Natural carriage of Streptococcus pneumoniae is associated with increased experimental pneumococcal carriage but reduced conjugate vaccine efficacy in a human challenge model.

BACKGROUND: In Malawi, the national pneumococcal conjugate vaccine (PCV13) demonstrated less herd immunity than the USA, likely due to higher natural pneumococcal carriage rates. We assessed PCV13 efficacy against experimental pneumococcal carriage in healthy Malawian adults. We explored how natural carriage (pneumococcal carriage of any other serotype apart from 6B) influenced experimental carriage rates and vaccine efficacy. METHODS: Healthy adults aged 18-40 were randomly assigned PCV13 (n=98) or saline (n=106), followed by intranasal SPN 6B inoculation at 20,000 (n=40), 80,000 (n=74), or 160,000 (n=90) CFU/100µl, 28 days post-vaccination. We evaluated natural and experimental pneumococcal carriage before and after vaccination on days 2, 7, and 14 post-inoculation using culture and multiplex qPCR targeting lytA/cpsA genes and compared carriage rates by vaccination status. RESULTS: Of 204 participants, 19.6% (40) exhibited experimental carriage, detected by culture and 25.5% (52) by qPCR. Vaccinated individuals had lower experimental carriage rates (10.2%, n=10/98) compared to the placebo group (28.3%, n=30/106). This difference in vaccine efficacy was more pronounced in participants without natural carriage (PCV13=8% n=6/75 vs. placebo=25.9%, n=21/81) compared to those with natural carriage (PCV13=14.8%, n=4/27 vs. placebo=26.5%, n=9/34). Using a log-binomial model, vaccine effectiveness (VE) was 62%, whether assessed by culture or qPCR. Natural carriers had a lower VE of 52% compared to participants with no natural carriage (VE=69%). CONCLUSION: We have shown that PCV13 VE estimate (62%) is robust whether carriage is assessed by culture or qPCR. PCV13 had lower VE in natural carriers compared to those without natural carriage at the inoculation visit.

Implementing health worker training on sepsis in South Eastern Nigeria using innovative digital strategies: an interventional study.

Background: Sepsis is a leading cause of morbidity and mortality especially in low- and middle-income countries such as Nigeria. Training of health workers using digital platforms may improve knowledge and lead to better patient outcomes. Objectives: To assess the effectiveness of a digital health educational module on sepsis in improving the knowledge of medical doctors in Cross River State Nigeria on the diagnosis and management of patients presenting with sepsis. Design: Quasi-experimental analytical study. Methods: We developed and deployed a sepsis module through an innovative application (Sepsis tutorial app) to doctors in Calabar, Nigeria. We assessed quantitative pre- and post-intervention knowledge scores for those completing the tutorial on sepsis between both assessments. A user satisfaction survey evaluated the content of the tutorial and the usability of the app. Results: One hundred and two doctors completed the course. There were more males than females (58.8% versus 41.2%). Over half (52%) were junior doctors, a minority were general practitioners and house officers (3% and 5%, respectively), and 72.6% had practiced for periods ranging from 1 to 15 years post-qualification. Gender and age appeared to have no significant association with pre- and post-test scores. The oldest age group (61-70) had the lowest mean pre- and post-test scores, while general practitioners had higher mean pre- and post-test scores than other cadres. The majority (95%) of participants recorded higher post-test than pre-test scores with a significant overall increase in mean scores (25.5 ± 14.7%, p < 0.0001). Participants were satisfied with the content and multimodal delivery of the material and found the app usable. Conclusion: Digital training using context-responsive platforms is feasible and may be used to close the critical knowledge gap required to respond effectively to medical emergencies such as sepsis in low- to middle-income settings.

Training health workers on sepsis using digital strategies Sepsis occurs when the body injures itself as it attempts to fight an infection. It is now recognized as a leading cause of death especially in low- and middle-income countries such as Nigeria. Training of health workers using digital platforms may improve knowledge and lead to better patient outcomes. We assessed the effectiveness of a digital health educational course on sepsis in improving the knowledge of medical doctors in Cross River State, Nigeria on the diagnosis and management of patients presenting with sepsis. One hundred and two doctors completed the course. Most participants recorded higher post-test than pre-test scores, were generally satisfied with the content and delivery of the material, and found the app usable. We conclude that digital training using digital platforms may be useful in bridging the critical knowledge gap required to respond effectively to sepsis in low- to middle-income settings.

Screening for post-TB lung disease at TB treatment completion: Are symptoms sufficient?

Pulmonary TB survivors face a high burden of post-TB lung disease (PTLD) after TB treatment completion. In this secondary data analysis we investigate the performance of parameters measured at TB treatment completion in predicting morbidity over the subsequent year, to inform programmatic approaches to PTLD screening in low-resource settings. Cohort data from urban Blantyre, Malawi were used to construct regression models for five morbidity outcomes (chronic respiratory symptoms or functional limitation, ongoing health seeking, spirometry decline, self-reported financial impact of TB disease, and death) in the year after PTB treatment, using three modelling approaches: logistic regression; penalised regression with pre-selected predictors; elastic net penalised regression using the full parent dataset. Predictors included demographic, clinical, symptom, spirometry and chest x-ray variables. The predictive performance of models were examined using the area under the receiver-operator curve (ROC AUC) values. Key predictors were identified, and their positive and negative predictive values (NPV) determined. The presence of respiratory symptoms at TB treatment completion was the strongest predictor of morbidity outcomes. TB survivors reporting breathlessness had higher odds of spirometry decline (aOR 20.5, 95%CI:3-199.1), health seeking (aOR 10.2, 2.4-50), and symptoms or functional limitation at 1-year (aOR 16.7, 3.3-133.4). Those reporting activity limitation were more likely to report symptoms or functional limitation at 1-year (aOR 4.2, 1.8-10.3), or severe financial impact of TB disease (aOR2.3, 1.0-5.0). Models were not significantly improved by including spirometry or imaging parameters. ROC AUCs were between 0.65-0.77 for the morbidity outcomes. Activity limitation at treatment completion had a NPV value of 78-98% for adverse outcomes. Our data suggest that whilst challenging to predict the development of post-TB morbidity, the use of symptom screening tools at TB treatment completion to prioritise post-TB care should be explored. We identified little benefit from the additional use of spirometry or CXR imaging.

Prevalence and Associated Factors of Chronic Obstructive Pulmonary Disease Among Adults in Neno District, Malawi: A Cross-Sectional Analytical Study.

Introduction: Chronic obstructive pulmonary disease (COPD) continues to pose a global public health challenge. However, literature is scarce on the burden of COPD in Malawi. We assessed the prevalence and risk factors for COPD among adults in Neno, Malawi. Methodology: We conducted a population-based analytical cross-sectional study in Neno District between December 2021 and November 2022. Using a multi-stage sampling technique, we included 525 adults aged≥40 years. All participants underwent spirometry according to the American Thoracic Society (ATS) guidelines and were interviewed using the IMPALA questionnaire. For this study, we utilized the definition of COPD as a post-bronchodilator FEV1/FVC <0.70. We collected data using Kobo collect, exported to Microsoft Excel, and analysed using R software. We used descriptive statistics and logistic regression analysis; a p-value of <0.05 was considered statistically significant. Results: Out of 525 participants, 510 participants were included in the final analysis. Fifty-eight percent of the participants were females (n=296), and 62.2% (n=317) were between 40 and 49 years with a median (IQR) age of 46 (40-86). For patient characteristics, 15.1% (n=77) were current smokers, and 4.1% (n=21) had a history of pulmonary tuberculosis (PTB). Cough was the most commonly reported respiratory symptom (n=249, 48.8%). The prevalence of COPD was 10.0% (n=51) and higher (15.0%) among males compared to females (6.4%). Factors significantly associated with COPD were age 60 years and above (adjusted odds ratio [aOR] = 3.27, 95% CI: 1.48-7.34, p<0.004), ever smoked (aOR = 6.17, 95% CI:1.89-18.7, p<0.002), current smoker (aOR = 17.6, 95% CI: 8.47-38.4, p<0.001), and previous PTB (aOR = 4.42, 95% CI: 1.16-15.5, p<0.023). Conclusion: The cross-sectional prevalence of COPD in rural Malawi is high, especially among males. Factors significantly associated were older age (60 years and above), cigarette smoking, and previous PTB. Longitudinal studies are needed to better understand disease etiology and progression in this setting.

Inflammation of the nasal mucosa is associated with susceptibility to experimental pneumococcal challenge in older adults.

Streptococcus pneumoniae colonization in the upper respiratory tract is linked to pneumococcal disease development, predominantly affecting young children and older adults. As the global population ages and comorbidities increase, there is a heightened concern about this infection. We investigated the immunological responses of older adults to pneumococcal-controlled human infection by analyzing the cellular composition and gene expression in the nasal mucosa. Our comparative analysis with data from a concurrent study in younger adults revealed distinct gene expression patterns in older individuals susceptible to colonization, highlighted by neutrophil activation and elevated levels of CXCL9 and CXCL10. Unlike younger adults challenged with pneumococcus, older adults did not show recruitment of monocytes into the nasal mucosa following nasal colonization. However, older adults who were protected from colonization showed increased degranulation of cluster of differentiation 8+ T cells, both before and after pneumococcal challenge. These findings suggest age-associated cellular changes, in particular enhanced mucosal inflammation, that may predispose older adults to pneumococcal colonization.

Multimorbidity-associated emergency hospital admissions: a "screen and link" strategy to improve outcomes for high-risk patients in sub-Saharan Africa: a prospective multicentre cohort study protocol.

Background: The prevalence of multimorbidity (the presence of two or more chronic health conditions) is rapidly increasing in sub-Saharan Africa. Hospital care pathways that focus on single presenting complaints do not address this pressing problem. This has the potential to precipitate frequent hospital readmissions, increase health system and out-of-pocket expenses, and may lead to premature disability and death. We aim to present a description of inpatient multimorbidity in a multicentre prospective cohort study in Malawi and Tanzania. Primary objectives: Clinical: Determine prevalence of multimorbid disease among adult medical admissions and measure patient outcomes. Health Economic: Measure economic costs incurred and changes in health-related quality of life (HRQoL) at 90 days post-admission. Situation analysis: Qualitatively describe pathways of patients with multimorbidity through the health system. Secondary objectives: Clinical: Determine hospital readmission free survival and markers of disease control 90 days after admission. Health Economic: Present economic costs from patient and health system perspective, sub-analyse costs and HRQoL according to presence of different diseases. Situation analysis: Understand health literacy related to their own diseases and experience of care for patients with multimorbidity and their caregivers. Methods: This is a prospective longitudinal cohort study of adult (≥18 years) acute medical hospital admissions with nested health economic and situation analysis in four hospitals: 1) Queen Elizabeth Central Hospital, Blantyre, Malawi; 2) Chiradzulu District Hospital, Malawi; 3) Hai District Hospital, Boma Ng'ombe, Tanzania; 4) Muhimbili National Hospital, Dar-es-Salaam, Tanzania. Follow-up duration will be 90 days from hospital admission. We will use consecutive recruitment within 24 hours of emergency presentation and stratified recruitment across four sites. We will use point-of-care tests to refine estimates of disease pathology. We will conduct qualitative interviews with patients, caregivers, healthcare providers and policymakers; focus group discussions with patients and caregivers, and observations of hospital care pathways.

Background: In sub-Saharan Africa, multimorbidity (defined as people living with two or more chronic health conditions) is increasing due to high infectious ( e.g., human immunodeficiency virus (HIV)) and non-communicable ( e.g., high blood pressure and diabetes) disease burdens. Multimorbidity increases as people live longer and can be worsened by HIV and HIV-medications. Patients delay seeking help until they are severely ill, meaning hospitals are key to healthcare delivery for chronic diseases, however hospital clinicians often focus on a single disease. Failure to identify and treat multimorbidity may lead to frequent readmissions, high costs, preventable disability and death. Aim: This cohort study is the first in a three-phase study with the overarching goal to design and test a system to identify patients suffering from multimorbidity when they seek emergency care in sub-Saharan African hospitals. This could improve early disease treatment (reducing death), ensure better follow-up and prevent disability, readmission and excess costs. The cohort study aims to determine multimorbidity prevalence, outcomes and costs. The results will help us co-create with key stakeholders the most cost-effective way to deliver improved care for patients before testing this strategy in a randomised trial. Methods in Brief: In Malawi and Tanzania, we will identify multimorbidity among patients admitted to hospital (focusing on high blood pressure, diabetes, HIV and chronic kidney disease), by enhancing diagnostic tests in hospital departments treating acutely admitted medical patients. With the help of healthcare professional, patients and community groups we will find how best to link patients to long-term care and improve self-management. After mapping health system pathways, we will work with stakeholders (policymakers, healthcare worker representatives, community and patient groups) to co-develop an intervention to improve outcomes for patients with multimorbidity. This study will allow us to collect clinical, health economic and health system data to inform this process.

Causes, outcomes and diagnosis of acute breathlessness hospital admissions in Malawi: protocol for a multicentre prospective cohort study.

Background: Hospital admission due to breathlessness carries a significant burden to patients and healthcare systems, particularly impacting people in low-income countries. Prompt appropriate treatment is vital to improve outcomes, but this relies on accurate diagnostic tests which are of limited availability in resource-constrained settings. We will provide an accurate description of acute breathlessness presentations in a multicentre prospective cohort study in Malawi, a low resource setting in Southern Africa, and explore approaches to strengthen diagnostic capacity. Objectives: Primary objective: Delineate between causes of breathlessness among adults admitted to hospital in Malawi and report disease prevalence. Secondary objectives : Determine patient outcomes, including mortality and hospital readmission 90 days after admission; determine the diagnostic accuracy of biomarkers to differentiate between heart failure and respiratory infections (such as pneumonia) including brain natriuretic peptides, procalcitonin and C-reactive protein. Methods: This is a prospective longitudinal cohort study of adults (≥18 years) admitted to hospital with breathlessness across two hospitals: 1) Queen Elizabeth Central Hospital, Blantyre, Malawi; 2) Chiradzulu District Hospital, Chiradzulu, Malawi. Patients will be consecutively recruited within 24 hours of emergency presentation and followed-up until 90 days from hospital admission. We will conduct enhanced diagnostic tests with robust quality assurance and quality control to determine estimates of disease pathology. Diagnostic case definitions were selected following a systematic literature search. Discussion: This study will provide detailed epidemiological description of adult hospital admissions due to breathlessness in low-income settings, which is currently poorly understood. We will delineate between causes using established case definitions and conduct nested diagnostic evaluation. The results have the potential to facilitate development of interventions targeted to strengthen diagnostic capacity, enable prompt and appropriate treatment, and ultimately improve both patient care and outcomes.

BACKGROUND: People admitted to hospital with symptoms of breathlessness are often severely ill and need quick, accurate assessment to facilitate timely initiation of appropriate treatments. In low resource settings, such as Malawi, limited access to diagnostic equipment impedes patient assessment. Failure to identify and treat the underlying diagnosis may lead to preventable death. AIMS: This cohort study aims to delineate between common, treatable causes of breathlessness among adult patients admitted to hospital in Malawi and measure survival. We will also evaluate the performance of blood markers to diagnose and differentiate between conditions. The results will help us develop context-appropriate diagnostic and treatment algorithms based on resources available in the health system Methods in brief: We will recruit adult patients who present to hospital with breathlessness in a central national referral hospital (Queen Elizabeth Central Hospital, Blantyre), and a district hospital (Chiradzulu District Hospital, Chiradzulu). We will conduct enhanced diagnostic tests to determine causes of breathlessness against internationally accepted diagnostic guidelines. Patients will be followed up throughout their hospital admission and after discharge, until 90 days. INTERPRETATION: This study aligns with World Health Assembly resolutions on 'Strengthening diagnostics capacity' and on 'Integrated emergency, critical and operative care for universal health coverage and protection from health emergencies'. The results of this study will have the potential to facilitate development of interventions targeted to strengthen diagnostic capacity, enable prompt and appropriate treatment, and ultimately improve care and outcomes for acutely unwell patients.