C. Louise Thwaites

Maternal and neonatal tetanus.

Maternal and neonatal tetanus is still a substantial but preventable cause of mortality in many developing countries. Case fatality from these diseases remains high and treatment is limited by scarcity of resources and effective drug treatments. The Maternal and Neonatal Tetanus Elimination Initiative, launched by WHO and its partners, has made substantial progress in eliminating maternal and neonatal tetanus. Sustained emphasis on improvement of vaccination coverage, birth hygiene, and surveillance, with specific approaches in high-risk areas, has meant that the incidence of the disease continues to fall. Despite this progress, an estimated 58,000 neonates and an unknown number of mothers die every year from tetanus. As of June, 2014, 24 countries are still to eliminate the disease. Maintenance of elimination needs ongoing vaccination programmes and improved public health infrastructure.

Recommendations for infection management in patients with sepsis and septic shock in resource-limited settings

Introduction Studies indicate that sepsis and septic shock in resourcelimited settings are at least as common as in resourcerich settings. The surviving sepsis campaign (SSC) guidelines have been widely adopted throughout the world, but in resource-limited settings are often unfeasible [1]. The guidelines are based almost exclusively on evidence from resource-rich settings and are not necessarily applicable elsewhere due to differences in etiology and diagnostic or treatment capacity. An international team of physicians with extensive practical experience in resource-limited intensive care units (ICUs) identified key questions concerning the SSC’s infection management recommendations, and evidence from resourcelimited settings regarding these was evaluated using the grading of recommendations assessment, development and evaluation (GRADE) tools. This article focuses primarily on bacterial causes of sepsis and septic shock. Other infections common in resource-limited settings, such as malaria, are covered in a separate article in this series. Evidence quality was scored as high (grade A), moderate (B), low (C), or very low (D), and recommendations as strong (1) or weak (2). The major difference from the grading of recommendations in the SSC-guidelines was in taking account of contextual factors relevant to resource-limited settings, such as the availability, affordability and feasibility of interventions in resource-limited ICUs. Strong recommendations have been worded as ‘we recommend’ and weak recommendations as ‘we suggest’ (details in online supplement).

Prognosis of neonatal tetanus in the modern management era: an observational study in 107 Vietnamese infants

Highlights • Large contemporary case-series in a setting of improved critical care facilities.• Analysis of variables, some not analysed in previous studies/meta-analyses.• Age and weight were associated with a poor outcome.• Delay in admission to hospital and leukocytosis were also associated with a poor outcome.

Association of the Quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) Score With Excess Hospital Mortality in Adults With Suspected Infection in Low- and Middle-Income Countries

Importance The quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) score has not been well-evaluated in low- and middle-income countries (LMICs). Objective To assess the association of qSOFA with excess hospital death among patients with suspected infection in LMICs and to compare qSOFA with the systemic inflammatory response syndrome (SIRS) criteria. Design, Settings, and Participants Retrospective secondary analysis of 8 cohort studies and 1 randomized clinical trial from 2003 to 2017. This study included 6569 hospitalized adults with suspected infection in emergency departments, inpatient wards, and intensive care units of 17 hospitals in 10 LMICs across sub-Saharan Africa, Asia, and the Americas. Exposures Low (0), moderate (1), or high (≥2) qSOFA score (range, 0 [best] to 3 [worst]) or SIRS criteria (range, 0 [best] to 4 [worst]) within 24 hours of presentation to study hospital. Main Outcomes and Measures Predictive validity (measured as incremental hospital mortality beyond that predicted by baseline risk factors, as a marker of sepsis or analogous severe infectious course) of the qSOFA score (primary) and SIRS criteria (secondary). Results The cohorts were diverse in enrollment criteria, demographics (median ages, 29-54 years; males range, 36%-76%), HIV prevalence (range, 2%-43%), cause of infection, and hospital mortality (range, 1%-39%). Among 6218 patients with nonmissing outcome status in the combined cohort, 643 (10%) died. Compared with a low or moderate score, a high qSOFA score was associated with increased risk of death overall (19% vs 6%; difference, 13% [95% CI, 11%-14%]; odds ratio, 3.6 [95% CI, 3.0-4.2]) and across cohorts (P < .05 for 8 of 9 cohorts). Compared with a low qSOFA score, a moderate qSOFA score was also associated with increased risk of death overall (8% vs 3%; difference, 5% [95% CI, 4%-6%]; odds ratio, 2.8 [95% CI, 2.0-3.9]), but not in every cohort (P < .05 in 2 of 7 cohorts). High, vs low or moderate, SIRS criteria were associated with a smaller increase in risk of death overall (13% vs 8%; difference, 5% [95% CI, 3%-6%]; odds ratio, 1.7 [95% CI, 1.4-2.0]) and across cohorts (P < .05 for 4 of 9 cohorts). qSOFA discrimination (area under the receiver operating characteristic curve [AUROC], 0.70 [95% CI, 0.68-0.72]) was superior to that of both the baseline model (AUROC, 0.56 [95% CI, 0.53-0.58; P < .001) and SIRS (AUROC, 0.59 [95% CI, 0.57-0.62]; P < .001). Conclusions and Relevance When assessed among hospitalized adults with suspected infection in 9 LMIC cohorts, the qSOFA score identified infected patients at risk of death beyond that explained by baseline factors. However, the predictive validity varied among cohorts and settings, and further research is needed to better understand potential generalizability.

Neonatal Tetanus in Vietnam: Comprehensive Intensive Care Support Improves Mortality

We report a 66% reduction in neonatal tetanus mortality after introducing a new management bundle integrating antibiotic therapy, muscle relaxation and invasive monitoring. The latter allowed rapid detection of autonomic instability which was treated with magnesium sulphate. This is the first report of its use in neonatal tetanus.

A one-year prospective study of colonization with antimicrobial-resistant organisms on admission to a Vietnamese intensive care unit

There is a paucity of data regarding initial bacterial colonization on admission to Intensive Care Units (ICUs) in low and middle-income countries (LMICs). Patients admitted to ICUs in LMICs are at high-risk of subsequent infection with antimicrobial-resistant organisms (AROs). We conducted a prospective, observational study at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam from November 2014 to January 2016 to assess the colonization and antimicrobial susceptibility of Staphylococcus aureus, Escherichia coli, Klebsiella spp., Pseudomonas spp. and Acinetobacter spp. among adult patients within 48 hours of ICU admission. We found the admission colonization prevalence (with at least one of the identified organisms) was 93.7% (785/838) and that of AROs was 63.1% (529/838). The colonization frequency with AROs among patients admitted from the community was comparable to those transferred from other hospitals (62.2% vs 63.8%). Staphylococcus aureus was the most commonly isolated bacteria from nasal swabs (13.1%, 110/838) and the methicillin-resistant Staphylococcus aureus nasal colonization prevalence was 8.6% (72/838). We isolated Escherichia coli from rectal swabs from almost all enrolled patients (88.3%, 740/838) and 52.1% (437/838) of patients were colonized by extended spectrum β-lactamase producing Escherichia coli. Notably, Klebsiella pneumoniae was the most frequently isolated bacteria from the tracheal swabs (11.8%, 18/153). Vietnamese ICU patients have a high rate of colonization with AROs and are thus at risk of subsequent infections with these organisms if good infection control practices are not in place.

Tetanus in Southern Vietnam: Current Situation

In Vietnam, there are no accurate data on tetanus incidence to allow assessment of disease burden or vaccination program efficacy. We analyzed age structure of 786 tetanus cases admitted to a tertiary referral center in Vietnam for three separate years during an 18-year period to examine the impact of tetanus prevention programs, namely the Expanded Program on Immunization (EPI) and the Maternal and Neonatal Tetanus (MNT) initiative. Most cases were born before the initiation of EPI. Median age increased from 33 (interquartile range: 20–52) in 1994, to 46 (32–63) in 2012 (P < 0.001). Birth-year distribution was unchanged, indicating the same birth cohorts presented with tetanus in 1994, 2003, and 2012. Enzyme-linked immunosorbent assay measurements in 90 men and 90 women covered by MNT but not EPI showed 73.3% (95% confidence interval [CI]: 62.9–82.1%) of women had anti-tetanus antibody compared with 24.4% (95% CI: 15.9–34.7%) of men, indicating continued tetanus vulnerability in older men in Vietnam.

Infection management in patients with sepsis and septic shock in resource-limited settings.

Recommendations on the management of infections in patients with sepsis and septic shock are mainly derived from studies on bacterial sepsis in high-income settings and are not necessarily applicable elsewhere due to differences in etiology and diagnostic or treatment capacity. In this chapter, we provide recommendations on infection management in resource-limited ICUs, taking into account relevant contextual factors such as the availability, affordability, and feasibility of interventions.

Intrathecal Immunoglobulin for treatment of adult patients with tetanus: A randomized controlled 2x2 factorial trial

Despite long-standing availability of an effective vaccine, tetanus remains a significant problem in many countries. Outcome depends on access to mechanical ventilation and intensive care facilities and in settings where these are limited, mortality remains high. Administration of tetanus antitoxin by the intramuscular route is recommended treatment for tetanus, but as the tetanus toxin acts within the central nervous system, it has been suggested that intrathecal administration of antitoxin may be beneficial. Previous studies have indicated benefit, but with the exception of one small trial no blinded studies have been performed. The objective of this study is to establish whether the addition of intrathecal tetanus antitoxin reduces the need for mechanical ventilation in patients with tetanus. Secondary objectives: to determine whether the addition of intrathecal tetanus antitoxin reduces autonomic nervous system dysfunction and length of hospital/ intensive care unit stay; whether the addition of intrathecal tetanus antitoxin in the treatment of tetanus is safe and cost-effective; to provide data to inform recommendation of human rather than equine antitoxin. This study will enroll adult patients (≥16 years old) with tetanus admitted to the Hospital for Tropical Diseases, Ho Chi Minh City. The study is a 2x2 factorial blinded randomized controlled trial. Eligible patients will be randomized in a 1:1:1:1 manner to the four treatment arms (intrathecal treatment and human intramuscular treatment, intrathecal treatment and equine intramuscular treatment, sham procedure and human intramuscular treatment, sham procedure and equine intramuscular treatment). Primary outcome measure will be requirement for mechanical ventilation. Secondary outcome measures: duration of hospital/ intensive care unit stay, duration of mechanical ventilation, in-hospital and 240-day mortality and disability, new antibiotic prescription, incidence of ventilator associated pneumonia and autonomic nervous system dysfunction, total dose of benzodiazepines and pipecuronium, and incidence of adverse events. Trial registration: ClinicalTrials.gov NCT02999815 Registration date: 21 December 2016.

A57 Clinical features and virology of hand, foot, and mouth disease in southern Vietnam from July 2013 to July 2015

points of FMDV are mostly located in the boundaries between capsid and non-capsid proteins. Here, we investigated the recombination patterns of viral lineages (determined by VP1 phylogeny) known to be endemic to Southeast Asia (SEA): FMDV serotype O lineages PanAsia and Mya-98, and serotype A lineage Sea-97). We analyzed ninety-three full ORF sequences from SEA countries and reference sequences from other Asian regions. Of these, thirty sequences were generated by our laboratory and the remaining were obtained from GenBank. We used maximum likelihood phylogenetic reconstruction for each of the protein coding regions and RDP4 to detect recombination. Specific recombinant viruses were further analyzed using RIP to visualize their mosaic patterns. Three specific mosaic viruses of lineage A/Sea97 and O/Mya98 sequences were detected. Reconstruction of the phylogenies revealed a closer relationship between O/Mya98 and A/Sea97 lineages in the non-structural proteins. We further analyzed intra-lineage recombination, using homoplasy test (after removal of mosaic sequences), revealing hot spots of recombination regions that differ depending on the lineages A/Sea97 (hotspots in VP2, 2 C, and 3 D), O/Mya98 (in Lpro, VP1, 3 C, and 3 D), and PanAsia (in Lpro and 2 C). This study integrates knowledge of molecular FMD epidemiology and the specific implications of viral recombination. Furthermore, these results suggest novel understanding of the evolutionary interdependence of FMDV serotypes and lineages. Unveiling the evolutionary mechanisms of FMDV may help predict emergence of new lineages, and inform the risk posed by co-circulating lineages in FMD-endemic regions.