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Efforts to quantify the global burden of enteric fever are valuable for understanding the health lost and the large-scale spatial distribution of the disease. We present the estimates of typhoid and paratyphoid fever burden from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, and the approach taken to produce them. For this systematic analysis we broke down the relative contributions of typhoid and paratyphoid fevers by country, year, and age, and analysed trends in incidence and mortality. We modelled the combined incidence of typhoid and paratyphoid fevers and split these total cases proportionally between typhoid and paratyphoid fevers using aetiological proportion models. We estimated deaths using vital registration data for countries with sufficiently high data completeness and using a natural history approach for other locations. We also estimated disability-adjusted life-years (DALYs) for typhoid and paratyphoid fevers. Globally, 14·3 million (95% uncertainty interval [UI] 12·5–16·3) cases of typhoid and paratyphoid fevers occurred in 2017, a 44·6% (42·2–47·0) decline from 25·9 million (22·0–29·9) in 1990. Age-standardised incidence rates declined by 54·9% (53·4–56·5), from 439·2 (376·7–507·7) per 100 000 person-years in 1990, to 197·8 (172·0–226·2) per 100 000 person-years in 2017. In 2017, Salmonella enterica serotype Typhi caused 76·3% (71·8–80·5) of cases of enteric fever. We estimated a global case fatality of 0·95% (0·54–1·53) in 2017, with higher case fatality estimates among children and older adults, and among those living in lower-income countries. We therefore estimated 135·9 thousand (76·9–218·9) deaths from typhoid and paratyphoid fever globally in 2017, a 41·0% (33·6–48·3) decline from 230·5 thousand (131·2–372·6) in 1990. Overall, typhoid and paratyphoid fevers were responsible for 9·8 million (5·6–15·8) DALYs in 2017, down 43·0% (35·5–50·6) from 17·2 million (9·9–27·8) DALYs in 1990. Despite notable progress, typhoid and paratyphoid fevers remain major causes of disability and death, with billions of people likely to be exposed to the pathogens. Although improvements in water and sanitation remain essential, increased vaccine use (including with typhoid conjugate vaccines that are effective in infants and young children and protective for longer periods) and improved data and surveillance to inform vaccine rollout are likely to drive the greatest improvements in the global burden of the disease. Bill & Melinda Gates Foundation.

The management of childhood infections remains inadequate in resource-limited countries, resulting in high mortality and irrational use of antimicrobials. Current disease management tools, such as the Integrated Management of Childhood Illness (IMCI) algorithm, rely solely on clinical signs and have not made use of available point-of-care tests (POCTs) that can help to identify children with severe infections and children in need of antibiotic treatment. e-POCT is a novel electronic algorithm based on current evidence; it guides clinicians through the entire consultation and recommends treatment based on a few clinical signs and POCT results, some performed in all patients (malaria rapid diagnostic test, hemoglobin, oximeter) and others in selected subgroups only (C-reactive protein, procalcitonin, glucometer). The objective of this trial was to determine whether the clinical outcome of febrile children managed by the e-POCT tool was non-inferior to that of febrile children managed by a validated electronic algorithm derived from IMCI (ALMANACH), while reducing the proportion with antibiotic prescription. We performed a randomized (at patient level, blocks of 4), controlled non-inferiority study among children aged 2-59 months presenting with acute febrile illness to 9 outpatient clinics in Dar es Salaam, Tanzania. In parallel, routine care was documented in 2 health centers. The primary outcome was the proportion of clinical failures (development of severe symptoms, clinical pneumonia on/after day 3, or persistent symptoms at day 7) by day 7 of follow-up. Non-inferiority would be declared if the proportion of clinical failures with e-POCT was no worse than the proportion of clinical failures with ALMANACH, within statistical variability, by a margin of 3%. The secondary outcomes included the proportion with antibiotics prescribed on day 0, primary referrals, and severe adverse events by day 30 (secondary hospitalizations and deaths). We enrolled 3,192 patients between December 2014 and February 2016 into the randomized study; 3,169 patients (e-POCT: 1,586; control [ALMANACH]: 1,583) completed the intervention and day 7 follow-up. Using e-POCT, in the per-protocol population, the absolute proportion of clinical failures was 2.3% (37/1,586), as compared with 4.1% (65/1,583) in the ALMANACH arm (risk difference of clinical failure -1.7, 95% CI -3.0, -0.5), meeting the prespecified criterion for non-inferiority. In a non-prespecified superiority analysis, we observed a 43% reduction in the relative risk of clinical failure when using e-POCT compared to ALMANACH (risk ratio [RR] 0.57, 95% CI 0.38, 0.85, p = 0.005). The proportion of severe adverse events was 0.6% in the e-POCT arm compared with 1.5% in the ALMANACH arm (RR 0.42, 95% CI 0.20, 0.87, p = 0.02). The proportion of antibiotic prescriptions was substantially lower, 11.5% compared to 29.7% (RR 0.39, 95% CI 0.33, 0.45, p < 0.001). Using e-POCT, the most common indication for antibiotic prescription was severe disease (57%, 103/182 prescriptions), while it was non-severe respiratory infections using the control algorithm (ALMANACH) (70%, 330/470 prescriptions). The proportion of clinical failures among the 544 children in the routine care cohort was 4.6% (25/544); 94.9% (516/544) of patients received antibiotics on day 0, and 1.1% (6/544) experienced severe adverse events. e-POCT achieved a 49% reduction in the relative risk of clinical failure compared to routine care (RR 0.51, 95% CI 0.31, 0.84, p = 0.007) and lowered antibiotic prescriptions to 11.5% from 94.9% (p < 0.001). Though this safety study was an important first step to evaluate e-POCT, its true utility should be evaluated through future implementation studies since adherence to the algorithm will be an important factor in making use of e-POCT's advantages in terms of clinical outcome and antibiotic prescription. e-POCT, an innovative electronic algorithm using host biomarker POCTs, including C-reactive protein and procalcitonin, has the potential to improve the clinical outcome of children with febrile illnesses while reducing antibiotic use through improved identification of children with severe infections, and better targeting of children in need of antibiotic prescription. ClinicalTrials.gov NCT02225769.

Background Typhoid and paratyphoid fever are common infectious diseases and remain a heavy burden, especially in some low-income countries. Although the global burden has decreased over the past three decades, an analysis of the burden of typhoid and paratyphoid fever will help inform public health strategies. Methods This study is aimed to comprehensively evaluate the global, regional, and national burden of typhoid and paratyphoid, and the temporal trends while exploring potential associations with socio-demographic development over three decades (1990–2021). Data on typhoid and paratyphoid fever were analyzed using the Global Burden of Disease (GBD) study in 2021. For this analysis, we calculated to demonstrate temporal trends in the incidence, mortality, and disability adjusted life years (DALYs) of typhoid and paratyphoid fever from 1990 to 2021. Results From 1990 to 2021, both typhoid and paratyphoid fever showed declining trends globally and in different socio-demographic index (SDI) regions, including incidence, mortality, and DALYs. For typhoid fever worldwide, new cases decreased by 62.12%, with an EAPC of -3.92 (-4.14, -3.71); deaths decreased by 50.65%, EAPC − 2.83 (-2.99, -2.66), and DALYs decreased by 52.30%, EAPC − 2.82 (-3.00, -2.64). For paratyphoid fever, new cases decreased by 73.15%, with an EAPC of -4.77 (-5.29, -4.26); deaths decreased by 65.44%, EAPC − 3.74 (-4.24, -3.24), and DALYs decreased by 68.42%, EAPC − 3.87 (-4.42, -3.31). For both typhoid and paratyphoid fever, children had the highest morbidity and mortality rates; males had higher rates of incidence, mortality, and DALYs than females. However, among older patients, the absolute number of new cases and DALYs was higher in women. The burden is concentrated in South Asia, Southeast Asia, and Oceania, with only South Asia suffering severely from paratyphoid fever. Regarding typhoid fever, the top three countries with the highest ASRs of incidence are Burkina Faso (328.48) (SDI: 0.285), Bangladesh (303.14) (SDI: 0.492), and Papua New Guinea (299.45) (SDI: 418) which are in Western Sub-Saharan, South Asia, and Oceania. The top three countries in terms of mortality and DALYs are Bhutan (5.61; 434.23) (SDI: 0.473), Bangladesh (5.06; 382.38), and Burkina Faso (4.64; 352.57). Regarding paratyphoid fever, the top three countries with the highest ASRs of mortality and DALYs are the same, including Pakistan (1.05; 72.66), India (0.75; 53.42), and Nepal (0.72; 50.65) (SDI: 0.433), all of which are located in South Asia.

Early rapid fluid resuscitation (boluses) in African children with severe febrile illnesses increases the 48-hour mortality by 3.3% compared with controls (no bolus). We explored the effect of boluses on 48-hour all-cause mortality by clinical presentation at enrolment, hemodynamic changes over the first hour, and on different modes of death, according to terminal clinical events. We hypothesize that boluses may cause excess deaths from neurological or respiratory events relating to fluid overload. Pre-defined presentation syndromes (PS; severe acidosis or severe shock, respiratory, neurological) and predominant terminal clinical events (cardiovascular collapse, respiratory, neurological) were described by randomized arm (bolus versus control) in 3,141 severely ill febrile children with shock enrolled in the Fluid Expansion as Supportive Therapy (FEAST) trial. Landmark analyses were used to compare early mortality in treatment groups, conditional on changes in shock and hypoxia parameters. Competing risks methods were used to estimate cumulative incidence curves and sub-hazard ratios to compare treatment groups in terms of terminal clinical events. Of 2,396 out of 3,141 (76%) classifiable participants, 1,647 (69%) had a severe metabolic acidosis or severe shock PS, 625 (26%) had a respiratory PS and 976 (41%) had a neurological PS, either alone or in combination. Mortality was greatest among children fulfilling criteria for all three PS (28% bolus, 21% control) and lowest for lone respiratory (2% bolus, 5% control) or neurological (3% bolus, 0% control) presentations. Excess mortality in bolus arms versus control was apparent for all three PS, including all their component features. By one hour, shock had resolved (responders) more frequently in bolus versus control groups (43% versus 32%, P <0.001), but excess mortality with boluses was evident in responders (relative risk 1.98, 95% confidence interval 0.94 to 4.17, P = 0.06) and 'non-responders' (relative risk 1.67, 95% confidence interval 1.23 to 2.28, P = 0.001), with no evidence of heterogeneity (P = 0.68). The major difference between bolus and control arms was the higher proportion of cardiogenic or shock terminal clinical events in bolus arms (n = 123; 4.6% versus 2.6%, P = 0.008) rather than respiratory (n = 61; 2.2% versus 1.3%, P = 0.09) or neurological (n = 63, 2.1% versus 1.8%, P = 0.6) terminal clinical events. Excess mortality from boluses occurred in all subgroups of children. Contrary to expectation, cardiovascular collapse rather than fluid overload appeared to contribute most to excess deaths with rapid fluid resuscitation. These results should prompt a re-evaluation of evidence on fluid resuscitation for shock and a re-appraisal of the rate, composition and volume of resuscitation fluids. ISRCTN69856593.

We conducted a systematic literature review and meta-analysis and estimated the case fatality rate of enteric fever to be 2.49% (95% confidence interval, 1.65%-3.75%; n = 44), 2.5 times higher than what was assumed up until now. Abstract Enteric fever is a febrile illness, occurring mostly in Asia and Africa, which can present as a severe and possibly fatal disease. Currently, a case fatality rate (CFR) of 1% is assumed when evaluating the global burden of enteric fever. Until now, no meta-analysis has been conducted to summarize mortality from enteric fever. Therefore, we conducted a systematic review and meta-analysis to aggregate all available evidence. We estimated an overall CFR of 2.49% (95% confidence interval, 1.65%-3.75%; n = 44), and a CFR in hospitalized patients of 4.45% (2.85%-6.88%; n = 21 of 44). There was considerably heterogeneity in estimates of the CFR from individual studies. Neither age nor antimicrobial resistance were significant prognostic factors, but limited data were available for these analyses. The combined estimate of the CFR for enteric fever is higher than previously estimated, and the evaluation of prognostic factors, including antimicrobial resistance, urgently requires more data.

Ebola virus causes a devastating clinical illness that is associated with high mortality. In this trial conducted primarily in West Africa during an outbreak, ZMapp (a cocktail of three monoclonal antibodies against Ebola) showed some clinical activity. The 2014–2016 Ebola outbreak in West Africa was unprecedented in sheer scope, duration, and number of human casualties. 1 , 2 The outbreak resulted in more than 28,000 suspected or confirmed cases of Ebola virus disease (EVD) and more than 11,000 deaths. 3 Fragile health care infrastructures that were often already severely compromised by past years of civil strife played a substantial role in the propagation of the outbreak. Although the final postmortem analysis of the global response has yet to be written, there can be little doubt that the lack of therapeutic agents and vaccines with proven efficacy against EVD further contributed . . .

Ebola transmission has been ongoing in the Democratic Republic of Congo since August 2018. In this trial of MAb114, REGN-EB3, remdesivir, and ZMapp (as the control), mortality from Ebola virus disease was lower in the MAb114 and REGN-EB3 groups than in the other groups.

Purpose It is unknown whether protocols targeting systematic prevention and treatment of fever achieve lower mean body temperature than usual care in intensive care unit (ICU) patients. The objective of the Randomised Evaluation of Active Control of temperature vs. ORdinary temperature management trial was to confirm the feasibility of such a protocol with a view to conducting a larger trial. Methods We randomly assigned 184 adults without acute brain pathologies who had a fever in the previous 12 h, and were expected to be ventilated beyond the calendar day after recruitment, to systematic prevention and treatment of fever or usual care. The primary outcome was mean body temperature in the ICU within 7 days of randomisation. Secondary outcomes included in-hospital mortality, ICU-free days and survival time censored at hospital discharge. Results Compared with usual temperature management, active management significantly reduced mean temperature. In both groups, fever generally abated within 72 h. The mean temperature difference between groups was greatest in the first 48 h, when it was generally in the order of 0.5 °C. Overall, 23 of 89 patients assigned to active management (25.8%) and 23 of 89 patients assigned to usual management (25.8%) died in hospital (odds ratio 1.0, 95% CI 0.51–1.96, P  = 1.0). There were no statistically significant differences between groups in ICU-free days or survival to day 90. Conclusions Active temperature management reduced body temperature compared with usual care; however, fever abated rapidly, even in patients assigned to usual care, and the magnitude of temperature separation was small. Trial registration Australian and New Zealand Clinical Trials Registry Number, ACTRN12616001285448

Pork accounts for almost one-third of the meat consumed worldwide. Infectious diseases have a marked impact on pig production. Epidemiological indicators are considered the most useful criteria in decision-making; however, a health status assessment remains a challenge at the national and regional levels. This study proposes a health index including herd-losses, morbidity, fatality, and type of diseases, to rate the health situation in a region or country; it contributes to assessing the effectiveness of control, damage manifestation, and trends. It is a multidimensional index with a structure of triads and simple quantitative, semi-quantitative, and qualitative expressions that use flexible and dynamics limits. With it, we analyzed twenty-one countries in 2005–2018, focusing on African swine fever, classical swine fever, foot-mouth-disease, and porcine respiratory and reproductive syndrome, diseases that caused 72% of the morbidity. Our multidimensional approach estimates farm, local, and regional impact from infectious agents and outbreaks, and apprises trends aiming to be useful to control measures, strategic actions, and animal health policies.