Sepsis In sub-Saharan Africa Research Articles

Unsupervised Classification of the Host Response Identifies Dominant Pathobiological Signatures of Sepsis in Sub-Saharan Africa.

The global burden of sepsis is concentrated in sub-Saharan Africa, where inciting pathogens are diverse and HIV co-infection is a major driver of poor outcomes. Biological heterogeneity inherent to sepsis in this setting is poorly defined. To identify dominant pathobiological signatures of sepsis in sub-Saharan Africa and their relationship to clinical phenotypes, patient outcomes, and biological classifications of sepsis identified in high-income-countries (HICs). We analyzed two prospective cohorts of adults hospitalized with sepsis (severe infection with qSOFA score≥1) at disparate settings in Uganda (discovery cohort [Entebbe,urban], N=242; validation cohort [Tororo,rural], N=253). To identify pathobiological signatures in the discovery cohort, we applied unsupervised clustering to 173 soluble proteins reflecting key domains of the host response to severe infection. A random forest-derived classifier was used to predict signature assignment in the validation cohort. Two signatures (Uganda Sepsis Signature [USS]-1 and USS-2) were identified in the discovery cohort, distinguished by expression of proteins involved in myeloid cell and inflammasome activation, T cell co-stimulation and exhaustion, and endothelial barrier dysfunction. A five-protein classifier (AUROC 0.97) reproduced two signatures in the validation cohort with similar biological profiles. In both cohorts, USS-2 mapped to a more severe clinical phenotype associated with HIV and related immunosuppression, severe tuberculosis, and increased risk of 30-day mortality. Substantial biological overlap was observed between USS-2 and hyperinflammatory and reactive sepsis phenotypes identified in HICs. We identified prognostically-enriched pathobiological signatures among sepsis patients with diverse infections and high HIV prevalence in Uganda. Globally inclusive investigations are needed to define generalizable and context-specific mechanisms of sepsis pathobiology, with the goal of improving access to precision medicine treatment strategies.

HETEROGENEOUS EXPANSION OF POLYMORPHONUCLEAR MYELOID-DERIVED SUPPRESSOR CELLS DISTINGUISHES HIGH-RISK SEPSIS IMMUNOPHENOTYPES IN UGANDA.

Background: Understanding of immune cell phenotypes associated with inflammatory and immunosuppressive host responses in sepsis is imprecise, particularly in low- and middle-income countries, where the global sepsis burden is concentrated. In these settings, elucidation of clinically relevant immunophenotypes is necessary to determine the relevance of emerging therapeutics and refine mechanistic investigations of sepsis immunopathology. Methods: In a prospective cohort of adults hospitalized with suspected sepsis in Uganda (N = 43; median age 46 years [IQR 36-59], 24 [55.8%] living with HIV, 16 [37.2%] deceased at 60 days), we combined high-dimensional flow cytometry with unsupervised machine learning and manual gating to define peripheral immunophenotypes associated with increased risk of 60-day mortality. Results: Patients who died showed heterogeneous expansion of polymorphonuclear myeloid-derived suppressor cells, with increased and decreased abundance of CD16 - PD-L1 dim and CD16 bright PD-L1 bright subsets, respectively, significantly associated with mortality. While differences between CD16 - PD-L1 dim cell abundance and mortality risk appeared consistent throughout the course of illness, those for the CD16 bright PD-L1 bright subset were more pronounced early after illness onset. Independent of HIV co-infection, depletion of CD4 + T cells, dendritic cells, and CD56 - CD16 bright NK cells were significantly associated with mortality risk, as was expansion of immature, CD56 + CD16 - CD11c + NK cells. Abundance of T cells expressing inhibitory checkpoint proteins (PD-1, CTLA-4, LAG-3) was similar between patients who died versus those who survived. Conclusions: This is the first study to define high-risk immunophenotypes among adults with sepsis in sub-Saharan Africa, an immunologically distinct region where biologically informed treatment strategies are needed. More broadly, our findings highlight the clinical importance and complexity of myeloid derived suppressor cell expansion during sepsis and support emerging data that suggest a host-protective role for PD-L1 myeloid checkpoints in acute critical illness.

Prevalence and factors associated with maternal and neonatal sepsis in sub-Saharan Africa: a systematic review and meta-analysis.

This study aimed to determine the prevalence and factors associated with maternal and neonatal sepsis in sub-Saharan Africa. This systematic review and meta-analysis used the PRISMA guideline on sepsis data in sub-Saharan Africa. The bibliographic search was carried out on the following databases: Medline/PubMed, Cochrane Library, African Index Medicus, and Google Scholar. Additionally, the reference lists of the included studies were screened for potentially relevant studies. The last search was conducted on 15 October 2022. The Joanna Briggs Institute quality assessment checklist was applied for critical appraisal. Estimates of the prevalence of maternal and neonatal sepsis were pooled using a random-effects meta-analysis model. Heterogeneity between studies was estimated using the Q statistic and the I2 statistic. The funnel plot and Egger's regression test were used to assess the publication bias. A total of 39 studies were included in our review: 32 studies on neonatal sepsis and 7 studies on maternal sepsis. The overall pooled prevalence of maternal and neonatal sepsis in Sub-Saharan Africa was 19.21% (95% CI, 11.46-26.97) and 36.02% (CI: 26.68-45.36), respectively. The meta-analyses revealed that Apgar score < 7 (OR: 2.4, 95% CI: 1.6-3.5), meconium in the amniotic fluid (OR: 2.9, 95% CI: 1.8-4.5), prolonged rupture of membranes >12 h (OR: 2.8, 95% CI: 1.9-4.1), male sex (OR: 1.2, 95% CI: 1.1-1.4), intrapartum fever (OR: 2.4, 95% CI: 1.5-3.7), and history of urinary tract infection in the mother (OR: 2.7, 95% CI: 1.4-5.2) are factors associated with neonatal sepsis. Rural residence (OR: 2.3, 95% CI: 1.01-10.9), parity (OR: 0.5, 95% CI: 0.3-0.7), prolonged labor (OR: 3.4, 95% CI: 1.6-6.9), and multiple digital vaginal examinations (OR: 4.4, 95% CI: 1.3-14.3) were significantly associated with maternal sepsis. The prevalence of maternal and neonatal sepsis was high in sub-Saharan Africa. Multiple factors associated with neonatal and maternal sepsis were identified. These factors could help in the prevention and development of strategies to combat maternal and neonatal sepsis. Given the high risk of bias and high heterogeneity, further high-quality research is needed in the sub-Saharan African context, including a meta-analysis of individual data.Systematic review registration: PROSPERO (ID: CRD42022382050).

Development of a Novel Clinicomolecular Risk Index to Enhance Mortality Prediction and Immunological Stratification of Adults Hospitalized with Sepsis in Sub-Saharan Africa: A Pilot Study from Uganda.

The global burden of sepsis is concentrated in sub-Saharan Africa (SSA), where epidemic HIV and unique pathogen diversity challenge the effective management of severe infections. In this context, patient stratification based on biomarkers of a dysregulated host response may identify subgroups more likely to respond to targeted immunomodulatory therapeutics. In a prospective cohort of adults hospitalized with suspected sepsis in Uganda, we applied machine learning methods to develop a prediction model for 30-day mortality that integrates physiology-based risk scores with soluble biomarkers reflective of key domains of sepsis immunopathology. After model evaluation and internal validation, whole-blood RNA sequencing data were analyzed to compare biological pathway enrichment and inferred immune cell profiles between patients assigned differential model-based risks of mortality. Of 260 eligible adults (median age, 32 years; interquartile range, 26-43 years; 59.2% female, 53.9% living with HIV), 62 (23.8%) died by 30 days after hospital discharge. Among 14 biomarkers, soluble tumor necrosis factor receptor 1 (sTNFR1) and angiopoietin 2 (Ang-2) demonstrated the greatest importance for mortality prediction in machine learning models. A clinicomolecular model integrating sTNFR1 and Ang-2 with the Universal Vital Assessment (UVA) risk score optimized 30-day mortality prediction across multiple performance metrics. Patients assigned to the high-risk, UVA-based clinicomolecular subgroup exhibited a transcriptional profile defined by proinflammatory innate immune and necroptotic pathway activation, T-cell exhaustion, and expansion of key immune cell subsets including regulatory and gamma-delta T cells. Clinicomolecular stratification of adults with suspected sepsis in Uganda enhanced 30-day mortality prediction and identified a high-risk subgroup with a therapeutically targetable immunological profile. Further studies are needed to advance pathobiologically informed sepsis management in SSA.

Prospective multicentre study of host response signatures in neonatal sepsis in Sub Saharan Africa

Few biomarkers for sepsis diagnosis are commonly used in neonatal sepsis. While the role of host response is increasingly recognized in sepsis pathogenesis and prognosis, there is a need for evaluating new biomarkers targeting host response in regions where sepsis burden is high and medico-economic resources are scarce. The objective of the study is to evaluate diagnostic and prognostic accuracy of biomarkers of neonatal sepsis in Sub Saharan Africa. This prospective multicentre study included newborn infants delivered in the Abomey-Calavi region in South Benin and their follow-up from birth to 3 months of age. Accuracy of transcriptional (CD74, CX3CR1), proteic (PCT, IL-6, IL-10, IP-10) biomarkers and clinical characteristics to diagnose and prognose neonatal sepsis were measured. At delivery, cord blood from all consecutive newborns were sampled and analysed, and infants were followed for a 12 weeks’ period. Five hundred and eighty-one newborns were enrolled. One hundred and seventy-two newborns developed neonatal sepsis (29.6%) and death occurred in forty-nine infants (8.4%). Although PCT, IL-6 and IP-10 levels were independently associated with sepsis diagnosis, diagnostic accuracy of clinical variables combinations was similar to combinations with biomarkers and superior to biomarkers alone. Nonetheless, CD74, being the only biomarkers independently associated with mortality, showed elevated prognosis accuracy (AUC > 0.9) either alone or in combination with other biomarkers (eg. CD74/IP-10) or clinical criterion (eg. Apgar 1, birth weight). These results suggest that cord blood PCT had a low accuracy for diagnosing early onset neonatal sepsis in Sub Saharan African neonates, while association of clinical criterion showed to be more accurate than any biomarkers taken independently. At birth, CD74, either associated with IP-10 or clinical criterion, had the best accuracy in prognosing sepsis mortality.Trial registration Clinicaltrial.gov registration number: NCT03780712. Registered 19 December 2018. Retrospectively registered.

Risk factors for neonatal sepsis in Sub-Saharan Africa: a systematic review with meta-analysis

ObjectivesTo identify the risk factors for neonatal sepsis in Sub-Saharan Africa.DesignSystematic review and meta-analysis.Data sourcesPubMed, Embase, Web of Science, African Index Medicus and ClinicalTrials.gov were searched for observational studies from...

Early empiric anti-Mycobacterium tuberculosis therapy for sepsis in sub-Saharan Africa: a protocol of a randomised clinical trial

IntroductionSub-Saharan Africa shoulders the highest burden of global sepsis and associated mortality. In high HIV and tuberculosis (TB) prevalent settings such as sub-Saharan Africa, TB is the leading cause of...

Emergency care of sepsis in sub-Saharan Africa: Mortality and non-physician clinician management of sepsis in rural Uganda from 2010 to 2019.

IntroductionLittle data exists from sub-Saharan Africa describing incidence and outcomes of sepsis in emergency units and uncertainty exists surrounding optimal management of sepsis in low-income settings. There exists limited data regarding quality care metrics for non-physician clinicians trained in emergency care. The objective of this study was to describe changes in septic patients over time and evaluate associations between sepsis care and mortality.MethodsSecondary analysis of a prospective cohort of all consecutive patients seen from 2010–2019 in a rural Ugandan emergency unit staffed by non-physician clinicians was performed using an electronic database based on paper charts. Sepsis was defined as suspected infection with a quick Sequential Organ Failure Assessment score (qSOFA)≥1. Multi-variable logistic regression was used to analyze three-day mortality.ResultsOverall, 48,653 patient visits from 2010–2019 yielded 17,490 encounters for patients age≥18 who had suspected infection, including 10,437 with sepsis. The annual proportion of patients with sepsis decreased from 45.0%% to 21.3% and the proportion with malarial sepsis decreased from 17.7% to 2.1% during the study period. Rates of septic patients receiving quality care (“both fluids and anti-infectives”) increased over time (21.2% in 2012 to 32.0% in 2019, p<0.001), but mortality did not significantly improve (4.5% in 2012 to 6.4% in 2019, p = 0.50). The increasing quality of non-physician clinician care was not associated with reduced mortality, and treatment with “both fluids and antibiotics” was associated with increased mortality (RR = 1.55, 95%CI 1.10–2.00).ConclusionThe largest study of sepsis management and outcomes ever published in both Uganda and sub-Saharan Africa showed sepsis and malarial sepsis decreasing from 2010 to 2019. The increasing quality of non-physician clinician care did not significantly reduce mortality and treatment with “both fluids and antibiotics” increased mortality. With causal associations between antibiotics and mortality deemed implausible, associations between sepsis mortality and interventions likely represent confounding by indication. Defining optimal sepsis care regionally will likely require randomized controlled trials.

A Longitudinal, Observational Study of Etiology and Long-Term Outcomes of Sepsis in Malawi Revealing the Key Role of Disseminated Tuberculosis.

BackgroundSepsis protocols in sub-Saharan Africa are typically extrapolated from high-income settings, yet sepsis in sub-Saharan Africa is likely caused by distinct pathogens and may require novel treatment strategies. Data to guide such strategies are lacking. We aimed to define causes and modifiable factors associated with sepsis outcomes in Blantyre, Malawi, in order to inform the design of treatment strategies tailored to sub-Saharan Africa.MethodsWe recruited 225 adults who met a sepsis case definition defined by fever and organ dysfunction in an observational cohort study at a single tertiary center. Etiology was defined using culture, antigen detection, serology, and polymerase chain reaction. The effect of treatment on 28-day outcomes was assessed using Bayesian logistic regression.ResultsThere were 143 of 213 (67%) participants living with human immunodeficiency virus (HIV). We identified a diagnosis in 145 of 225 (64%) participants, most commonly tuberculosis (TB; 34%) followed by invasive bacterial infections (17%), arboviral infections (13%), and malaria (9%). TB was associated with HIV infection, whereas malaria and arboviruses with the absence of HIV infection. Antituberculous chemotherapy was associated with survival (adjusted odds ratio for 28-day death, 0.17; 95% credible interval, 0.05–0.49 for receipt of antituberculous therapy). Of those with confirmed etiology, 83% received the broad-spectrum antibacterial ceftriaxone, but it would be expected to be active in only 24%.ConclusionsSepsis in Blantyre, Malawi, is caused by a range of pathogens; the majority are not susceptible to the broad-spectrum antibacterials that most patients receive. HIV status is a key determinant of etiology. Novel antimicrobial strategies for sepsis tailored to sub-Saharan Africa, including consideration of empiric antituberculous therapy in individuals living with HIV, should be developed and trialed.

Stratifying Sepsis in Uganda Using Rapid Pathogen Diagnostics and Clinical Data: A Prospective Cohort Study.

The global burden of sepsis is concentrated in sub-Saharan Africa, where extensive pathogen diversity and limited laboratory capacity challenge targeted antimicrobial management of life-threatening infections. In this context, established and emerging rapid pathogen diagnostics may stratify sepsis patients into subgroups with prognostic and therapeutic relevance. In a prospective cohort of adults (age ≥18 years) hospitalized with suspected sepsis in Uganda, we stratified patients using rapid diagnostics for HIV, tuberculosis (TB), malaria, and influenza, and compared clinical characteristics and 30-day outcomes across these pathogen-driven subgroups. From April 2017 to August 2019, 301 adults were enrolled (median age, 32 years [interquartile range, 26-42 years]; female, n = 178 [59%]). A total of 157 patients (53%) were HIV infected. Sixty-one patients (20%) tested positive for malaria, 52 (17%), for TB (including 49 of 157 [31%] HIV-infected patients), and 17 (6%), for influenza. Co-infection was identified in 33 (11%) patients. The frequency of multi-organ failure, including shock and acute respiratory failure, was greatest among patients with HIV-associated TB. Mortality at 30 days was 19% among patients with malaria, 40% among patients with HIV-associated TB, 32% among HIV-infected patients without microbiological evidence of TB, 6% among patients with influenza, and 11% among patients without a pathogen identified. Despite improvements in anti-retroviral delivery, the burden of sepsis in Uganda remains concentrated among young, HIV-infected adults, with a high incidence of severe HIV-associated TB. In parallel with improvements in acute-care capacity, use of rapid pathogen diagnostics may enhance triage and antimicrobial management during emergency care for sepsis in sub-Saharan Africa, and could be used to enrich study populations when trialing pathogen-specific treatment strategies in the region.

Antimicrobial Resistance in Enterobacterales and Its Contribution to Sepsis in Sub-saharan Africa.

Antibiotic resistant Enterobacterales (formerly Enterobactereaceae) are a growing threat to Sub-Saharan Africa. Genes causing antibiotic resistance are easily spread between the environment and humans and infections due to drug resistant organisms contribute to sepsis mortality via delayed time to appropriate antimicrobial therapy. Additionally, second or third-line antibiotics are often not available or are prohibitively expensive in resource-constrained settings leading to limited treatment options. Lack of access to water and sanitation facilities, unregulated use of antibiotics, and malnutrition are contributors to high rates of antibiotic resistance in the region. Improvements in the monitoring of drug resistant infections and antibiotic stewardship are needed to preserve the efficacy of antibiotics for the future.

Recommendations for fluid management of adults with sepsis in sub-Saharan Africa: a systematic review of guidelines

BackgroundSepsis 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.MethodsWe 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.ResultsPublished 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.ConclusionsWidely 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.

Aetiology and outcomes of sepsis in adults in sub-Saharan Africa: a systematic review and meta-analysis

BackgroundAetiology and outcomes of sepsis in sub-Saharan Africa (sSA) are poorly described; we performed a systematic review and meta-analysis to summarise the available data.MethodsSystematic searches of PubMed and Scopus were undertaken to identify prospective studies recruiting adults (> 13 years) with community-acquired sepsis in sSA post-2000. Random effects meta-analysis of in-hospital and 30-day mortality was undertaken and available aetiology data also summarised by random effects meta-analysis.ResultsFifteen studies of 2800 participants were identified. Inclusion criteria were heterogeneous. The majority of patients were HIV-infected, and Mycobacterium tuberculosis was the most common cause of blood stream infection where sought. Pooled in-hospital mortality for Sepsis-2-defined sepsis and severe sepsis was 19% (95% CI 12–29%) and 39% (95% CI 30–47%) respectively, and sepsis mortality was associated with the proportion of HIV-infected participants. Mortality and morbidity data beyond 30 days were absent.ConclusionsSepsis in sSA is dominated by HIV and tuberculosis, with poor outcomes. Optimal antimicrobial strategies, including the role of tuberculosis treatment, are unclear. Long-term outcome data are lacking. Standardised sepsis diagnostic criteria that are easily applied in low-resource settings are needed to establish an evidence base for sepsis management in sSA.

Effect of Empiric Anti-Mycobacterium tuberculosis Therapy on Survival Among Human Immunodeficiency Virus-Infected Adults Admitted With Sepsis to a Regional Referral Hospital in Uganda.

Background Mycobacterium tuberculosis is the leading cause of bloodstream infection among human immunodeficiency virus (HIV)–infected patients with sepsis in sub-Saharan Africa and is associated with high mortality rates.MethodsWe conducted a retrospective study of HIV-infected adults with sepsis at the Mbarara Regional Referral Hospital in Uganda to measure the proportion who received antituberculosis therapy and to determine the relationship between antituberculosis therapy and 28-day survival.ResultsOf the 149 patients evaluated, 74 (50%) had severe sepsis and 48 (32%) died. Of the 55 patients (37%) who received antituberculosis therapy, 19 (35%) died, compared with 29 of 94 (31%) who did not receive such therapy (odds ratio, 1.34; 95% confidence interval [CI], .56–3.18; P = .64). The 28-day survival rates did not differ significantly between these 2 groups (log-rank test, P = .21). Among the 74 patients with severe sepsis, 9 of 26 (35%) who received antituberculosis therapy died, versus 23 of 48 (48%) who did not receive such therapy (odds ratio, 0.58; 95% CI, .21–1.52; P = .27). In patients with severe sepsis, antituberculosis therapy was associated with an improved 28-day survival rate (log-rank test P = .01), and with a reduced mortality rate in a Cox proportional hazards model (hazard ratio, 0.32; 95% CI, .13–.80; P = .03).ConclusionsEmpiric antituberculosis therapy was associated with improved survival rates among patients with severe sepsis, but not among all patients with sepsis.

The Early Recognition and Management of Sepsis in Sub-Saharan African Adults: A Systematic Review and Meta-Analysis.

Sepsis is a common cause of morbidity and mortality in sub-Saharan African adults. Standardised management pathways have been documented to improve the survival of adults with sepsis from high-resource settings. Our aim was to assess the current evidence base for early sepsis interventions (recognition, empirical antibiotics, and resuscitation) in resource-poor settings of sub-Saharan Africa. We searched MEDLINE, EMBASE and CINHAL Plus databases to identify interventional studies for the early recognition and management of sepsis in sub-Saharan Africa (1 January 2000 to 1 August 2018) using a protocol-driven search strategy: adults, protocolised care pathway, and sub-Saharan Africa. We identified 725 publications of which three met criteria for final selection. Meta-analysis from two randomised controlled trials demonstrated that mortality was increased by ‘early goal-directed therapy’ interventions that increased fluid resuscitation (R.R. 1.26, 95% C.I. 1.00–1.58, p = 0.045; I2 53%). The third observational cohort study demonstrated improved survival after implementation of protocolised management for sepsis (mortality 33.0% vs. 45.7%, p = 0.005). No study incorporated standardised protocols for empirical antibiotic administration. High rates of pneumonia and mycobacteraemia were reported. There has been little research into the early recognition and management of sepsis in sub-Saharan Africa. Interventional trials of early goal-directed therapy have, to date, increased mortality. There is an urgent need to develop effective strategies to improve outcomes for adults with sepsis in sub-Saharan Africa.

Etiology of Sepsis in Uganda Using a Quantitative Polymerase Chain Reaction-based TaqMan Array Card.

Knowledge of causes of sepsis in sub-Saharan Africa is limited. A better understanding of the microbiology of bloodstream infections could improve outcomes. 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. 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). 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.

Maternal colonization with Staphylococcus aureus and Group B streptococcus is associated with colonization in newborns

ObjectivesAlthough Staphylococcus aureus and Group B streptococcus (GBS) are major causes of neonatal sepsis in sub-Saharan Africa, it is unclear how these bacteria are transmitted to the neonate. MethodsIn a cohort of 377 Gambian women and their newborns, nasopharyngeal swabs were collected at delivery (day 0), and 3, 6, 14 and 28 days later. Breast milk samples and vaginal swabs were collected from the mother. Staphylococcus aureus and GBS were isolated using conventional microbiological methods. ResultsMost women were carriers of S. aureus (264 out of 361 with all samples collected, 73.1%) at some point during follow up and many were carriers of GBS (114 out of 361, 31.6%). Carriage of S. aureus was common in all three maternal sites and GBS was common in the vaginal tract and breast milk. Among newborns, carriage of S. aureus peaked at day 6 (238 out of 377, 63.1%) and GBS at day 3 (39 out of 377, 10.3%). Neonatal carriage of S. aureus at day 6 was associated with maternal carriage in the breast milk adjusted OR 2.54; 95% CI 1.45–4.45, vaginal tract (aOR 2.55; 95% CI 1.32–4.92) and nasopharynx (aOR 2.49; 95% CI 1.56–3.97). Neonatal carriage of GBS at day 6 was associated with maternal carriage in the breast milk (aOR 3.75; 95% CI 1.32–10.65) and vaginal tract (aOR 3.42; 95% CI 1.27–9.22). ConclusionsMaternal colonization with S. aureus or GBS is a risk factor for bacterial colonization in newborns.

Surviving paediatric sepsis in Tanzania: a prospective cohort study to identify risk factors

Abstract Background In 2015, there were 5·9 million deaths in children aged under 5 years worldwide: mortality is highest in sub-Saharan Africa (81 per 1000 livebirths) and sepsis is an important cause of these deaths. Paediatric sepsis is preventable and treatable, yet remains a serious and life-threatening condition. Prompt recognition and early treatment can improve survival; however, the understanding of how to identify and manage paediatric sepsis in sub-Saharan Africa is poor because of a lack of regional data. These data are crucial for the identification of high-risk patients, development of triage systems, and the reduction of barriers to care. In this study, we aim to identify mortality risk factors for paediatric sepsis patients at a national referral hospital in Tanzania. Methods We conducted an exploratory analysis of prospective cohort pilot data. We included children aged between 28 days and 14 years in the emergency medicine department at Muhimbili National Hospital in Dar es Salaam with sepsis (defined as ≥2 clinical criteria for systemic inflammatory response syndrome). The primary outcome was in-hospital mortality and secondary outcomes included mortality in the emergency department and length of stay. We used t -tests and Wilcoxon rank-sum, Kruskal Wallis, χ 2 , and Fisher's exact tests for data analysis. Findings Of the 2232 children screened between July 1 and September 30, 2017, 433 were eligible, 405 were enrolled, and 402 were followed to discharge or death. Median age was 25·2 months (IQR 11·4–63·5) and prevalence of malaria and HIV was 9·1% (28/307) and 1·7% (n=7), respectively. 247 (61·0%) patients were referred from outside health facilities and 116/244 (47·5%) had received antibiotics before arrival. Mortality was 14·2% (n=57): 89·5% (n=51) died on a hospital ward and 10·5% (n=6) died in the emergency department. Non-survivors were younger than survivors (median age 16 and 27 months, respectively, p=0·002), and more likely to have respiratory insufficiency (54 (94·7%) vs 293 (84·9%), p=0·046) or altered mental status (43 (75·4%) vs 171 (49·6%), p Interpretation We identified several risk factors for mortality, but only that of referral status can be modified. Most children—and a disproportionately high number of non-survivors—were assessed at other health facilities before coming to Muhimbili, suggesting that there could be an opportunity for improved sepsis identification and earlier intervention. Next steps include development of a clinical illness severity score to allow risk stratification of patients and also investigation of barriers to care. Data collection is ongoing. Funding University of California, San Francisco, Department of Pediatrics Clinical-Translational Pilot.

Inverting the pyramid: increasing awareness of mycobacterial sepsis in sub-Saharan Africa

Disseminated Mycobacterium tuberculosis is a leading cause of bloodstream infection and severe sepsis in sub-Saharan African settings with a high burden of tuberculosis (TB) and human immunodeficiency virus (HIV) infection. Despite the high prevalence of M. tuberculosis bacteremia in these settings it is under-recognized. This is in part because timely diagnosis of M. tuberculosis bacteremia is difficult using traditional TB diagnostics. Novel triage algorithms and rapid diagnostic tests are needed to expedite the identification and treatment of patients with severe sepsis due to M. tuberculosis bacteremia. In this article, we emphasize the importance of M. tuberculosis bacteremia as an under-recognized etiology of severe sepsis, and discuss the potential role of two emerging rapid diagnostic tests in the triage and prognostication of critically ill patients with advanced HIV infection and suspected disseminated M. tuberculosis. We conclude with the recommendation that clinicians in high TB-HIV burden settings strongly consider empiric anti-tuberculosis treatment in patients with advanced HIV infection and severe sepsis in the appropriate clinical context. Future studies are needed to assess diagnostic and prognostic algorithms for severe sepsis caused by disseminated M. tuberculosis in these settings, and the safety, efficacy, and duration of empiric anti-tuberculosis treatment.

A Review of Neonatal Morbidity and Mortality in an Intensive Care Unit of a Paediatric Health Facility in Lagos, Nigeria

Introduction: Neonatal period in developing countries is characterized by various infectious diseases that make up leading causes and significant contributors to dismal morbidity and mortality statistics in this period of life. The diagnosis of neonatal sepsis in sub-Saharan Africa represents a challenge due to unavailability or scarcity of laboratory aids. The clinical diagnosis of sepsis may be difficult without laboratory aids irrespective of where the infant is born due to the fact that other non-infectious conditions can present with sepsis-like picture. Objectives : The main objectives of this study were to document frequently diagnosed illnesses, record the management of the ill neonates and present the leading causes of death during the neonatal period for the purpose of future planning. Methodology : This was a retrospective review of the medical records of children admitted into the Intensive Care Unit (ICU) of a public health facility between March 2005 and February 2007. Descriptive analysis was used to illustrate findings. The study was conducted between March 31, 2009 and June 30, 2009. Results: Majority (135, 60.3%) of the study neonates (135 males, 89 females) were aged between 2-7 days. In all, 46 (20.5%) neonates weighed less than 2.5 kg. There was a considerable difference (t=-2.45; p=0.015; CI -0.60, -0.06) in the mean (± SEM) body temperature of 24-hour old neonates (36.7 ± 0.11) compared with those 2-7 days old (37.1 ± 0.06). Fever (56, 44%) was the most frequent presentation among neonates diagnosed with septicaemia (126, 56.3%), yellowness of the eyes (47, 65.3%) among those diagnosed with jaundice (72, 32.1%) and failure to cry (9, 25.7%) among those diagnosed with birth asphyxia (35, 15.6%). Full blood count was the most frequent (207, 92.4%) investigation requested for while antibiotics was the commonest (461, 205.8%) medication prescribed. Medications were administered to the neonates mainly through the intravenous route (538, 240.2%). In all, mortality among the studied neonates was 76 (33.9%). Conclusion: More effective measures to improve neonatal mortality could be 1) improving access to antenatal care provided by trained medical professionals 2) giving general instructions to mothers who just gave birth regarding when to seek medical attention for her newborn infant 3) assessing local professional competencies 4) reviewing obstetrical procedures and interventions around the time of labour for women who deliver in hospital/private clinic settings, etc. For example appropriate chemoprophylaxis of pregnant mothers colonized with Group B Strep (GBS) proved to be a very effective prophylactic measure for early-onset neonatal GBS sepsis.