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BackgroundSub-Saharan Africa has the highest estimated death rate attributable to antimicrobial resistance, especially from extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E). However, the dynamics of human colonization in the community with ESBL-E are not well described. Inadequate water, sanitation, and hygiene infrastructure and associated behaviors are believed to play an important role in transmission of ESBL-E, and an improved understanding of the temporal dynamics of within-household transmission could help inform the design of future policies.MethodsIn this 18-month study, using microbiological data and household surveys, we built a multivariable hierarchical harmonic logistic regression model to identify risk factors for colonization with ESBL-producing Escherichia coli and Klebsiella pneumoniae, reflecting household structure and temporal correlation of colonization status.ResultsBeing male was associated with a lower risk of colonization with ESBL-producing E. coli (odds ratio [OR], 0.786; credible interval [CrI], .678–.910), whereas the use of a tube well or a borehole was associated with an increased risk (OR, 1.550; CrI, 1.003–2.394). For ESBL-producing K. pneumoniae, recent antibiotic exposure increased risk of colonization (OR, 1.281; CrI, 1.049–1.565), whereas sharing plates decreased that risk (OR, 0.672; CrI, .460–.980). Finally, the temporal correlation range of 8 to 11 weeks provided evidence that within-household transmission occurs within this time frame.ConclusionsWe describe different risks for colonization with different enteric bacterial species. Our findings suggest interventions to reduce transmission targeted at the household level need to focus on improving water, sanitation, and hygiene infrastructure and associated behaviors, whereas at the community level, they should focus on both environmental hygiene and antibiotic stewardship.

BackgroundLow- and middle-income countries (LMICs) have high morbidity and mortality from drug-resistant infections, especially from enteric bacteria such as Escherichia coli. LMICs have varying infrastructure and services in the community to separate people from human and animal waste, creating risks for ESBL-Enterobacterales (ESBL-E) transmission. Limited data exist from Southern Africa on the prevalence of ESBL-E the community.Methods and findingsIn this longitudinal cohort study we took a one-health approach to investigating prevalence and distribution of ESBL-E in urban, peri-urban and rural Malawian households between May 2018 and October 2020. We described human health, antibiotic usage (ABU), health seeking behaviour, structural and behavioural environmental health practices, and animal husbandry at these households. In parallel, human and animal stool and diverse environmental samples were collected and cultured to identify presence of ESBL E. coli and ESBL K. pneumoniae. Univariable and multivariable analysis was performed to determine associations with human ESBL-E colonisation.We recruited 300 households, totalling 841 visits, and a paucity of environmental health infrastructure and materials for safe sanitation was noted across all sites. In total, 11,975 samples were cultured and ESBL-E were isolated from 41.8% (n=1190) of human stool and 29.8% (n=290) of animal stool samples. Animal species with particularly high rates of ESBL-E colonisation included pigs (56.8%, n=21) poultry (32.5%, n=148) and dogs (58.8% n= 30). ESBL-E were isolated from 66.2% (n=339) of river water samples and 46.0% (n=138) of drain samples. Urban areas had greater ESBL-E contamination of food, household surfaces, floors and the external environment, alongside the highest rates of ESBL-E colonisation in humans (47.1%, n=384) and animals (55.1%, n=65). Multivariable models illustrated that human ESBL E. coli colonisation was associated with the wet season (aOR = 1.66, 95%CrI: 1.38-2.00), living in urban areas (aOR = 2.01, 95%CrI: 1.26-3.24), advanced age (aOR = 1.14, 95%CrI: 1.05-1.24) and in households where animals were observed interacting with food (aOR = 1.62, 95%CrI: 1.17-2.28) or kept inside (aOR = 1.58, 95%CrI: 1.00-2.43). Human ESBL K. pneumoniae colonisation was also associated with the wet season (aOR = 2.23, 95%CrI: 1.63-2.76.ConclusionWe identified extremely high levels of ESBL-E colonisation in humans and animals and contamination of the environment in Southern Malawi. Urbanisation and season are key risks for ESBL-E colonisation, perhaps reflecting environmental contamination as toilets overflow in high population density areas in heavy rains in the wet season. Without adequate efforts to improve environmental health, ESBL transmission is likely to persist in this setting.

BackgroundAntimicrobial resistance (AMR) represents an important threat to achieving the sustainable development goals in Sub-Saharan Africa (sSA). sSA is reported to have the highest estimated death rate attributable to AMR, with Extended-Spectrum Beta-Lactamase-producing Enterobacterales, such as Klebsiella pneumoniae and Escherichia coli, representing the greatest challenge. However, the dynamics of human colonisation with such bacteria in the sSA community setting are not well known. Inadequate water, sanitation and hygiene (WASH) infrastructure and associated behaviours are thought to play an important role in transmission of AMR-bacteria, and an improved understanding of the temporal dynamics of within-household transmission could help inform the design of public health policies that interrupt transmission of AMR-bacteria.Methods and FindingsIn this 18-month study, individuals from households in diverse areas of Southern Malawi were recruited and human stool samples were longitudinally collected. Using microbiological data and household surveys, we built a multivariable hierarchical harmonic logistic regression model to identify risk factors for colonisation with ESBL-producing E. coli and K. pneumoniae, reflecting household structure and temporal correlation of colonisation status between timepoints.Important risk factors were identified, with men having a lower risk of becoming colonised with ESBL-producing E. coli (OR 0.786 CrI[0.678-0.910]) and the use of a tube well or a borehole as a water drinking source highly increasing the risk of becoming colonised (OR 1.550 CrI[1.003-2.394]). Coming into contact with standing water also appeared to be negatively associated with colonisation status (OR 0.749 CrI[0.574-0.978]). For ESBL-producing K. pneumoniae, having recently taken a course of antibiotics increased the risk of being colonised (OR 1.281 CrI[1.049-1.565]). We also found a negative association between eating from shared plates and colonisation with ESBL-producing K. pneumoniae (OR 0.672 CrI[0.460-0.980]). Finally, we detected a temporal correlation range of eight to eleven weeks, providing evidence that within-household transmission occurs within this time frame.ConclusionsWe suggest that interventions aimed at preventing transmission might have the best impact when targeted at the household-level and focused on a combination of improving WASH infrastructure and modifying associated behaviours. Additionally, we showed that antibiotic use is important when looking at colonisation with ESBL-producing K. pneumoniae and therefore infection prevention and control measures and antibiotic use and stewardship training could help in reducing transmission.

IntroductionSepsis is a leading cause of morbidity and mortality worldwide. In low- to middle-income countries (LMICs) such as Nigeria, the disproportionately high mortality rate is linked to lack of awareness, poor recognition, and late implementation of sepsis care bundles among health workers. Training of health workers using digital platforms may improve knowledge and skills and lead to better patient outcomes.MethodsThis Cross-sectional study involved developing and deploying a sepsis module through an innovative application (FHIND/ARCS Sepsis tutorial app) to doctors in Calabar, Nigeria. We assessed quantitative pre- and post-intervention knowledge scores for those completing the electronic training module on sepsis between both assessments. A user satisfaction survey evaluated the content of the tutorial and the usability of the app.ResultsOne 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 one to 15 years post qualification. Gender and age appeared to have no statistically 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 demonstrated by a statistically significant overall increase in mean scores (25.5% ±14.7, PParticipants were satisfied with the content and multimodal delivery of the material and found the app useable.ConclusionDigital training in sub-Saharan Africa is feasible and can sustainably close the critical knowledge gap required to respond more effectively to medical emergencies such as sepsis in LMIC settings.

Sepsis has been recognised as a global health priority by the United Nations World Health Assembly, which adopted a resolution in 2017 to improve sepsis prevention, diagnosis, and management globally. This study investigated how sepsis is prioritised in Gabon. From May to November 2021, we conducted a qualitative study in healthcare stakeholders at the local, regional, and national levels. Stakeholders included the Ministry of Health (MOH), ethics/regulatory bodies, research institutions, academic institutions, referral hospitals, international funders, and the media. Twenty-three multisectoral stakeholders were interviewed. Respondents indicated that sepsis is not yet prioritised in Gabon due to the lack of evidence of its burden. They also suggest that the researchers should focus on linkages between sepsis and the countries’ existing health sector priorities to accelerate sepsis prioritisation in health policy. Stakeholder awareness and engagement might be accelerated by involving the media in the generation of communication strategies around sepsis awareness and prioritisation. There is a need for local, regional and national evidence to be generated by researchers and taken up by policymakers, focusing on linkages between sepsis and a country’s existing health sector priorities. The MOH should set sepsis reporting structures and develop appropriate sepsis guidelines for identification, management, and prevention.

In sub-Saharan Africa (sSA), there is high morbidity and mortality from severe bacterial infection and this is compounded by antimicrobial resistance, in particular, resistance to 3rd-generation cephalosporins. This resistance is typically mediated by extended-spectrum beta lactamases (ESBLs). To interrupt ESBL transmission it will be important to investigate how human behaviour, water, sanitation, and hygiene (WASH) practices, environmental contamination, and antibiotic usage in both urban and rural settings interact to contribute to transmission of ESBL E. coli and ESBL K. pneumoniae between humans, animals, and the environment. Here we present the protocol for the Drivers of Resistance in Uganda and Malawi (DRUM) Consortium, in which we will collect demographic, geospatial, clinical, animal husbandry and WASH data from a total of 400 households in Uganda and Malawi. Longitudinal human, animal and environmental sampling at each household will be used to isolate ESBL E. coli and ESBL K. pneumoniae. This will be complimented by a Risks, Attitudes, Norms, Abilities and Self-Regulation (RANAS) survey and structured observations to understand the contextual and psychosocial drivers of regional WASH practices. Bacterial isolates and plate sweeps will be further characterised using a mixture of short-,long-read and metagenomic whole-genome sequencing. These datasets will be integrated into agent-based models to describe the transmission of EBSL resistance in Uganda and Malawi and allow us to inform the design of interventions for interrupting transmission of ESBL-bacteria.

Background Clinical scores for sepsis have been primarily developed for, and applied in High-Income Countries. This systematic review and meta-analysis examined the performance of the quick Sequential Organ Failure Assessment (qSOFA), Systemic Inflammatory Response Syndrome (SIRS), Modified Early Warning Score (MEWS), and Universal Vital Assessment (UVA) scores for diagnosis and prediction of mortality in patients with suspected infection in Low-and-Middle-Income Countries. Methods PubMed, Science Direct, Web of Science, and the Cochrane Central Register of Controlled Trials databases were searched until May 18, 2021. Studies reporting the performance of at least one of the above-mentioned scores for predicting mortality in patients of 15 years of age and older with suspected infection or sepsis were eligible. The Quality Assessment of Diagnostic Accuracy Studies tool was used for risk-of-bias assessment. PRISMA guidelines were followed (PROSPERO registration: CRD42020153906). The bivariate random-effects regression model was used to pool the individual sensitivities, specificities and areas-under-the-curve (AUC). Findings Twenty-four articles (of 5669 identified) with 27,237 patients were eligible for inclusion. qSOFA pooled sensitivity was 0·70 (95% confidence interval [CI] 0·60–0·78), specificity 0·73 (95% CI 0·67–0·79), and AUC 0·77 (95% CI 0·72–0·82). SIRS pooled sensitivity, specificity and AUC were 0·88 (95% CI 0·79 -0·93), 0·34 (95% CI 0·25–0·44), and 0·69 (95% CI 0·50–0·83), respectively. MEWS pooled sensitivity, specificity and AUC were 0·70 (95% CI 0·57 -0·81), 0·61 (95% CI 0·42–0·77), and 0·72 (95% CI 0·64–0·77), respectively. UVA pooled sensitivity, specificity and AUC were 0·49 (95% CI 0·33 -0·65), 0·91(95% CI 0·84–0·96), and 0·76 (95% CI 0·44–0·93), respectively. Significant heterogeneity was observed in the pooled analysis. Interpretation Individual score performances ranged from poor to acceptable. Future studies should combine selected or modified elements of different scores. Funding Partially funded by the UK National Institute for Health Research (NIHR) (17/63/42).

Background\ud Sepsis poses a global threat to millions of lives. The Surviving Sepsis Campaign (SSC) guidelines provide evidence-based recommendations on the recognition and management of sepsis and its complications.\ud Methods\ud We formed a panel of 60 experts from 22 countries and 11 members of the public. The panel prioritized questions that are relevant to the recognition and management of sepsis and septic shock in adults. New questions and sections were addressed, relative to the previous guidelines. These questions were grouped under 6 subgroups (screening and early treatment, infection, hemodynamics, ventilation, additional therapies, and long-term outcomes and goals of care). With input from the panel and methodologists, professional medical librarians performed the search strategy tailored to either specific questions or a group of relevant questions. A dedicated systematic review team performed screening and data abstraction when indicated. For each question, the methodologists, with input from panel members, summarized the evidence assessed and graded the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. The panel generated recommendations using the evidence-to-decision framework. Recommendations were either strong or weak, or in the form of best practice statements. When evidence was insufficient to support a recommendation, the panel was surveyed to generate “in our practice” statements.\ud Results\ud The SSC panel issued 93 statements: 15 best practice statements, 15 strong recommendations, and 54 weak recommendations and no recommendation was provided for 9 questions. The recommendations address several important clinical areas related to screening tools, acute resuscitation strategies, management of fluids and vasoactive agents, antimicrobials and diagnostic tests and the use of additional therapies, ventilation management, goals of care, and post sepsis care.\ud Conclusion\ud The SSC panel issued evidence-based recommendations to help support key stakeholders caring for adults with sepsis or septic shock and their families.

Background In 2016, the third international consensus definitions for sepsis and septic shock (Sepsis-3) task force provided revised definitions for sepsis and septic shock. This study explores knowledge regarding sepsis among health workers in Lambaréné, Gabon.\ud \ud Methods\ud We conducted a self-administered questionnaire-based survey about sepsis among health workers from the referral regional hospital, the research center, and primary care health facilities in the Lambaréné region. Participants were from the referral regional hospital, the research center, and primary health care facilities. A score of one was given to each correct answer. The global score out of a possible score of twenty was calculated, and the proportion of correct responses was determined.\ud \ud Results\ud A total of 115 health workers (physicians, nurses and assistant nurses) completed the questionnaire, of which 48.7% (56/115) provided a valid definition of sepsis, but 74% (85/115) had never heard about the quick Sequential Organ Failure Assessment (qSOFA) score. The proportion of correct answers was comparable across the three health profession categories. The median global score across all health workers was 11 [IQR, 9-14.5] out of 20. Physicians attained higher global scores [14 (IQR, 11-15)] than assistant nurses [11 (IQR, 8-13), P=0.007]; their global score was comparable to that of nurses.\ud \ud Conclusion \ud There are considerable knowledge gaps regarding sepsis among health workers in Lambaréné, potentially impairing the prompt recognition and management of sepsis. There is a need to establish periodic up-to-date training to improve sepsis knowledge.

Background Sepsis is the leading cause of global mortality, and it is frequently attributed to lower respiratory tract infections and subsequent acute respiratory distress syndrome (ARDS). Patients from sub-Saharan Africa (sSA) are underrepresented in existing studies of sepsis, and little is known about ARDS in sSA. Severe respiratory distress (SRD) is a surrogate for ARDS defined by the WHO as O2 saturation 30 breaths/minute and a systolic blood pressure >90 mmHg plus suspected infection in the absence of cardiac failure. In the context of the current COVID-19 pandemic, a better understanding of SRD in sSA is urgently needed. In this study, we aimed to determine the prevalence, clinical characteristics, and in-hospital mortality of adults with SRD in sSA. Methods We analyzed pooled individual-level data from 16 studies of hospitalized patients conducted in 6 countries throughout sSA from 2009 to 2019. We used multiple imputation with chained equations with 10 iterations to impute missing data. We performed multivariable logistic regression to estimate associations between patient vital signs, laboratory studies, SRD, and in-hospital mortality. We characterized factors associated with in-hospital mortality in the subset of patients with SRD. Results The pooled data included 7385 patients with a median age of 37 years, of whom 3584 (49%) were women, 2282 (31%) were living with HIV, 3190 (43%) had a known acute infection, and 946 (13%) had SRD. The mortality for the total population and for patients with SRD was 15% and 22%, respectively. Older age, lower temperature, increased heart rate, increased respiratory rate, decreased oxygen saturation, Glasgow Coma Scale score

Background Infections are among the leading causes of maternal mortality and morbidity. The Global Maternal Sepsis and Neonatal Initiative, launched in 2016 by WHO and partners, sought to reduce the burden of maternal infections and sepsis and was the basis upon which the Global Maternal Sepsis Study (GLOSS) was implemented in 2017. In this Article, we aimed to describe the availability of facility resources and services and to analyse their association with maternal outcomes. Methods GLOSS was a facility-based, prospective, 1-week inception cohort study implemented in 713 health-care facilities in 52 countries and included 2850 hospitalised pregnant or recently pregnant women with suspected or confirmed infections. All women admitted for or in hospital with suspected or confirmed infections during pregnancy, childbirth, post partum, or post abortion at any of the participating facilities between Nov 28 and Dec 4 were eligible for inclusion. In this study, we included all GLOSS participating facilities that collected facility-level data (446 of 713 facilities). We used data obtained from individual forms completed for each enrolled woman and their newborn babies by trained researchers who checked the medical records and from facility forms completed by hospital administrators for each participating facility. We described facilities according to country income level, compliance with providing core clinical interventions and services according to women's needs and reported availability, and severity of infection-related maternal outcomes. We used a logistic multilevel mixed model for assessing the association between facility characteristics and infection-related maternal outcomes. Findings We included 446 facilities from 46 countries that enrolled 2560 women. We found a high availability of most services and resources needed for obstetric care and infection prevention. We found increased odds for severe maternal outcomes among women enrolled during the post-partum or post-abortion period from facilities located in low-income countries (adjusted odds ratio 1middot84 [95% CI 1middot05-3middot22]) and among women enrolled during pregnancy or childbirth from non-urban facilities (adjusted odds ratio 2middot44 [1middot02-5middot85]). Despite compliance being high overall, it was low with regards to measuring respiratory rate (85 [24%] of 355 facilities) and measuring pulse oximetry (184 [57%] of 325 facilities). Interpretation While health-care facilities caring for pregnant and recently pregnant women with suspected or confirmed infections have access to a wide range of resources and interventions, worse maternal outcomes are seen among recently pregnant women located in low-income countries than among those in higher-income countries; this trend is similar for pregnant women. Compliance with cost-effective clinical practices and timely care of women with particular individual characteristics can potentially improve infection-related maternal outcomes. Funding UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, WHO, Merck for Mothers, and US Agency for International Development. Copyright (c) 2021 World Health Organization; licensee Elsevier. This is an Open Access article under the CC BY 3.0 IGO license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products, or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.

We propose platform trials with outcome-adaptive randomization to efficiently select the most effective coronavirus disease 2019 (COVID-19) treatments. The global spread of severe acute respiratory syndrome coronavirus 2 infection is alarming in its geographic scope and in the number of associated deaths. There are currently no treatments proven to decrease mortality from COVID-19 further than what can be achieved through supportive care. Thus far, the choice of therapeutics has been limited to existing, repurposed medications. Given that some of the medications are perceived to have low toxicity, many have been embraced without evidence. Although remdesivir was recently found to shorten time to symptom resolution, evidence for survival benefit is inconclusive

Background The public health impact of Chikungunya virus (CHIKV) is often underestimated. Usually considered a mild condition of short duration, recent outbreaks have reported greater incidence of severe illness, fatality, and longer-term disability. In 2018/19, Eastern Sudan experienced the largest epidemic of CHIKV in Africa to date, affecting an estimated 487,600 people. Known locally as Kankasha, this study examines clinical characteristics, risk factors, and phylogenetics of the epidemic in Kassala City. Methodology/Principal findings A prospective cohort of 102 adults and 40 children presenting with chikungunya-like illness were enrolled at Kassala Teaching Hospital in October 2018. Clinical information, socio-demographic data, and sera samples were analysed to confirm diagnosis, characterise illness, and identify viral strain. CHIKV infection was confirmed by real-time reverse transcription-PCR in 84.5% (120/142) of participants. Nine (7.5%) CHIKV-positive participants had concurrent Dengue virus (DENV) infection; 34/118 participants (28.8%) had a positive Rapid Diagnostic Test for Plasmodium falciparum; six (5.0%) had haemorrhagic symptoms including two children with life-threatening bleeding. One CHIKV-positive participant died with acute renal injury. Age was not associated with severity of illness although CHIKV-infected participants were younger (p = 0.003). Two to four months post-illness, 63% of adults available for follow-up (30) were still experiencing arthralgia in one or more joints, and 11% remained moderately disabled on Rapid3 assessment. Phylogenetic analysis showed all CHIKV sequences from this study belonged to a single clade within the Indian Ocean Lineage (IOL) of the East/Central/South African (ECSA) genotype. History of contact with an infected person was the only factor associated with infection (p = 0.01), and likely related to being in the same vector environment. Conclusions/Significance Vulnerability to CHIKV remains in Kassala and elsewhere in Sudan due to widespread Aedes aegypti presence and mosquito-fostering household water storage methods. This study highlights the importance of increasing awareness of the severity and impact of CHIKV outbreaks, and the need for urgent actions to reduce transmission risk in households., Author summary Chikungunya is an arboviral disease transmitted to humans by infected mosquitoes and characterised by fever and arthralgia. Although it is generally considered a short self-limiting infection, long term sequelae and severe disease are increasingly recognised. In 2018/19, Eastern Sudan experienced the largest epidemic of Chikungunya in Africa to date, affecting approximately 500,000 people. We undertook a prospective hospital-based cohort study of patients presenting with undifferentiated febrile illness in Kassala city, Sudan, supported by next-generation sequencing. We confirmed that CHIKV was the dominant pathogen, with positive CHIKV RT-PCR in 85% of patients presenting during the 7-day study period. Dengue virus was also circulating with nine CHIKV RT-PCR-positive patients co-infected, and we identified high rates of Plasmodium falciparum infection and CHIKV/P.falciparum co-infection. Genetic sequencing confirmed Indian Ocean Lineage of the East/Central/South African CHIKV genotype. A quarter of participants available for follow-up (16/60, 26.6%) reported being admitted to hospital including two children with haemorrhage, reflecting the severe phenotype linked to this genotype. Increased understanding of the health and economic burden of Chikungunya is needed, and recognition that severe and occasionally fatal infection exists. With widespread presence of Ae. aegypti and household water storage practices that encourage mosquito breeding, timely actions will be essential to prevent further large outbreaks.

ObjectiveTo evaluate changes in awareness of maternal sepsis among healthcare providers resulting from the WHO Global Maternal Sepsis Study (GLOSS) awareness campaign.DesignIndependent sample precampaign/postcampaign through online and paper-based surveys available for over 30 days before campaign roll-out (pre) and after study data collection (post). Descriptive statistics were used for campaign recognition and exposure, and odds ratio (OR) and percentage change were calculated for differences in awareness, adjusting for confounders using multivariate logistic regression.Setting and participantsHealthcare providers from 398 participating facilities in 46 low, middle and high-income countries.InterventionAn awareness campaign to accompany GLOSS launched 3 weeks prior to data collection and lasting the entire study period (28 November 2017 to 15 January 2018) and beyond.Main outcome measuresCampaign recognition and exposure, and changes in awareness.ResultsA total of 2188 surveys were analysed: 1155 at baseline and 1033 at postcampaign. Most survey respondents found the campaign materials helpful (94%), that they helped increase awareness (90%) and that they helped motivate to act differently (88%). There were significant changes with regard to: not having heard of maternal sepsis (−63.4% change, pre-OR/post-OR 0.35, 95% CI 0.18 to 0.68) and perception of confidence in making the right decisions with regard to maternal sepsis identification and management (7.3% change, pre-OR/post-OR 1.44, 95% CI 1.01 to 2.06).ConclusionsAwareness raising campaigns can contribute to an increase in having heard of maternal sepsis and an increase in provider perception of confidence in making correct decisions. Offering the information to make accurate and timely decisions while promoting environments that enable self-confidence and support could improve maternal sepsis identification and management.

Background Sepsis guidelines are widely used in high-income countries and intravenous fluids are an important supportive treatment modality. However, fluids have been harmful in intervention trials in low-income countries, most notably in sub-Saharan Africa. We assessed the relevance, quality and applicability of available guidelines for the fluid management of adult patients with sepsis in this region. Methods We identified sepsis guidelines by systematic review with broad search terms, duplicate screening and data extraction. We included peer-reviewed publications with explicit relevance to sepsis and fluid therapy. We excluded those designed exclusively for specific aetiologies of sepsis, for limited geographic locations, or for non-adult populations. We used the AGREE II tool to assess the quality of guideline development, performed a narrative synthesis and used theoretical case scenarios to assess practical applicability to everyday clinical practice in resource-constrained settings. Results Published sepsis guidelines are heterogeneous in sepsis definition and in quality: 8/10 guidelines had significant deficits in applicability, particularly with reference to resource considerations in low-income settings. Indications for intravenous fluid were hypotension (8/10), clinical markers of hypoperfusion (6/10) and lactataemia (3/10). Crystalloids were overwhelmingly recommended (9/10). Suggested volumes varied; 5/10 explicitly recommended “fluid challenges” with reassessment, totalling between 1 L and 4 L during initial resuscitation. Fluid balance, including later de-escalation of therapy, was not specifically described in any. Norepinephrine was the preferred initial vasopressor (5/10), specifically targeted to MAP > 65 mmHg (3/10), with higher values suggested in pre-existing hypertension (1/10). Recommendations for guidelines were almost universally derived from evidence in high-income countries. None of the guidelines suggested any refinement for patients with malnutrition. Conclusions Widely used international guidelines contain disparate recommendations on intravenous fluid use, lack specificity and are largely unattainable in low-income countries given available resources. A relative lack of high-quality evidence from sub-Saharan Africa increases reliance on recommendations which may not be relevant or implementable.

Background The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI. Methods We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022. Findings We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per μL (the median for the cohort) was 45% (95% CI 38–52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63–87), increasing to 89% (80–94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05–3·08) but not after 30 days (1·25, 0·84–2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16–8·84). Interpretation In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients. Funding This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A .

Ebola virus disease (EVD) is a severe and frequently lethal disease caused by Ebola virus (EBOV). EVD outbreaks typically start from a single case of probable zoonotic transmission, followed by human-to-human transmission via direct contact or contact with infected bodily fluids or contaminated fomites. EVD has a high case–fatality rate; it is characterized by fever, gastrointestinal signs and multiple organ dysfunction syndrome. Diagnosis requires a combination of case definition and laboratory tests, typically real-time reverse transcription PCR to detect viral RNA or rapid diagnostic tests based on immunoassays to detect EBOV antigens. Recent advances in medical countermeasure research resulted in the recent approval of an EBOV-targeted vaccine by European and US regulatory agencies. The results of a randomized clinical trial of investigational therapeutics for EVD demonstrated survival benefits from two monoclonal antibody products targeting the EBOV membrane glycoprotein. New observations emerging from the unprecedented 2013–2016 Western African EVD outbreak (the largest in history) and the ongoing EVD outbreak in the Democratic Republic of the Congo have substantially improved the understanding of EVD and viral persistence in survivors of EVD, resulting in new strategies toward prevention of infection and optimization of clinical management, acute illness outcomes and attendance to the clinical care needs of patients., Ebola virus disease (EVD) is caused by the filovirus Ebola virus (EBOV). Although the natural host of EBOV is undefined, a single zoonotic transmission is the probable start of most EVD outbreaks. EVD is characterized by gastrointestinal manifestations and multiple organ dysfunction syndrome and has a high case–fatality rate.

Shifting the Paradigm As the treatment paradigm for patients with Ebola virus disease shifts from isolation to aggressive supportive care and antiviral therapy, the global health community can work...

IntroductionThe burden of childhood mortality continues to be born largely by low-income and middle-income countries. The critical postdischarge period has been largely neglected despite evidence that mortality rates during this period can exceed inpatient mortality rates. However, there is a paucity of data on the paediatric discharge process from the perspective of the healthcare provider. Provider perspectives may be important in the development of an improved understanding of the barriers and facilitators to improving the transition from hospital to home.ObjectivesTo explore healthcare providers’ and facility administrators’ perspectives of the paediatric discharge process with respect to: (1) current procedures, (2) barriers and challenges, (3) ideas for change, (4) facilitators for change and (5) the importance of discharge planning.DesignA qualitative exploratory approach using focus groups (14) and in-depth interviews (7).SettingThis study was conducted at seven hospitals providing paediatric care in Uganda.ResultsCurrent discharge procedures are largely based on hospital-specific protocols or clinician opinion, as opposed to national guidelines. Some key barriers to an improved discharge process included caregiver resources and education, critical communication gaps, traditional practices, and a lack of human and physical resources. Teamwork and motivation to see improved paediatric transitions to home were identified as facilitators to implementing the ideas for change proposed by participants. The need for a standardised national policy guiding paediatric discharges, implemented through education at many levels and coupled with appropriate community referral and follow-up, was broadly perceived as essential to improving outcomes for children.ConclusionsAlthough significant challenges and gaps were identified within the current health system, participants’ ideas and the identified facilitators provide a significant basis from which change may occur. This work can facilitate the development of sustainable and effective interventions to improve postdischarge outcomes in Uganda and other similar settings.

Disease processes that frequently require emergency care constitute approximately 50% of the total disease burden in low-income and middle-income countries (LMICs). Many LMICs continue to deal with emergencies caused by communicable disease states such as pneumonia, diarrhoea, malaria and meningitis, while also experiencing a marked increase in non-communicable diseases, such as cardiovascular diseases, diabetes mellitus and trauma. For many of these states, emergency care interventions have been developed through research in high-income countries (HICs) and advances in care have been achieved. However, in LMICs, clinical research, especially interventional trials, in emergency care are rare. Furthermore, there exists minimal research on the emergency management of diseases, which are rarely encountered in HICs but impact the majority of LMIC populations. This paper explores challenges in conducting clinical research in patients with emergency conditions in LMICs, identifies examples of successful clinical research and highlights the system, individual and study design characteristics that made such research possible in LMICs. Derived from the available literature, a focused list of high impact research considerations are put forth.

BACKGROUND Sepsis is a complex clinical syndrome with substantial heterogeneity. We sought to identify patterns of serum biomarkers of endothelial activation and dysfunction in individuals with sepsis and evaluate subgroup-specific differences in mortality. METHODS Adult patients with sepsis (n=426) were consecutively recruited from two hospitals in Uganda. Clinical information was collected and serum concentrations of eleven biomarkers involved in the endothelial response to infection were measured in samples from 315 patients. Latent variable models were fit to evaluate whether the endothelial response to sepsis consists of one unified biological process or multiple processes and to identify subgroups of patients with distinct host-response profiles. Differences in survival at day 28 were evaluated using Kaplan-Meier survival curves. RESULTS We identified three patient subgroups characterized by unique host endothelial response profiles. Patients fitting Profile 2 had significantly worse survival (log-rank p

BACKGROUND: Intravenous fluid (IVF) is a frequently recommended intervention in Ebola virus disease (EVD), yet its impact on patient outcomes remains unclear. METHODS: This retrospective cohort study evaluated patients with EVD admitted to 5 Ebola treatment units (ETUs) in West Africa. The primary outcome was the difference in 28-day survival between cases treated and not treated with IVF. To control for demographic and clinical factors related to both IVF exposure and survival, cases were compared using propensity score matching. To control for time-varying patient and treatment factors over the course of ETU care, a marginal structural proportional hazards model (MSPHM) with inverse probability weighting was used to assess for 28-day survival differences. RESULTS: Among 424 EVD-positive cases with data for analysis, 354 (83.5%) were treated with IVF at some point during their ETU admission. Overall, 146 (41.3%) cases treated with IVF survived, whereas 31 (44.9%) cases not treated with any IVF survived (P = .583). Matched propensity score analysis found no significant difference in 28-day survival between cases treated and not treated with IVF during their first 24 and 48 hours of care. Adjusted MSPHM survival analyses also found no significant difference in 28-day survival for cases treated with IVF (27.3%) compared to those not treated with IVF (26.9%) during their entire ETU admission (P = .893). CONCLUSIONS: After adjustment for patient- and treatment-specific time-varying factors, there was no significant difference in survival among patients with EVD treated with IVF as compared to those not treated with IVF.

Sepsis is a major reason for intensive care unit (ICU) admission, also in resource–poor settings. ICUs in low– and middle–income countries (LMICs) face many challenges that could affect patient outcome. The aim of this review is to describe differences between resource–poor and resource–rich settings regarding the epidemiology, pathophysiology, economics and research aspects of sepsis. We restricted this manuscript to the ICU setting even knowing that many sepsis patients in LMICs are treated outside an ICU. Although many bacterial pathogens causing sepsis in LMICs are similar to those in high–income countries, resistance patterns to antimicrobial drugs can be very different; in addition, causes of sepsis in LMICs often include tropical diseases in which direct damaging effects of pathogens and their products can sometimes be more important than the response of the host. There are substantial and persisting differences in ICU capacities around the world; not surprisingly the lowest capacities are found in LMICs, but with important heterogeneity within individual LMICs. Although many aspects of sepsis management developed in rich countries are applicable in LMICs, implementation requires strong consideration of cost implications and the important differences in resources. Addressing both disease–specific and setting–specific factors is important to improve performance of ICUs in LMICs. Although critical care for severe sepsis is likely cost–effective in LMIC setting, more detailed evaluation at both at a macro– and micro–economy level is necessary. Sepsis management in resource–limited settings is a largely unexplored frontier with important opportunities for research, training, and other initiatives for improvement.

In this chapter, we provide guidance on some basic structural requirements, focusing on organization, staffing, and infrastructure. We suggest a closed-format intensive care unit (ICU) with dedicated physicians and nurses, specifically trained in intensive care medicine whenever feasible. Regarding infrastructural components, a reliable electricity supply is essential, with adequate backup systems. Facilities for oxygen therapy are crucial, and the choice between oxygen concentrators, cylinders, and a centralized system depends on the setting. For use in mechanical ventilators, a centralized piped system is preferred. Facilities for proper hand hygiene are essential. Alcohol-based solutions are preferred, except in the context of Ebola virus disease (chloride-based solutions) and Clostridium difficile infection (soap and water). Availability of disposable gloves is important for self-protection; for invasive procedures masks, caps, sterile gowns, sterile drapes, and sterile gloves are recommended. Caring for patients with highly contagious infectious diseases requires access to personal protective equipment. Basic ICU equipment should include vital signs monitors and mechanical ventilators, which should also deliver noninvasive ventilator modes. We suggest that ICUs providing invasive ventilatory support have the ability to measure end-tidal carbon dioxide and if possible can perform blood gas analysis. We recommend availability of glucometers and capabilities for measuring blood lactate. We suggest implementation of bedside ultrasound as diagnostic tool. Finally, we recommend proper administration of patient data; suggest development of locally applicable bundles, protocols, and checklists for the management of sepsis; and implement systematic collection of quality and performance indicators to guide improvements in ICU performance.

Background: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis blood stream infection (MTB-BSI) is incompletely understood. We hypothesised that MTB-BSI prevalence has been underestimated, that MTB-BSI independently predicts death, and sputum Xpert has suboptimal diagnostic yield for MTB-BSI. Methods: We conducted a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood-culture (TBBC), including HIV-positive adults aged ≥13-years with suspected tuberculosis. Predicted probabilities of MTB-BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum (Xpert or culture if Xpert unavailable) and urinelipoarabinomannan for MTB-BSI were obtained by two-level random-effect meta-analysis, mortality hazard of MTB-BSI by mixed-effect Cox proportional-hazard modelling, and effect of treatment delay with propensity-score analysis. Findings 5751 patients met inclusion criteria. Predicted probability of MTB-BSI was 45% (95%CI 38-52%) for danger-sign positive tuberculosis inpatients with cohort median CD4 count of 76 cells/μL. Diagnostic yield of sputum was 77% (95%CI 63–87%), rising to 89% (95%CI 80-94%) when combined with urinelipoarabinomannan testing. MTB-BSI increased hazard of death before 30-days (aHR2·5, 95%CI 2·1–3·1). In a propensity-score matched cohort (n=630), mortality increased with treatment delay >4 days in MTB-BSI (OR 3·2, 95%CI 1·1–10·3). Interpretation: In critically-ill adults with HIV-tuberculosis, MTB-BSI is a very frequent manifestation of tuberculosis and strongly predicts mortality. Better diagnostic yield in patients with MTB-BSI can be achieved by parallel use of sputum-Xpert and urine-LAM. Treatment delay may increase mortality hazard. Funding Statement: This study was supported by Wellcome fellowships 109105z/15/a, 105165/Z14/A. Charlotte Schutz was funded by the South African Medical Research Council under the National Health Scholars Programme. Moshi, Tanzania research was supported by an International Studies on AIDS Associated Co-infections (ISAAC) award, a program funded by the US National Institutes of Health (NIH) (U01 AI062563). John A. Crump receives support from US NIH R01AI121378. Elizabeth L. Corbett is supported by a Wellcome trust senior fellowship in clinical science (WT200901). Gary Maartens was supported in part by National Research Fund incentive funding (UID: 85810). Susan E. Dorman was supported by contract #HHSN2722000900050C and grant K24AI104830 (to SED), both from the US National Institutes of Health. Douglas Wilson was supported by BMS Secure the Future. Graeme Meintjes was supported by the Wellcome Trust (098316 and 203135/Z/16/Z), the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787), NRF incentive funding (UID: 85858) and the South African Medical Research Council through its TB and HIV Collaborating Centres Programme with funds received from the National Department of Health (RFA# SAMRC-RFA-CC: TB/HIV/AIDS-01-2014). Declaration of Interests: David Alland is on the Scientific Advisory Board of Specific Technologies and receives a portion of the licensing income paid by Cepheid to Rutgers University for sales of the Xpert Ultra assay. Neil Martinson has received institutional grants for collection of specimens for Roche and Becton Dickinson, and from Pfizer for assessing incident pneumonia. All other authors declare no competing interests. Ethics Approval Statement: PROSPERO registration: CRD42016050022.

Background.Kenema Government Hospital (KGH) has developed an advanced clinical and laboratory research capacity to manage the threat of Lassa fever, a viral hemorrhagic fever (VHF). The 2013–2016 Ebola virus (EBOV) disease (EVD) outbreak is the first to have occurred in an area close to a facility with established clinical and laboratory capacity for study of VHFs. Methods.Because of its proximity to the epicenter of the EVD outbreak, which began in Guinea in March 2014, the KGH Lassa fever Team mobilized to establish EBOV surveillance and diagnostic capabilities. Results.Augustine Goba, director of the KGH Lassa laboratory, diagnosed the first documented case of EVD in Sierra Leone, on 25 May 2014. Thereafter, KGH received and cared for numbers of patients with EVD that quickly overwhelmed the capacity for safe management. Numerous healthcare workers contracted and lost their lives to EVD. The vast majority of subsequent EVD cases in West Africa can be traced back to a single transmission chain that includes this first diagnosed case. Conclusions.Responding to the challenges of confronting 2 hemorrhagic fever viruses will require continued investments in the development of countermeasures (vaccines, therapeutic agents, and diagnostic assays), infrastructure, and human resources.

BACKGROUND: Knowledge of causes of sepsis in sub-Saharan Africa is limited. A better understanding of the microbiology of bloodstream infections could improve outcomes. METHODS: We used a quantitative polymerase chain reaction (qPCR)-based TaqMan Array Card (TAC) to directly test for 43 targets from whole blood. We analyzed 336 cryopreserved specimens from adult Ugandans with sepsis enrolled in a multisite study; 84% were infected with human immunodeficiency virus. We compared qPCR TAC results with blood culture and determined the association of qPCR with study participant outcomes using logistic regression. RESULTS: The most frequently detected targets were cytomegalovirus (CMV, n = 139, 41%), Mycobacterium tuberculosis (TB, n = 70, 21%), Plasmodium (n = 35, 10%), and Streptococcus pneumoniae (n = 31, 9%). Diagnostic performance varied by target with qPCR sensitivity averaging 61 ± 28% and specificity 98 ± 3% versus culture. In multivariable analysis, independent factors associated with in-hospital mortality included CMV viremia (adjusted odds ratio [aOR] 3.2, 95% confidence interval [CI], 1.8–5.5; p < .01) and TB qPCR-positivity, whether blood culture-positive (aOR 4.6, 95% CI, 2.1–10.0; p < .01) or blood culture-negative (aOR 2.9, 95% CI, 1.2–6.9; p = .02). CONCLUSIONS: Using qPCR TAC on direct blood specimens, CMV and TB were the most commonly identified targets and were independently associated with increased in-hospital mortality. qPCR TAC screening of blood for multiple targets may be useful to guide triage and treatment of sepsis in sub-Saharan Africa.

Dear Editor, Sepsis is a global challenge affecting more than 19.5 million people each year [1]. Broad challenges in Low- and Middle-Income Countries relate to the wide-ranging paucity of evidence from epidemiology, through clinical management at the healthcare facility and rehabilitation, to implementation of prevention and treatment at the health system level. The Global Sepsis Alliance (GSA) has long advocated for high-quality evidence and patient management [2]. Following the World Health Assembly global resolution on sepsis in May 2017, the formation of the African Sepsis Alliance (ASA) marks a commitment from clinicians and researchers to drive this agenda in Africa, which disproportionately suffers the burden of infection-related mortality [3]. Action is essential to achieve universal health coverage, address antimicrobial resistance, and meet the sustainable development goals. Emerging from the inaugural meeting of the African Federation of Critical Care Nurses (AFCCN) meeting in October 2017, the "Kampala declaration" was co-drafted by the ASA, along with the AFCNN, GSA, and World Federation of Critical Care Nurses, as a clarion call for African-led global advocacy for sepsis and other severe illness in Africa [4]. With over 2,500 signatories representing over 100 countries, the declaration demonstrates the multidisciplinary and wide-ranging response we hope to invoke at the patient, health facility, societal, and governmental level.

Setting: Four in-patient health facilities in western Uganda. Objective: To determine the impact of an innovative multi-modal quality improvement program on human immunodeficiency virus (HIV) status assessment and the impact of HIV status on severe illness conditions and mortality. Design: This was a staggered, pre-post quasi-experimental study designed to assess a multi-modal intervention (collaborative improvement meetings, audit and feedback, clinical mentoring) for improving quality of care following formal training in the management of severe illness in low-income settings. Results: From August 2014 to May 2015, 5759 patients were hospitalized, of whom 2451 (42.6%) had their HIV status assessed; 395 (16.1%) were HIV-infected. HIV-infected patients were significantly more likely to meet criteria for shock (27.5% vs. 15.1%, risk ratio [RR] 1.8, 95% confidence interval [CI] 1.7-1.9, P < 0.001) and severe respiratory distress (6.7% vs. 4.3%, RR 1.5, 95%CI 1.2-2.0, P < 0.001), and were significantly more likely to die in hospital (12.0% vs. 2.9%, RR 4.1, 95%CI 3.2-5.4, P < 0.001). There was no evidence of improved HIV status assessment during the intervention period (36.5% vs. 44.8%, +8.3%, 95%CI -8.3 to 24.8, P = 0.33). Conclusions: Hospitalized HIV-infected patients in western Uganda are at high risk for severe illness and death. Novel quality improvement strategies are needed to enhance hospital-based HIV testing in high-burden settings.