity (FVC); 6.3% obstruction) were seen in 13.0% of children. Maximum CO exposure and carboxyhaemoglobin levels (COHb) exceeded WHO guidelines in 50.1% and 68.5% of children, respectively. Children from CAPS intervention households had lower COHb (median 3.50% vs 4.85%, p=0.006) and higher FVC z-scores (-0.22 vs -0.44, p=0.05) than controls. CONCLUSION: The substantial burden of chronic respiratory symptoms, abnormal spirometry and air pollution exposures in children in rural Malawi is concerning; effective prevention and control strategies are needed. Our finding of potential benefit in CAPS intervention households calls for further research into clean-air interventions to maximise healthy lung development in children.

Effect of antiretroviral therapy on longitudinal lung function trends in older children and adolescents with HIV-infection.

INTRODUCTION: Chronic respiratory disease is a common cause of morbidity in children with HIV infection. We investigated longitudinal lung function trends among HIV-infected children, to describe the evolution of lung disease and assess the effect of anti-retroviral therapy (ART). METHODS: Prospective follow-up of two cohorts of HIV-infected children, aged 6 to 16 years, in Harare, Zimbabwe; one group were ART-naïve at enrolment, the other established on ART for a median of 4.7-years. Standardised spirometric assessments were repeated over a 2-year follow-up period. Forced expiratory volume (FEV1) and forced vital capacity (FVC) were expressed as Global Lung Initiative defined z-scores (FEV1z and FVCz). Linear mixed-effects regression modelling of lung function was performed, with co-variate parameters evaluated by likelihood ratio comparison. RESULTS: We included 271 ART-naïve and 197 ART-established children (median age 11 years in both groups) incorporating 1144 spirometric assessments. Changes in FEV1 and FVC were associated with age at ART initiation and body mass index for both cohorts. Our models estimate that ART initiation earlier in life could prevent a deterioration of 0.04 FVCz/year. In the ART-naïve cohort, likelihood ratio comparison suggested an improvement in 0.09 FVCz/year during the two years following treatment initiation, but no evidence for this among participants established on ART. CONCLUSION: Early ART initiation and improved nutrition are positively associated with lung function and are important modifiable factors. An initial improvement in lung growth was seen in the first 2-years following ART initiation, although this did not appear to be sustained beyond this timeframe.

Noncommunicable Respiratory Disease and Air Pollution Exposure in Malawi (CAPS). A Cross-Sectional Study.

RATIONALE: Noncommunicable respiratory diseases and exposure to air pollution are thought to be important contributors to morbidity and mortality in sub-Saharan African adults. OBJECTIVES: We set out to explore the prevalence and determinants of noncommunicable respiratory disease among adults living in Chikhwawa District, Malawi. METHODS: We performed a cross-sectional study among adults in communities participating in a randomized controlled trial of a cleaner-burning biomass-fueled cookstove intervention (CAPS [Cooking and Pneumonia Study]) in rural Malawi. We assessed chronic respiratory symptoms, spirometric abnormalities, and personal exposure to air pollution (particulate matter <2.5 µm in aerodynamic diameter [PM2.5] and carbon monoxide [CO]). Weighted prevalence estimates were calculated; multivariable and intention-to-treat analyses were done. MEASUREMENTS AND MAIN RESULTS: One thousand four hundred eighty-one participants (mean [SD] age, 43.8 [17.8] yr; 57% female) were recruited. The prevalence of chronic respiratory symptoms, spirometric obstruction, and restriction were 13.6% (95% confidence interval [CI], 11.9-15.4), 8.7% (95% CI, 7.0-10.7), and 34.8% (95% CI, 31.7-38.0), respectively. Median 48-hour personal PM2.5 and CO exposures were 71.0 µg/m3 (interquartile range [IQR], 44.6-119.2) and 1.23 ppm (IQR, 0.79-1.93), respectively. Chronic respiratory symptoms were associated with current/ex-smoking (odds ratio [OR], 1.59; 95% CI, 1.05-2.39), previous tuberculosis (OR, 2.50; 95% CI, 1.04-15.58), and CO exposure (OR, 1.46; 95% CI, 1.04-2.05). Exposure to PM2.5 was not associated with any demographic, clinical, or spirometric characteristics. There was no effect of the CAPS intervention on any of the secondary trial outcomes. CONCLUSIONS: The burden of chronic respiratory symptoms, abnormal spirometry, and air pollution exposures in adults in rural Malawi is of considerable potential public health importance. We found little evidence that air pollution exposures were associated with chronic respiratory symptoms or spirometric abnormalities and no evidence that the CAPS intervention had effects on the secondary trial outcomes. More effective prevention and control strategies for noncommunicable respiratory disease in sub-Saharan Africa are needed. Clinical trial registered with www.isrctn.com (ISRCTN 59448623).

CD4+ cell count recovery following initiation of HIV antiretroviral therapy in older childhood and adolescence.

OBJECTIVE: To investigate CD4 cell count recovery following ART initiation in perinatally HIV-infected children diagnosed in later childhood. DESIGN: Observational prospective cohort study of newly diagnosed children aged 6-15 in Harare, Zimbabwe. METHODS: Participants were enrolled into a cohort at seven primary healthcare clinics between January 2013 and January 2015. ART was initiated according to national guidelines and CD4 cell counts were performed 6-monthly over 18 months. The relationship between CD4 cell count and time on ART was investigated using regression analysis with fixed (population) and random (individual) effects, and age at ART initiation as a covariate. RESULTS: Of the 307 participants who initiated ART, the median age at initiation was 11.7 years (interquartile range 9.6-13.8). The addition of an individual intercept and slope as random effects significantly improved the model fit compared with a fixed effects-only model. CD4 response (using a square-root transformation) was best modelled using a two-knot linear spline, with significant effects of time on ART and age at ART initiation. Younger children had a higher CD4 cell count at ART initiation (-17.9 cells/µl per year of age), an accelerated increase during the first 3 months on ART (-38.9 cells/µl per year of age at day 84), and a sustained higher CD4 cell count. CONCLUSION: Earlier ART initiation in older children is associated with accelerated CD4 cell count recovery and lasting immune reconstitution. Our findings support WHO guidance recommending ART initiation in all children, irrespective of disease stage and CD4 cell count.

Clinical Characteristics and Lung Function in Older Children Vertically Infected With Human Immunodeficiency Virus in Malawi.

BACKGROUND: Antiretroviral therapy (ART) has led to increased survival of children with vertically acquired human immunodeficiency virus infection. Significant morbidity arises from respiratory symptoms, but aetiology and pulmonary function abnormalities have not been systematically studied. METHODS: Human immunodeficiency virus-positive children aged 8-16 years were systematically recruited within clinics in Blantyre, Malawi. Clinical review, quality of life assessment, spirometry, and chest radiography were performed. RESULTS: One hundred sixty participants had a mean of age 11.1 (range, 8-16) years and 50.0% were female. Cough was present in 60 (37.5%) participants, and 55 (34.4%) had moderate or severe dyspnoea. Thirty-four (22.1%) participants had digital clubbing. Thirty-three (20.6%) participants were hypoxic at rest. One hundred eighteen (73.8%) of the children were receiving ART; median CD4 count was 698 cells/µL in these compared with 406 cells/µL in ART-naive individuals (P < .001). From 145 spirometry traces (90.6%), mean forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were 1.06 and 0.89 standard deviations below predicted mean, respectively. Twenty-one (14.5%) traces demonstrated obstructive defects and 26 (17.9%) reduced FVC. Lung function abnormality was not associated with any clinical findings. Of the 51 individuals with abnormal lung function, the mean increase in FEV1 after salbutamol was 3.8% (95% confidence interval, 0.02-7.53). "Tramlines" and ring shadows were seen on chest radiographs in over half of cases. CONCLUSIONS: Symptoms of chronic lung disease were highly prevalent with 2 main clinical phenotypes: "cough" and "hypoxia". Lung function abnormalities are common, poorly responsive to bronchodilators, and apparent throughout the age range of our cohort. Pathological causes remain to be elucidated. Cough and hypoxic phenotypes could be a useful part of diagnostic algorithms if further validated.