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Oxford Centre for Tropical Medicine and Global Health
The impact of 10-valent pneumococcal conjugate vaccine on the incidence of admissions to hospital with hypoxaemic and non-hypoxaemic pneumonia in Kenyan children.
Observational evidence suggests that pneumococcal conjugate vaccines (PCVs) are more effective at reducing the incidence of hypoxaemic pneumonia compared to non-hypoxaemic pneumonia. We examined the impact of 10-valent PCV (PCV10, Synflorix) on hypoxaemic pneumonia hospital admissions using data from an existing PCV impact study of clinical and radiographic pneumonia. PCV10 was introduced, with catch-up among children under 5 years, in the Kilifi Health and Demographic Surveillance System (KHDSS) in January 2011. We undertook an interrupted time-series (ITS) analysis using seasonally-adjusted segmented Poisson regression of hypoxaemic and non-hypoxaemic pneumonia, accounting for secular trends, from January 2007 to December 2019 among KHDSS residents aged 2-59 months. The median monthly crude incidence of hypoxaemic pneumonia per 100,000 person-years was 95 (IQR 80-139) in the pre-PCV10 period. Time-series regression estimated PCV10 introduction was associated with an increase in the incidence of hypoxaemic pneumonia in children aged 2-59 months (IRR 1.63, 95% CI 1.10-2.41), whereas it was associated with a decrease in the incidence of non-hypoxaemic pneumonia (IRR 0.61, 95% CI 0.48-0.77). Despite the consistent pneumonia surveillance and robust ITS analysis which accounted for pre-PCV10 secular trend and seasonality, the apparent association with hypoxaemic pneumonia is likely due to unmeasured time-varying confounders around the time of vaccine introduction, such as the epidemiology of other respiratory pathogens. This study highlights limitations in the analysis and interpretation of observational data in vaccine impact studies against pneumonia.
Modelling practices, data provisioning, sharing and dissemination needs for pandemic decision-making: a survey-based modellers’ perspective from four European countries
Background: Advanced outbreak analytics were instrumental in informing governmental decision-making during the COVID-19 pandemic. However, combined and systematic evaluations of how modelling practices, data use, and science-policy interactions evolved during this and previous emergencies remain scarce. Aim: This study assessed the evolution of European modelling practices, data usage, gaps, and engagement between modellers and decision-makers to inform future global epidemic-intelligence. Methods: We conducted a two-stage semi-quantitative survey among modellers in a large European epidemic-intelligence consortium. Responses were analysed descriptively across early, mid-, and late-pandemic phases. Policy citations in Overton were used to assess policy impact. Results: Our sample included 66 modelling contributions from 11 institutions in four European countries. COVID-19 modelling initially prioritised understanding epidemic dynamics, while evaluating non-pharmaceutical interventions and vaccination impacts became equally important in later phases. ‘Traditional’ surveillance data (e.g. case linelists) were widely available in near-real time. Conversely, real-time ‘non-traditional’ data (notably social contact and behavioural surveys), and serological data were frequently reported as lacking. Gaps included poor stratification and incomplete geographic coverage. Frequent bidirectional engagement with decision-makers shaped modelling scope and recommendations. However, fewer than half of the studies shared open-access code. Conclusions: We highlight the evolving use and needs of modelling during public health crises. Persistent gaps in non-traditional data availability underscore the need to rethink sustainable data collection and sharing practices, including from for-profit providers. Future preparedness should focus on strengthening collaborative platforms, research consortia and modelling networks to foster data and code sharing and effective collaboration between academia, decision-makers, and data providers.
Associations of Awake Prone Positioning-Induced Changes in Physiology with Intubation: An International Prospective Observational Study in Patients with Acute Hypoxemic Respiratory Failure Related to COVID-19.
IntroductionAwake prone positioning has the potential to improve oxygenation and decrease respiratory rate, potentially reducing the need for intubation in patients with acute hypoxemic respiratory failure. We investigated awake prone positioning-induced changes in oxygenation and respiratory rate, and the prognostic capacity for intubation in patients with COVID-19 pneumonia.MethodsInternational multicenter prospective observation study in critically ill adult patients with COVID-19 receiving supplemental oxygen. We collected data on oxygenation and respiratory rate at baseline, and at 1 h after being placed in prone positioning. The combined primary outcome was oxygenation and respiratory rate at 1 h. The secondary endpoint was treatment failure, defined as need for intubation within 24 h of start of awake prone positioning.ResultsBetween March 27th and November 2020, 101 patients were enrolled of which 99 were fully analyzable. Awake prone positioning lasted mean of 3 [2-4] h. In 77 patients (77.7%), awake prone positioning improved oxygenation, and in 37 patients (54.4%) it decreased respiratory rate. Twenty-nine patients (29.3%) were intubated within 24 h. An increase in SpO2/FiO2 of 2/FiO2 to > 116 mmHg (OR 3.6, 95% CI 1.2-10.8, P = 0.02), and a decrease in respiratory rate of ConclusionsAwake prone positioning improves oxygenation in the majority of patients, and decreases respiratory rate in more than half of patients with acute hypoxemic respiratory failure caused by COVID-19. One in three patients need intubation within 24 h. Awake prone position-induced changes in oxygenation and respiratory rate have prognostic capacity for intubation within 24 h.
The Use of Mechanical Insufflation-Exsufflation in Invasively Ventilated Critically Ill Adults.
Mechanical insufflation-exsufflation (MI-E) is traditionally used in the neuromuscular population. There is growing interest of MI-E use in invasively ventilated critically ill adults. We aimed to map current evidence on MI-E use in invasively ventilated critically ill adults. Two authors independently searched electronic databases MEDLINE, Embase, and CINAHL via the Ovid platform; PROSPERO; Cochrane Library; ISI Web of Science; and International Clinical Trials Registry Platform between January 1990-April 2021. Inclusion criteria were (1) adult critically ill invasively ventilated subjects, (2) use of MI-E, (3) study design with original data, and (4) published from 1990 onward. Data were extracted by 2 authors independently using a bespoke extraction form. We used Mixed Methods Appraisal Tool to appraise risk of bias. Theoretical Domains Framework was used to interpret qualitative data. Of 3,090 citations identified, 28 citations were taken forward for data extraction. Main indications for MI-E use during invasive ventilation were presence of secretions and mucus plugging (13/28, 46%). Perceived contraindications related to use of high levels of positive pressure (18/28, 68%). Protocolized MI-E settings with a pressure of ±40 cm H2O were most commonly used, with detail on timing, flow, and frequency of prescription infrequently reported. Various outcomes were re-intubation rate, wet sputum weight, and pulmonary mechanics. Only 3 studies reported the occurrence of adverse events. From qualitative data, the main barrier to MI-E use in this subject group was lack of knowledge and skills. We concluded that there is little consistency in how MI-E is used and reported, and therefore, recommendations about best practices are not possible.
Interaction between peri-operative blood transfusion, tidal volume, airway pressure and postoperative ARDS: an individual patient data meta-analysis.
BackgroundTransfusion of blood products and mechanical ventilation with injurious settings are considered risk factors for postoperative lung injury in surgical Patients.MethodsA systematic review and individual patient data meta-analysis was done to determine the independent effects of peri-operative transfusion of blood products, intra-operative tidal volume and airway pressure in adult patients undergoing mechanical ventilation for general surgery, as well as their interactions on the occurrence of postoperative acute respiratory distress syndrome (ARDS). Observational studies and randomized trials were identified by a systematic search of MEDLINE, CINAHL, Web of Science, and CENTRAL and screened for inclusion into a meta-analysis. Individual patient data were obtained from the corresponding authors. Patients were stratified according to whether they received transfusion in the peri-operative period [red blood cell concentrates (RBC) and/or fresh frozen plasma (FFP)], tidal volume size [≤7 mL/kg predicted body weight (PBW), 7-10 and >10 mL/kg PBW] and airway pressure level used during surgery (≤15, 15-20 and >20 cmH2O). The primary outcome was development of postoperative ARDS.ResultsSeventeen investigations were included (3,659 patients). Postoperative ARDS occurred in 40 (7.2%) patients who received at least one blood product compared to 40 patients (2.5%) who did not [adjusted hazard ratio (HR), 2.32; 95% confidence interval (CI), 1.25-4.33; P=0.008]. Incidence of postoperative ARDS was highest in patients ventilated with tidal volumes of >10 mL/kg PBW and having airway pressures of >20 cmH2O receiving both RBC and FFP, and lowest in patients ventilated with tidal volume of ≤7 mL/kg PBW and having airway pressures of ≤15 cmH2O with no transfusion. There was a significant interaction between transfusion and airway pressure level (P=0.002) on the risk of postoperative ARDS.ConclusionsPeri-operative transfusion of blood products is associated with an increased risk of postoperative ARDS, which seems more dependent on airway pressure than tidal volume size.
Recent advances in mechanical ventilation in patients without acute respiratory distress syndrome.
While being an essential part of general anesthesia for surgery and at times even a life-saving intervention in critically ill patients, mechanical ventilation has a strong potential to cause harm. Certain ventilation strategies could prevent, at least to some extent, the injury caused by this intervention. One essential element of so-called 'lung-protective' ventilation is the use of lower tidal volumes. It is uncertain whether higher levels of positive end-expiratory pressures have lung-protective properties as well. There are indications that too high oxygen fractions of inspired air, or too high blood oxygen targets, are harmful. Circumstantial evidence further suggests that spontaneous modes of ventilation are to be preferred over controlled ventilation to prevent harm to respiratory muscle. Finally, the use of restrictive sedation strategies in critically ill patients indirectly prevents ventilation-induced injury, as daily spontaneous awakening and breathing trials and bolus instead of continuous sedation are associated with shorter duration of ventilation and shorten the exposure to the injurious effects of ventilation.
The extent of ventilator-induced lung injury in mice partly depends on duration of mechanical ventilation.
Background. Mechanical ventilation (MV) has the potential to initiate ventilator-induced lung injury (VILI). The pathogenesis of VILI has been primarily studied in animal models using more or less injurious ventilator settings. However, we speculate that duration of MV also influences severity and character of VILI. Methods. Sixty-four healthy C57Bl/6 mice were mechanically ventilated for 5 or 12 hours, using lower tidal volumes with positive end-expiratory pressure (PEEP) or higher tidal volumes without PEEP. Fifteen nonventilated mice served as controls. Results. All animals remained hemodynamically stable and survived MV protocols. In both MV groups, PaO2 to FiO2 ratios were lower and alveolar cell counts were higher after 12 hours of MV compared to 5 hours. Alveolar-capillary permeability was increased after 12 hours compared to 5 hours, although differences did not reach statistical significance. Lung levels of inflammatory mediators did not further increase over time. Only in mice ventilated with increased strain, lung compliance declined and wet to dry ratio increased after 12 hours of MV compared to 5 hours. Conclusions. Deleterious effects of MV are partly dependent on its duration. Even lower tidal volumes with PEEP may initiate aspects of VILI after 12 hours of MV.
Bronchoalveolar Activation of Coagulation and Inhibition of Fibrinolysis during Ventilator-Associated Lung Injury.
Background and Objective. Bronchoalveolar coagulopathy is a characteristic feature of pulmonary inflammation. We compared bronchoalveolar and systemic levels of coagulation in patients who did and patients who did not develop ventilator-associated lung injury (VALI). Methods. Secondary analysis of a randomized controlled trial evaluating the effect of lower tidal volumes versus conventional tidal volumes in patients without acute lung injury or acute respiratory distress syndrome at the onset of mechanical ventilation. Results. Ten patients with VALI and 10 random control patients without lung injury during the course of mechanical ventilation, but all ventilated with conventional tidal volumes, were compared. Patients who developed VALI showed both bronchoalveolar activation of coagulation (increase in thrombin-antithrombin complex levels P < 0.001 versus baseline) and inhibition of fibrinolysis (decline in plasminogen activator activity P < 0.001 versus baseline). The later seemed to be dependent on higher levels of plasminogen activator inhibitor type 1 (P = 0.001 versus baseline). Patients who developed VALI also showed elevated systemic thrombin-antithrombin complex levels and decreased systemic plasminogen activator activity levels. Conclusions. VALI is characterized by bronchoalveolar coagulopathy. Systemic and bronchoalveolar coagulopathy at the onset of mechanical ventilation may be a risk factor for developing VALI in patients ventilated with conventional tidal volumes.
Relative Tissue Factor Deficiency Attenuates Ventilator-Induced Coagulopathy but Does Not Protect against Ventilator-Induced Lung Injury in Mice.
Preventing tissue-factor-(TF-) mediated systemic coagulopathy improves outcome in models of sepsis. Preventing TF-mediated pulmonary coagulopathy could attenuate ventilator-induced lung injury (VILI). We investigated the effect of relative TF deficiency on pulmonary coagulopathy and inflammation in a murine model of VILI. Heterozygous TF knockout (TF(+/-)) mice and their wild-type (TF(+/+)) littermates were sedated (controls) or sedated, tracheotomized, and mechanically ventilated with either low or high tidal volumes for 5 hours. Mechanical ventilation resulted in pulmonary coagulopathy and inflammation, with more injury after mechanical ventilation with higher tidal volumes. Compared with TF(+/+) mice, TF(+/-) mice demonstrated significantly lower pulmonary thrombin-antithrombin complex levels in both ventilation groups. There were, however, no differences in lung wet-to-dry ratio, BALF total protein levels, neutrophil influx, and lung histopathology scores between TF(+/-) and TF(+/+) mice. Notably, pulmonary levels of cytokines were significantly higher in TF(+/-) as compared to TF(+/+) mice. Systemic levels of cytokines were not altered by the relative absence of TF. TF deficiency is associated with decreased pulmonary coagulation independent of the ventilation strategy. However, relative TF deficiency does not reduce VILI and actually results in higher pulmonary levels of inflammatory mediators.
Systemic and urinary neutrophil gelatinase-associated lipocalins are poor predictors of acute kidney injury in unselected critically ill patients.
Background. Neutrophil gelatinase-associated lipocalin (NGAL) in serum and urine have been suggested as potential early predictive biological markers of acute kidney injury (AKI) in selected critically ill patients. Methods. We performed a secondary analysis of a multicenter prospective observational cohort study of unselected critically ill patients. Results. The analysis included 140 patients, including 57 patients who did not develop AKI, 31 patients who developed AKI, and 52 patients with AKI on admission to the ICU. Levels of sNGAL and uNGAL on non-AKI days were significantly lower compared to levels of sNGAL on RIFLE(RISK) days, RIFLE(INJURY) days, and RIFLE(FAILURE) days. The AUC of sNGAL for predicting AKI was low: 0.45 (95% confidence interval (CI) 0.27-0.63) and 0.53 (CI 0.38-0.67), 2 days and 1 day before development of AKI, respectively. The AUC of uNGAL for predicting AKI was also low: 0.48 (CI 0.33-0.62) and 0.48 (CI 0.33-0.62), 2 days and 1 day before development of AKI, respectively. AUC of sNGAL and uNGAL for the prediction of renal replacement therapy requirement was 0.47 (CI 0.37-0.58) and 0.26 (CI 0.03-0.50). Conclusions. In unselected critically ill patients, sNGAL and uNGAL are poor predictors of AKI or RRT.
Chest radiography practice in critically ill patients: a postal survey in the Netherlands.
BackgroundTo ascertain current chest radiography practice in intensive care units (ICUs) in the Netherlands.MethodsPostal survey: a questionnaire was sent to all ICUs with > 5 beds suitable for mechanical ventilation; pediatric ICUs were excluded. When an ICU performed daily-routine chest radiographs in any group of patients it was considered to be a "daily-routine chest radiography" ICU.ResultsFrom the number of ICUs responding, 63% practice a daily-routine strategy, in which chest radiographs are obtained on a daily basis without any specific reason. A daily-routine chest radiography strategy is practiced less frequently in university-affiliated ICUs (50%) as compared to other ICUs (68%), as well as in larger ICUs (> 20 beds, 50%) as compared to smaller ICUs (< 20 beds, 65%) (P > 0.05). Remarkably, physicians that practice a daily-routine strategy consider daily-routine radiographs helpful in guiding daily practice in less than 30% of all performed radiographs. Chest radiographs are considered essential for verification of the position of invasive devices (81%) and for diagnosing pneumothorax, pneumonia or acute respiratory distress syndrome (82%, 74% and 69%, respectively). On demand chest radiographs are obtained after introduction of thoracic drains, central venous lines and endotracheal tubes in 98%, 84% and 75% of responding ICUs, respectively. Chest films are also obtained in case of ventilatory deterioration (49% of responding ICUs), and after cardiopulmonary resuscitation (59%), tracheotomy (58%) and mini-tracheotomy (23%).ConclusionThere is notable lack of consensus on chest radiography practice in the Netherlands. This survey suggests that a large number of intensivists may doubt the value of daily-routine chest radiography, but still practice a daily-routine strategy.
Social resource as a critical and overlooked factor for patient safety in low-resource settings.
Clinicians, NGOs, funders and academics (among others) in global health are accustomed to discussion of the "low-resource setting". Commonly, the resources implicit in this term are physical (equipment, drugs) and infrastructural (electricity, water and sanitation) in nature. Human resources are well recognised as scarce in this context too, and the focus in most "workforce" research is on the number, distribution and/or training of healthcare workers. In this article, we make the case for closer examination of "social resource" as necessary to patient safety and distinct from simple enumeration of available/trained personnel. We use the clinical specialty of anaesthesia as a case study, identifying the different ways in which social resource is necessary to enable safe practice for anaesthesia providers, and the potential challenges to accessing social resource relevant in the low- and middle-income context. Finally, we suggest ways in which social resource for anaesthesia professionals in LMICs might be meaningfully investigated, with a view to improving its priority and access for safe anaesthesia care worldwide.
Estimating scrub typhus and murine typhus incidence among adolescents and adults in Yangon, Myanmar.
OBJECTIVES: Rickettsioses are frequent causes of treatable febrile illness in Southeast Asia, including Myanmar. Accurate estimates of the incidence of rickettsioses are needed to inform investments in disease prevention and control. We sought to estimate the incidence of rickettsioses among adults and adolescents by combining sentinel hospital surveillance with a healthcare utilisation survey in Yangon, Myanmar. METHODS: We conducted a household-based healthcare utilisation survey in the Yangon Region from 12 March through 5 April 2018. Multipliers derived from this survey were then applied to scrub typhus, murine typhus, and spotted fever group rickettsioses infections identified from a study of adolescent and adult community-onset febrile illness done from 5 October 2015 through 4 October 2016 at Yangon General Hospital to estimate disease incidence. Acute serum was collected at enrolment and convalescent serum 14-30 days after enrolment. Confirmed acute scrub typhus, murine typhus, and spotted fever group infections were diagnosed by a ≥ 4-fold rise between acute and convalescent immunofluorescent antibody test titre to Orientia tsutsugamushi pooled Karp, Kato, and Gilliam antigens; Rickettsia typhi Wilmington strain; and Rickettsia honei and Rickettsia conorii antigens, respectively. RESULTS: After applying multipliers, we estimated the overall annual incidence of acute scrub typhus among adolescents and adults in the Yangon Region at 211 cases per 100,000 persons, and the overall estimate of acute murine typhus among adults and adolescents was 44 cases per 100,000 persons per year for 2015-2016. There were no confirmed spotted fever group infections. CONCLUSIONS: We provide the first estimates of scrub typhus and murine typhus community incidence in Myanmar. Similar research in children and from other parts of Myanmar, as well as studies of illness duration, complications, and deaths, is needed to estimate the disease burden.
Enhancing Clinical Trial Sites in Low- and Middle-Income Countries to Facilitate Product Development in Response to the COVID-19 Pandemic
Abstract Background The swift development of coronavirus disease 2019 (COVID-19) vaccines marked a monumental effort in global coordination and collaboration; however, there remained major disparities in vaccine access and research capacity across countries. Unequal participation in vaccine development studies from low- and middle- income countries (LMICs) clearly signaled an urgent need to strengthen health research infrastructure in those regions. Methods With funding from the Gates Foundation (GF), this site readiness initiative carried out rapid capacity enhancement activities to enable large-scale, Phase 3 pivotal clinical trial conduct in LMICs. The International Vaccine Institute (IVI) worked with site partners in four countries (Mozambique, Ghana, Nepal, and the Philippines) after conducting feasibility assessments for site selection. Site-specific gaps were identified, and capacity building activities focused on staff training, site infrastructure, and resource mobilization were carried out over roughly 7 months from October 2020 to May 2021. Results Despite pandemic-related challenges such as supply chain shortages, by the end of the capacity building efforts all sites were either contracted to or in discussions with trial sponsors to conduct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine studies. This article provides an overview of the site selection process, critical components of site establishment, and final site readiness evaluations carried out amidst a global health emergency. Conclusions This experience illustrates the value of research capacity enhancement as essential to both pandemic preparedness and global health equity. The lessons learned are being carried into an ongoing initiative across West Africa, currently underway as the “Advancing Research Capabilities in West Africa (ARC-WA).”
High epilepsy prevalence and excess mortality in onchocerciasis-endemic counties of South Sudan: A call for integrated interventions.
BACKGROUND: Epilepsy is a major health concern in onchocerciasis-endemic regions with intense transmission, where the infection is associated with a high epilepsy burden. This study investigated epilepsy prevalence and mortality in five onchocerciasis-endemic counties of South Sudan, and the association between onchocerciasis transmission and epilepsy, including probable nodding syndrome (pNS). METHODOLOGY: House-to-house cross-sectional surveys (2021-2024) identified persons with suspected epilepsy (sPWE) and retrospectively documented deaths among sPWE and individuals without epilepsy (IWE). Epilepsy diagnoses, including pNS, were confirmed by trained clinicians. Ongoing transmission was assessed using anti-Ov16 seroprevalence in children aged 3‒9 years. Age- and sex-standardised epilepsy, pNS and anti-Ov16 prevalence were calculated, along with age- and sex-standardised mortality rates and standardised mortality ratios (SMRs) with 95% confidence intervals (95%CIs), using IWE as the reference population. Weighted arcsin-transformed linear regression was used to explore the association between epilepsy and anti-Ov16 prevalence. PRINCIPAL FINDINGS: Among 34,019 individuals screened, 166 deaths occurred in 3,101 person-years for sPWE versus 466 deaths in 63,420 person-years for IWE. Epilepsy prevalence was 4.1% (range: 2.3-7.1%), and pNS prevalence was 1.5% (range: 0.6-2.2%). Anti-Ov16 seroprevalence among children was 23.3% (range: 1.4-44.1%). Each 1.0 percentage point increase in standardised anti-Ov16 seroprevalence was statistically significantly associated with an average rise of 0.10 percentage points in standardised epilepsy prevalence and 0.04 percentage points in standardised pNS prevalence. Median age at death was lower for sPWE (20 years) than IWE (38 years; Mann-Whitney U-test p-value