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Tools to evaluate and accelerate tuberculosis (TB) vaccine development are needed to advance global TB control strategies. Validated human infection studies for TB have the potential to facilitate breakthroughs in understanding disease pathogenesis, identify correlates of protection, develop diagnostic tools, and accelerate and de-risk vaccine and drug development. However, key challenges remain for realizing the clinical utility of these models, which require further discussion and alignment among key stakeholders. In March 2023, the Wellcome Trust and the International AIDS Vaccine Initiative convened international experts involved in developing both TB and bacillus Calmette-Guérin (BCG) human infection studies (including mucosal and intradermal challenge routes) to discuss the status of each of the models and the key enablers to move the field forward. This report provides a summary of the presentations and discussion from the meeting. Discussions identified key issues, including demonstrating model validity, to provide confidence for vaccine developers, which may be addressed through demonstration of known vaccine effects (eg, BCG vaccination in specific populations), and by comparing results from field efficacy and human infection studies. The workshop underscored the importance of establishing safe and acceptable studies in high-burden settings, and the need to validate >1 model to allow for different scientific questions to be addressed as well as to provide confidence to vaccine developers and regulators around use of human infection study data in vaccine development and licensure pathways.
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Vacinas contra a Tuberculose , Tuberculose , Humanos , Tuberculose/prevenção & controle , Tuberculose/imunologia , Vacinas contra a Tuberculose/imunologia , Vacinas contra a Tuberculose/administração & dosagem , Desenvolvimento de Vacinas , Vacina BCG/imunologia , Vacina BCG/administração & dosagem , Mycobacterium tuberculosis/imunologia , AnimaisRESUMO
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.
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Rationale: Pneumococcal pneumonia remains a global health problem. Pneumococcal colonization increases local and systemic protective immunity, suggesting that nasal administration of live attenuated Streptococcus pneumoniae (Spn) strains could help prevent infections. Objectives: We used a controlled human infection model to investigate whether nasopharyngeal colonization with attenuated S. pneumoniae strains protected against recolonization with wild-type (WT) Spn (SpnWT). Methods: Healthy adults aged 18-50 years were randomized (1:1:1:1) for nasal administration twice (at a 2-wk interval) with saline solution, WT Spn6B (BHN418), or one of two genetically modified Spn6B strains, SpnA1 (Δfhs/piaA) or SpnA3 (ΔproABC/piaA) (Stage I). After 6 months, participants were challenged with SpnWT to assess protection against the homologous serotype (Stage II). Measurements and Main Results: 125 participants completed both study stages per intention to treat. No serious adverse events were reported. In Stage I, colonization rates were similar among groups: SpnWT, 58.1% (18 of 31); SpnA1, 60% (18 of 30); and SpnA3, 59.4% (19 of 32). Anti-Spn nasal IgG levels after colonization were similar in all groups, whereas serum IgG responses were higher in the SpnWT and SpnA1 groups than in the SpnA3 group. In colonized individuals, increases in IgG responses were identified against 197 Spn protein antigens and serotype 6 capsular polysaccharide using a pangenome array. Participants given SpnWT or SpnA1 in Stage I were partially protected against homologous challenge with SpnWT (29% and 30% recolonization rates, respectively) at stage II, whereas those exposed to SpnA3 achieved a recolonization rate similar to that in the control group (50% vs. 47%, respectively). Conclusions: Nasal colonization with genetically modified live attenuated Spn was safe and induced protection against recolonization, suggesting that nasal administration of live attenuated Spn could be an effective strategy for preventing pneumococcal infections. Clinical trial registered with the ISRCTN registry (ISRCTN22467293).
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Infecções Pneumocócicas , Streptococcus pneumoniae , Adulto , Humanos , Virulência , Nariz , Infecções Pneumocócicas/prevenção & controle , Imunização , Anticorpos Antibacterianos , Imunoglobulina G , Vacinas Pneumocócicas/uso terapêuticoRESUMO
Objective: To estimate the prevalence of individual chronic conditions and multimorbidity among adults admitted to hospital in countries in sub-Saharan Africa. Methods: We systematically searched MEDLINE®, Embase®, Global Index Medicus, Global Health and SciELO for publications reporting on patient cohorts recruited between 1 January 2010 and 12 May 2023. We included articles reporting prevalence of pre-specified chronic diseases within unselected acute care services (emergency departments or medical inpatient settings). No language restrictions were applied. We generated prevalence estimates using random-effects meta-analysis alongside 95% confidence intervals, 95% prediction intervals and I2 statistics for heterogeneity. To explore associations with age, sex, country-level income status, geographical region and risk of bias, we conducted pre-specified meta-regression, sub-group and sensitivity analyses. Findings: Of 6976 identified studies, 61 met the inclusion criteria, comprising data from 20 countries and 376 676 people. None directly reported multimorbidity, but instead reported prevalence for individual conditions. Among medical admissions, the highest prevalence was human immunodeficiency virus infection (36.4%; 95% CI: 31.3-41.8); hypertension (24.4%; 95% CI: 16.7-34.2); diabetes (11.9%; 95% CI: 9.9-14.3); heart failure (8.2%; 95% CI: 5.6-11.9); chronic kidney disease (7.7%; 95% CI: 3.9-14.7); and stroke (6.8%; 95% CI: 4.7-9.6). Conclusion: Among patients seeking hospital care in sub-Saharan Africa, multimorbidity remains poorly described despite high burdens of individual chronic diseases. Prospective public health studies of multimorbidity burden are needed to generate integrated and context-specific health system interventions that act to maximize patient survival and well-being.
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Doença Crônica , Atenção à Saúde , Pacientes , Adulto , Humanos , África Subsaariana/epidemiologia , Hospitais , Estudos ProspectivosRESUMO
BACKGROUND: Compared to the abundance of clinical and genomic information available on patients hospitalised with COVID-19 disease from high-income countries, there is a paucity of data from low-income countries. Our aim was to explore the relationship between viral lineage and patient outcome. METHODS: We enrolled a prospective observational cohort of adult patients hospitalised with PCR-confirmed COVID-19 disease between July 2020 and March 2022 from Blantyre, Malawi, covering four waves of SARS-CoV-2 infections. Clinical and diagnostic data were collected using an adapted ISARIC clinical characterization protocol for COVID-19. SARS-CoV-2 isolates were sequenced using the MinION™ in Blantyre. RESULTS: We enrolled 314 patients, good quality sequencing data was available for 55 patients. The sequencing data showed that 8 of 11 participants recruited in wave one had B.1 infections, 6/6 in wave two had Beta, 25/26 in wave three had Delta and 11/12 in wave four had Omicron. Patients infected during the Delta and Omicron waves reported fewer underlying chronic conditions and a shorter time to presentation. Significantly fewer patients required oxygen (22.7% [17/75] vs. 58.6% [140/239], p < 0.001) and steroids (38.7% [29/75] vs. 70.3% [167/239], p < 0.001) in the Omicron wave compared with the other waves. Multivariable logistic-regression demonstrated a trend toward increased mortality in the Delta wave (OR 4.99 [95% CI 1.0-25.0 p = 0.05) compared to the first wave of infection. CONCLUSIONS: Our data show that each wave of patients hospitalised with SARS-CoV-2 was infected with a distinct viral variant. The clinical data suggests that patients with severe COVID-19 disease were more likely to die during the Delta wave.
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COVID-19 , Adulto , Humanos , SARS-CoV-2 , Malaui , Estudos de Coortes , Confiabilidade dos DadosRESUMO
BACKGROUND: Neutrophil extracellular traps (NETs) facilitate bacterial clearance but also promote thrombosis and organ injury in sepsis. We quantified ex vivo NET induction in septic humans and murine models of sepsis to identify signalling pathways that may be modulated to improve outcome in human sepsis. METHODS: NET formation in human donor neutrophils was quantified after incubation with plasma obtained from patients with sepsis or systemic inflammation (double-blinded assessment of extracellular DNA using immunofluorescence microscopy). NET formation (% neutrophils forming NETs) was correlated with plasma cytokine levels (MultiPlex assay). Experimental sepsis (caecal ligation and puncture or intraperitoneal injection of Escherichia coli) was assessed in C57/BL6 male mice. The effect of pharmacological inhibition of CXCR1/2 signalling (reparixin) on NET formation, organ injury (hepatic, renal, and cardiac biomarkers), and survival in septic mice was examined. RESULTS: NET formation was higher after incubation with plasma from septic patients (median NETs=25% [10.5-46.5%]), compared with plasma obtained from patients with systemic inflammation (14% [4.0-23.3%]; P=0.02). Similar results were observed after incubation of plasma from mice with neutrophils from septic non-septic mice. Circulating CXCR1/2 ligands correlated with NETosis in patients (interleukin-8; r=0.643) and mice (macrophage inflammatory protein-2; r=0.902). In experimental sepsis, NETs were primarily observed in the lungs, correlating with fibrin deposition (r=0.702) and lung injury (r=0.692). Inhibition of CXCR1/2 using reparixin in septic mice reduced NET formation, multi-organ injury, and mortality, without impairing bacterial clearance. CONCLUSION: CXCR1/2 signalling-induced NET formation is a therapeutic target in sepsis, which may be guided by ex vivo NET assays.
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Armadilhas Extracelulares/metabolismo , Inflamação/complicações , Sepse/complicações , Sulfonamidas/farmacologia , Trombose/prevenção & controle , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Inflamação/tratamento farmacológico , Lesão Pulmonar/etiologia , Lesão Pulmonar/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Receptores de Interleucina-8A/antagonistas & inibidores , Receptores de Interleucina-8B/antagonistas & inibidores , Estudos Retrospectivos , Sepse/tratamento farmacológico , Sepse/mortalidade , Trombose/etiologiaRESUMO
BACKGROUND: The prevalence of diseases other than TB detected during chest X-ray (CXR) screening is unknown in sub-Saharan Africa. This represents a missed opportunity for identification and treatment of potentially significant disease. Our aim was to describe and quantify non-TB abnormalities identified by TB-focused CXR screening during the 2016 Kenya National TB Prevalence Survey. METHODS: We reviewed a random sample of 1140 adult (≥15 years) CXRs classified as 'abnormal, suggestive of TB' or 'abnormal other' during field interpretation from the TB prevalence survey. Each image was read (blinded to field classification and study radiologist read) by two expert radiologists, with images classified into one of four major anatomical categories and primary radiological findings. A third reader resolved discrepancies. Prevalence and 95% CIs of abnormalities diagnosis were estimated. FINDINGS: Cardiomegaly was the most common non-TB abnormality at 259 out of 1123 (23.1%, 95% CI 20.6% to 25.6%), while cardiomegaly with features of cardiac failure occurred in 17 out of 1123 (1.5%, 95% CI 0.9% to 2.4%). We also identified chronic pulmonary pathology including suspected COPD in 3.2% (95% CI 2.3% to 4.4%) and non-specific patterns in 4.6% (95% CI 3.5% to 6.0%). Prevalence of active-TB and severe post-TB lung changes was 3.6% (95% CI 2.6% to 4.8%) and 1.4% (95% CI 0.8% to 2.3%), respectively. INTERPRETATION: Based on radiological findings, we identified a wide variety of non-TB abnormalities during population-based TB screening. TB prevalence surveys and active case finding activities using mass CXR offer an opportunity to integrate disease screening efforts. FUNDING: National Institute for Health Research (IMPALA-grant reference 16/136/35).
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Programas de Rastreamento/métodos , Radiografia Torácica/métodos , Inquéritos e Questionários , Tuberculose Pulmonar/diagnóstico , Estudos Transversais , Diagnóstico Diferencial , Feminino , Humanos , Quênia/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Tuberculose Pulmonar/epidemiologiaRESUMO
Rationale: Neutrophil extracellular traps (NETs) are important in the host defense against infection, but they also promote intravascular coagulation and multiorgan failure in animal models. Their clinical significance remains unclear, and available assays for patient care lack specificity and reliability.Objectives: To establish a novel assay and test its clinical significance.Methods: A prospective cohort of 341 consecutive adult ICU patients was recruited. The NET-forming capacity of ICU admission blood samples was semiquantified by directly incubating patient plasma with isolated neutrophils ex vivo. The association of NET-forming capacity with Sequential Organ Failure Assessment scores, disseminated intravascular coagulation, and 28-day mortality was analyzed and compared with available NET assays.Measurements and Main Results: Using the novel assay, we could stratify ICU patients into four groups with absent (22.0%), mild (49.9%), moderate (14.4%), and strong (13.8%) NET formation, respectively. Strong NET formation was predominantly found in sepsis (P < 0.0001). Adjusted by Acute Physiology and Chronic Health Evaluation II score, multivariate regression showed that the degree of NET formation could independently predict disseminated intravascular coagulation and mortality, whereas other NET assays (e.g., cell-free DNA, myeloperoxidase, and myeloperoxidase-DNA complexes) could not. IL-8 concentrations were found to be strongly associated with NET formation, and inhibiting IL-8 significantly attenuated NETosis. Mitogen-activated protein kinase activation by IL-8 has been identified as a major pathway of NET formation in patients.Conclusions: This assay directly measures the NET-forming capacity in patient plasma. This could guide clinical management and enable identification of NET-inducing factors in individual patients for targeted treatment and personalized ICU medicine.
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Coagulação Intravascular Disseminada/epidemiologia , Armadilhas Extracelulares/metabolismo , Neutrófilos/metabolismo , Sepse/metabolismo , APACHE , Idoso , Doenças Cardiovasculares/metabolismo , Estudos de Coortes , Estado Terminal , Feminino , Gastroenteropatias/metabolismo , Humanos , Unidades de Terapia Intensiva , Interleucina-8/metabolismo , Nefropatias/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mortalidade , Análise Multivariada , Doenças do Sistema Nervoso/metabolismo , Escores de Disfunção Orgânica , Estudos Prospectivos , Reprodutibilidade dos Testes , Doenças Respiratórias/metabolismo , Medição de Risco , Ferimentos e Lesões/metabolismoRESUMO
BACKGROUND: The 'cannot intubate cannot oxygenate' (CICO) emergency requires urgent front of neck airway (FONA) access to prevent death. In cases reported to the 4th National Audit Project, the most successful FONA was a surgical technique, almost all of which were performed by surgeons. Subsequently, UK guidelines adopted surgical cricothyroidotomy as the preferred emergency surgical FONA technique. Despite regular skills-based training, anaesthetists may still be unwilling to perform an emergency surgical FONA. Consultant anaesthetists, head and neck surgeons, and general surgeons were compared in a high-fidelity simulated emergency. We hypothesised that head and neck surgeons would successfully execute emergency surgical FONA faster than anaesthetists and general surgeons. METHODS: We recruited 15 consultants from each specialty (total of 45) at a single tertiary care hospital in the UK. All agreed to participate in an in situ high-fidelity simulation of an 'anaesthetic emergency'. Participants were not told in advance that this would be a CICO scenario. RESULTS: There were no significant differences in total time to successful ventilation between anaesthetists, head and neck surgeons and general surgeons (median 86 vs 98 vs 126 s, respectively, P=0.078). Anaesthetists completed the emergency surgical FONA procedure significantly faster than general surgeons (median 50 vs 86 s, P=0.018). Despite this strong performance, qualitative data suggested some anaesthetists still believed 'surgeons' best placed to perform emergency surgical FONA in a genuine CICO situation. CONCLUSION: Anaesthetists regularly trained in emergency surgical FONA function at levels comparable with head and neck surgeons and should feel empowered to lead this procedure in the event of a CICO emergency.
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Manuseio das Vias Aéreas/normas , Competência Clínica , Cartilagem Cricoide/cirurgia , Traqueotomia/normas , Manuseio das Vias Aéreas/métodos , Anestesiologia/normas , Contraindicações de Procedimentos , Emergências , Inglaterra , Cirurgia Geral/normas , Humanos , Intubação Intratraqueal/efeitos adversos , Simulação de Paciente , Distribuição Aleatória , Cartilagem Tireóidea/cirurgia , Traqueotomia/métodosRESUMO
OBJECTIVES: The prevalence and impact of longer-term outcomes following percutaneous tracheostomy, particularly tracheal stenosis, are unclear. Previous meta-analyses addressing this problem have been confounded by the low prevalence of tracheal stenosis and a limited number of studies. DESIGN: Embase, PubMed-Medline, and the Cochrane Central Register of Clinical Trials were searched to identify all prospective studies of tracheostomy insertion in the critically ill. To reflect contemporary practice, the search was limited to studies published from 2000 onward. We scrutinized the bibliographies of returned studies for additional articles. Meta-analyses were undertaken to estimate the pooled risk difference of tracheal stenosis, bleeding, and wound infection comparing different techniques. MEASUREMENTS AND MAIN RESULTS: We identified a total of 463 studies, 29 (5,473 patients) of which met the inclusion criteria. Nine were randomized controlled trials, six were nonrandomized comparative studies, and 14 were single-arm cohort studies. Risk of wound infection was greater for the surgical tracheostomy than for the Ciaglia multiple dilator technique, pooled risk difference 0.12 (95% CI, 0.02-0.23). We did not identify significant risk differences in other meta-analyses. Pooling across all studies according to the random-effects proportion meta-analysis suggests a higher prevalence of tracheal stenosis, wound infection, and major bleeding for surgical tracheostomies. CONCLUSIONS: Considering comparative data, there was no significant difference in the prevalence of tracheal stenosis or major bleeding between percutaneous and surgical tracheostomy. In relation to wound infection, we have found a reduction associated with the original Ciaglia technique when compared with that with the surgical tracheostomy. Considering all published data reporting long-term outcomes pooled proportion meta-analysis indicates a trend toward a higher rate of tracheal stenosis and an increased risk of major bleeding and wound infection for surgical tracheostomies. This finding may be biased as a result of targeted patient selection, and further, high-quality long-term comparative data are needed to confirm these findings.
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Cuidados Críticos , Traqueostomia , Dilatação , Humanos , Estenose Traqueal/cirurgia , Resultado do TratamentoRESUMO
RATIONALE: New vaccines are urgently needed to protect the vulnerable from bacterial pneumonia. Clinical trials of pneumonia vaccines are slow and costly, requiring tens of thousands of patients. Studies of pneumococcal vaccine efficacy against colonization have been proposed as a novel method to down-select between vaccine candidates. OBJECTIVES: Using our safe and reproducible experimental human pneumococcal colonization model, we aimed to determine the effect of 13-valent pneumococcal conjugate vaccine (PCV) on colonization. METHODS: A total of 100 healthy participants aged 18-50 years were recruited into this double-blind randomized placebo-controlled trial. They were randomly assigned to PCV (n = 49) or hepatitis A (control, n = 50) vaccination and inoculated with 80,000 CFU/100 µl of Streptococcus pneumoniae (6B) per naris. MEASUREMENTS AND MAIN RESULTS: Participants were followed up for 21 days to determine pneumococcal colonization by culture of nasal wash. The PCV group had a significantly reduced rate of 6B colonization (10% [5 of 48]) compared with control subjects (48% [23 of 48]) (risk ratio, 0.22; confidence interval, 0.09-0.52; P < 0.001). Density of colonization was reduced in the PCV group compared with the control group following inoculation. The area under the curve (density vs. day) was significantly reduced in the PCV compared with control group (geometric mean, 259 vs. 11,183; P = 0.017). CONCLUSIONS: PCV reduced pneumococcal colonization rate, density, and duration in healthy adults. The experimental human pneumococcal colonization model is a safe, cost-effective, and efficient method to determine the protective efficacy of new vaccines on pneumococcal colonization; PCV provides a gold standard against which to test these novel vaccines. Clinical trial registered with ISRCTN: 45340436.
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Vacinas Pneumocócicas , Pneumonia Pneumocócica/prevenção & controle , Vacinas Conjugadas , Adolescente , Adulto , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
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.
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Multimorbidity is an emerging challenge for health systems globally. It is commonly defined as the co-occurrence of two or more chronic conditions in one person, but its meaning remains a lively area of academic debate, and the utility of the concept beyond high-income settings is uncertain. This article presents the findings from an interdisciplinary research initiative that drew together 60 academic and applied partners working in 10 African countries to answer the questions: how useful is the concept of multimorbidity within Africa? Can the concept be adapted to context to optimise its transformative potentials? During a three-day concept-building workshop, we investigated how the definition of multimorbidity was understood across diverse disciplinary and regional perspectives, evaluated the utility and limitations of existing concepts and definitions, and considered how to build a more context-sensitive, cross-cutting description of multimorbidity. This iterative process was guided by the principles of grounded theory and involved focus- and whole-group discussions during the workshop, thematic coding of workshop discussions, and further post-workshop development and refinement. Three thematic domains emerged from workshop discussions: the current focus of multimorbidity on constituent diseases; the potential for revised concepts to centre the priorities, needs, and social context of people living with multimorbidity (PLWMM); and the need for revised concepts to respond to varied conceptual priorities amongst stakeholders. These themes fed into the development of an expanded conceptual model that centres the catastrophic impacts multimorbidity can have for PLWMM, families and support structures, service providers, and health systems.
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There is a high burden of critical illness in low-income countries (LICs), adding pressure to already strained health systems. Over the next decade, the need for critical care is expected to grow due to ageing populations with increasing medical complexity; limited access to primary care; climate change; natural disasters; and conflict. In 2019, the 72nd World Health Assembly emphasised that an essential part of universal health coverage is improved access to effective emergency and critical care and to "ensure the timely and effective delivery of life-saving health care services to those in need". In this narrative review, we examine critical care capacity building in LICs from a health systems perspective. We conducted a systematic literature search, using the World Heath Organisation (WHO) health systems framework to structure findings within six core components or "building blocks": (1) service delivery; (2) health workforce; (3) health information systems; (4) access to essential medicines and equipment; (5) financing; and (6) leadership and governance. We provide recommendations using this framework, derived from the literature identified in our review. These recommendations are useful for policy makers, health service researchers and healthcare workers to inform critical care capacity building in low-resource settings.
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Atenção à Saúde , Mão de Obra em Saúde , Humanos , Cuidados Críticos , Análise de Sistemas , Recursos em SaúdeRESUMO
Background: Tuberculosis (TB) remains a major challenge in many domains including diagnosis, pathogenesis, prevention, treatment, drug resistance and long-term protection of the public health by vaccination. A controlled human infection model (CHIM) could potentially facilitate breakthroughs in each of these domains but has so far been considered impossible owing to technical and safety concerns. Methods: A systematic review of mycobacterial human challenge studies was carried out to evaluate progress to date, best possible ways forward and challenges to be overcome. We searched MEDLINE (1946 to current) and CINAHL (1984 to current) databases; and Google Scholar to search citations in selected manuscripts. The final search was conducted 3 rd February 2022. Inclusion criteria: adults ≥18 years old; administration of live mycobacteria; and interventional trials or cohort studies with immune and/or microbiological endpoints. Exclusion criteria: animal studies; studies with no primary data; no administration of live mycobacteria; retrospective cohort studies; case-series; and case-reports. Relevant tools (Cochrane Collaboration for RCTs and Newcastle-Ottawa Scale for non-randomised studies) were used to assess risk of bias and present a narrative synthesis of our findings. Results: The search identified 1,388 titles for review; of these 90 were reviewed for inclusion; and 27 were included. Of these, 15 were randomised controlled trials and 12 were prospective cohort studies. We focussed on administration route, challenge agent and dose administered for data extraction. Overall, BCG studies including fluorescent BCG show the most immediate utility, and genetically modified Mycobacteria tuberculosis is the most tantalising prospect of discovery breakthrough. Conclusions: The TB-CHIM development group met in 2019 and 2022 to consider the results of the systematic review, to hear presentations from many of the senior authors whose work had been reviewed and to consider best ways forward. This paper reports both the systematic review and the deliberations. Registration: PROSPERO ( CRD42022302785; 21 January 2022).
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The SARS-CoV-2 Omicron variant has resulted in a high number of cases, but a relatively low incidence of severe disease and deaths, compared to the pre-Omicron variants. Therefore, we assessed the differences in symptom prevalence between Omicron and pre-Omicron infections in a sub-Saharan African population. We collected data from outpatients presenting at two primary healthcare facilities in Blantyre, Malawi, from November 2020 to March 2022. Eligible participants were aged >1month old, with signs suggestive of COVID-19, and those not suspected of COVID-19, from whom we collected nasopharyngeal swabs for SARS-CoV-2 PCR testing, and sequenced positive samples to identify infecting-variants. In addition, we calculated the risk of presenting with a given symptom in individuals testing SARS-CoV-2 PCR positive before and during the Omicron variant-dominated period. Among 5176 participants, 6.4% were under 5, and 77% were aged 18 to 50 years. SARS-CoV-2 infection prevalence peaked in January 2021 (Beta), July 2021 (Delta), and December 2021 (Omicron). We found that cough (risk ratio (RR), 1.50; 95% confidence interval (CI), 1.00 to 2.30), fatigue (RR 2.27; 95% CI, 1.29 to 3.86) and headache (RR 1.64; 95% CI, 1.15 to 2.34) were associated with a high risk of SARS-CoV-2 infection during the pre-Omicron period. In comparison, only headache (RR 1.41; 95% CI, 1.07 to 1.86) did associate with a high risk of SARS-CoV-2 infection during the Omicron-dominated period. In conclusion, clinical symptoms associated with Omicron infection differed from prior variants and were harder to identify clinically with current symptom guidelines. Our findings encourage regular review of case definitions and testing policies to ensure case ascertainment.
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BACKGROUND: The effect of childhood pneumococcal conjugate vaccine implementation in Malawi is threatened by absence of herd effect. There is persistent vaccine-type pneumococcal carriage in both vaccinated children and the wider community. We aimed to use a human infection study to measure 13-valent pneumococcal conjugate vaccine (PCV13) efficacy against pneumococcal carriage. METHODS: We did a double-blind, parallel-arm, randomised controlled trial investigating the efficacy of PCV13 or placebo against experimental pneumococcal carriage of Streptococcus pneumoniae serotype 6B (strain BHN418) among healthy adults (aged 18-40 years) from Blantyre, Malawi. We randomly assigned participants (1:1) to receive PCV13 or placebo. PCV13 and placebo doses were prepared by an unmasked pharmacist to maintain research team and participant masking with identification only by a randomisation identification number and barcode. 4 weeks after receiving either PCV13 or placebo, participants were challenged with 20â000 colony forming units (CFUs) per naris, 80â000 CFUs per naris, or 160â000 CFUs per naris by intranasal inoculation. The primary endpoint was experimental pneumococcal carriage, established by culture of nasal wash at 2, 7, and 14 days. Vaccine efficacy was estimated per protocol by means of a log-binomial model adjusting for inoculation dose. The trial is registered with the Pan African Clinical Trials Registry, PACTR202008503507113, and is now closed. FINDINGS: Recruitment commenced on April 27, 2021 and the final visit was completed on Sept 12, 2022. 204 participants completed the study protocol (98 PCV13, 106 placebo). There were lower carriage rates in the vaccine group at all three inoculation doses (0 of 21 vs two [11%] of 19 at 20â000 CFUs per naris; six [18%] of 33 vs 12 [29%] of 41 at 80â000 CFUs per naris, and four [9%] of 44 vs 16 [35%] of 46 at 160â000 CFUs per naris). The overall carriage rate was lower in the vaccine group compared with the placebo group (ten [10%] of 98 vs 30 [28%] of 106; Fisher's p value=0·0013) and the vaccine efficacy against carriage was estimated at 62·4% (95% CI 27·7-80·4). There were no severe adverse events related to vaccination or inoculation of pneumococci. INTERPRETATION: This is, to our knowledge, the first human challenge study to test the efficacy of a pneumococcal vaccine against pneumococcal carriage in Africa, which can now be used to establish vaccine-induced correlates of protection and compare alternative strategies to prevent pneumococcal carriage. This powerful tool could lead to new means to enhance reduction in pneumococcal carriage after vaccination. FUNDING: Wellcome Trust.
Assuntos
Vacinas Pneumocócicas , Streptococcus pneumoniae , Adulto , Criança , Humanos , Malaui/epidemiologia , Vacinas Conjugadas , Sorogrupo , Vacinas Pneumocócicas/uso terapêuticoRESUMO
INTRODUCTION: Experimental Human Pneumococcal Challenge (EHPC) involves the controlled exposure of adults to a specific antibiotic-sensitive Streptococcus pneumoniae serotype, to induce nasopharyngeal colonisation for the purpose of vaccine research. The aims are to review comprehensively the safety profile of EHPC, explore the association between pneumococcal colonisation and frequency of safety review and describe the medical intervention required to undertake such studies. METHODS: A single-centre review of all EHPC studies performed 2011-2021. All recorded serious adverse events (SAE) in eligible studies are reported. An unblinded meta-analysis of collated anonymised individual patient data from eligible EHPC studies was undertaken to assess the association between experimental pneumococcal colonisation and the frequency of safety events following inoculation. RESULTS: In 1416 individuals (median age 21, IQR 20-25), 1663 experimental pneumococcal inoculations were performed. No pneumococcal-related SAE have occurred. 214 safety review events were identified with 182 (12.85%) participants presenting with symptoms potentially in keeping with pneumococcal infection, predominantly in pneumococcal colonised individuals (colonised = 96/658, non-colonised = 86/1005, OR 1.81 (95% CI 1.28-2.56, P = <0.001). The majority were mild (pneumococcal group = 72.7% [120/165 reported symptoms], non-pneumococcal = 86.7% [124/143 reported symptoms]). 1.6% (23/1416) required antibiotics for safety. DISCUSSION: No SAEs were identified directly relating to pneumococcal inoculation. Safety review for symptoms was infrequent but occurred more in experimentally colonised participants. Most symptoms were mild and resolved with conservative management. A small minority required antibiotics, notably those serotype 3 inoculated. CONCLUSION: Outpatient human pneumococcal challenge can be conducted safely with appropriate levels of safety monitoring procedures in place.