Lung health across the life course in Malawi

Background: Chronic respiratory symptoms are common in Malawian adults and might be determined by lung development, growth and exposures in earlier life: alternative cooking methods, such as cleaner-burning cookstoves, have been proposed as a way to reduce biomassfuel smoke exposure and improve lung health. Tailored strategies for resource-limited settings are needed to improve the management of common childhood respiratory conditions. Aims: 1. To explore the prevalence of non-communicable lung disease and air pollution associated determinants in children and adults in rural Malawi 2. Evaluate a novel task shifting approach to asthma management for children. Methods: Within the same rural Chikhwawa communities, we conducted a prospective cohort study of adults, collecting respiratory questionnaire data, spirometry and personal air pollution exposure measurements at three timepoints over 3-years, and a cross-sectional study, collecting similar data from children aged 6-8 years at one timepoint. We also conducted a randomised-controlled trial and qualitative sub-study to evaluate the feasibility and effectiveness of a task shifting intervention, using non-medically trained asthma educators, on asthma outcomes. The intervention comprised detailed clinical assessment, optimisation of inhaled treatment, and asthma education delivered by lay educators. Asthma symptoms and exacerbations, spirometry and exhaled nitric oxide were assessed at 3-months. Results: We recruited 1481 adults, mean (SD) age 43.8 (17.8) years, (654 with acceptable spirometry at ≥2 timepoints) and 804 children, mean (SD) age 7.1 (0.8) years, (522 with acceptable spirometry) in Chikhwawa. Forced expiratory volume in 1 second (FEV1) and Forced Vital Capacity (FVC) decline were 30.9 ml/year (95% confidence interval (CI): 21.6-40.1) and 38.3ml/year (95% CI: 28.5-48.1), respectively: comparable to natural age-related decline seen in healthy non-smokers in high-income settings. Lung function z-scores, referencing Global Lung Initiative African-American predicted values, were similar in children and adults and we found no evidence of an association between personal air pollution exposure and lung function or respiratory symptoms. Secondary analysis of a sub-group of children from households previously enrolled in a cookstove trial suggested a potential benefit: children from intervention households had a lower carboxyhaemoglobin level and higher FVC z-scores compared to controls. We recruited 120 asthmatic children at a tertiary hospital in urban Blantyre; 59 received the intervention, 61 continued with standard care in the outpatient clinic. At 3-months, we found a clinically and statistically significant improvement in the primary outcome: asthma control in intervention vs standard care group (increase in mean (SD) cACT score of 2.7 (2.8) vs 0.6 (2.8), p<0.001). In addition, fewer children receiving the intervention required emergency health care (7.3% vs 23.7%, p=0.03) or missed school (20.0% vs 61.0%, p<0.001) due to exacerbations. Children and carers described the positive impact of asthma education on their knowledge levels and increased confidence to self-manage symptoms. Implications: Our findings from Chikhwawa suggest that lung function deficits seen in adults are present in childhood, and that early life influences are likely an important contributor to adult lung health. Future research should consider public health interventions addressing multiple adverse risk factors encountered in utero and early childhood. Task shifting asthma education roles resulted in improved asthma outcomes and high levels of patient satisfaction, suggesting this could be an effective strategy in resource-limited settings. Further research is needed to assess the wider application of this approach across all levels of health facility

Determinants of lung health across the life course in sub-Saharan Africa

Lung health across the life course is influenced by factors affecting airway and alveolar development and growth during antenatal and perinatal periods, throughout childhood and adolescence, and into adulthood. Lung function trajectories are set in early life and childhood deficits may predispose to non-communicable respiratory diseases, such as asthma and chronic obstructive pulmonary disease, in later years. Potential risk factors are common in many sub-Saharan African (sSA) countries; adverse antenatal environments cause in utero growth restriction and prematurity; HIV and respiratory infections, including TB are common; exposure to air pollution is widespread, including household air pollution from biomass fuel use, traffic-related pollution in rapidly expanding cities, and tobacco smoke exposure. Multiple disadvantages experienced in early life require an integrated approach that addresses reproductive, maternal and child health. Public health strategies need to tackle multiple risk factors, emphasising Universal Health Coverage, to maximise lung health in the world’s poorest, most vulnerable populations. This review explores potential determinants of lung health across the life course. Due to the extensive topic and wide range of related literature, we prioritised more recent citations, especially those from sSA, focusing on risk factors for which there is most information, and which are most prevalent in the region

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

RationaleNoncommunicable respiratory diseases and exposure to air pollution are thought to be important contributors to morbidity and mortality in sub-Saharan African adults.ObjectivesWe set out to explore the prevalence and determinants of noncommunicable respiratory disease among adults living in Chikhwawa District, Malawi.MethodsWe 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 &lt;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 resultsOne 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.ConclusionsThe 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)

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 (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

Can bio-inspired information processing steps be realized as synthetic biochemical processes?

We consider possible designs and experimental realiza-tions in synthesized rather than naturally occurring bio-chemical systems of a selection of basic bio-inspired information processing steps. These include feed-forward loops, which have been identified as the most common information processing motifs in many natural pathways in cellular functioning, and memory-involving processes, specifically, associative memory. Such systems should not be designed to literally mimic nature. Rather, we can be guided by nature's mechanisms for experimenting with new information/signal processing steps which are based on coupled biochemical reactions, but are vastly simpler than natural processes, and which will provide tools for the long-term goal of understanding and harnessing nature's information processing paradigm. Our biochemical processes of choice are enzymatic cascades because of their compatibility with physiological processes in vivo and with electronics (e.g., electrodes) in vitro allowing for networking and interfacing of enzyme-catalyzed processes with other chemical and biochemical reactions. In addition to designing and realizing feed-forward loops and other processes, one has to develop approaches to probe their response to external control of the time-dependence of the input(s), by measuring the resulting time-dependence of the output. The goal will be to demonstrate the expected features, for example, the delayed response and stabilizing effect of the feed-forward loops

CD4 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 counts were performed 6-monthly over 18 months. The relationship between CD4 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 to a fixed effects-only model. CD4 response (using a square root transformation) was best modelled using a 2-knot linear spline, with significant effects of time on ART and age at ART initiation. Younger children had a higher CD4 count at ART initiation (-17.9 cells/mm per year of age), an accelerated increase during the first three months on ART (-38.9 cells/mm per year of age at day 84), and a sustained higher CD4 count. CONCLUSIONS Earlier ART initiation in older children is associated with accelerated CD4 count recovery and lasting immune reconstitution. Our findings support WHO guidance recommending ART initiation in all children, irrespective of disease stage and CD4 count

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

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

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

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