Prevalence and distribution of non-typhoidal Salmonella enterica serogroups and serovars isolated from normally sterile sites: A global systematic review.

To inform coverage by potential vaccines, we aimed to systematically review evidence on the prevalence and distribution of non-typhoidal Salmonella enterica serogroups and serovars. We searched four databases from inception through 4 June 2021. Articles were included that reported at least one non-typhoidal S. enterica strain by serogroup or serovar isolated from a normally sterile site. Of serogrouped isolates, we pooled the prevalence of serogroup O:4, serogroup O:9, and other serogroups using random-effects meta-analyses. Of serotyped isolates, we pooled the prevalence of Salmonella Typhimurium (member of serogroup O:4), Salmonella Enteritidis (member of serogroup O:9), and other serovars. Of 82 studies yielding 24,253 serogrouped isolates, the pooled prevalence (95% CI) was 44.6% (36.2%-48.2%) for serogroup O:4, 45.5% (37.0%-49.1%) for serogroup O:9, and 9.9% (6.1%-13.3%) for other serogroups. Of serotyped isolates, the pooled prevalence (95%CI) was 36.8% (29.9%-44.0%) for Salmonella Typhimurium, 37.8% (33.2%-42.4%) for Salmonella Enteritidis, and 18.4% (11.4%-22.9%) for other serovars. Of global serogrouped non-typhoidal Salmonella isolates from normally sterile sites, serogroup O:4 and O:9 together accounted for 90%, and among serotyped isolates, serovars Typhimurium and Enteritidis together accounted for 75%. Vaccine development strategies covering serogroups O:4 and O:9, or serovars Typhimurium and Enteritidis, have the potential to prevent the majority of non-typhoidal Salmonella invasive disease.

Characterization of Typhoid Intestinal Perforation in Africa: Results From the Severe Typhoid Fever Surveillance in Africa Program.

Background: Typhoid intestinal perforation (TIP) remains the most serious complication of typhoid fever. In many countries, the diagnosis of TIP relies on intraoperative identification, as blood culture and pathology capacity remain limited. As a result, many cases of TIP may not be reported as typhoid. This study demonstrates the burden of TIP in sites in Burkina Faso, Democratic Republic of Congo (DRC), Ethiopia, Ghana, Madagascar, and Nigeria. Methods: Patients with clinical suspicion of nontraumatic intestinal perforation were enrolled and demographic details, clinical findings, surgical records, blood cultures, tissue biopsies, and peritoneal fluid were collected. Participants were then classified as having confirmed TIP, probable TIP, possible TIP, or clinical intestinal perforation based on surgical descriptions and cultures. Results: A total of 608 participants were investigated for nontraumatic intestinal perforation; 214 (35%) participants had surgically-confirmed TIP and 33 participants (5%) had culture-confirmed typhoid. The overall proportion of blood or surgical site Salmonella enterica subspecies enterica serovar Typhi positivity in surgically verified TIP cases was 10.3%. TIP was high in children aged 5-14 years in DRC, Ghana, and Nigeria. We provide evidence for correlation between monthly case counts of S. Typhi and the occurrence of intestinal perforation. Conclusions: Low S. Typhi culture positivity rates, as well as a lack of blood and tissue culture capability in many regions where typhoid remains endemic, significantly underestimate the true burden of typhoid fever. The occurrence of TIP may indicate underlying typhoid burden, particularly in countries with limited culture capability.

Magnetic Appendix: An Uncommon Indication for Appendectomy.

Foreign object ingestions are a common occurrence in pediatrics, often necessitating endoscopic or surgical intervention. The ingestion of multiple magnets poses an increased risk for serious complications. Our article presents a case of a five-year-old boy who swallowed two pennies and four magnets. The latter failed to pass spontaneously and were lodged in the appendiceal orifice resulting in a challenging and unsuccessful endoscopic retrieval and hence required laparoscopic exploration, appendectomy, and partial cecal resection.

Safety and immunogenicity of AGS-v PLUS, a mosquito saliva peptide vaccine against arboviral diseases: A randomized, double-blind, placebo-controlled Phase 1 trial.

BACKGROUND: Immunity to mosquito salivary proteins could provide protection against multiple mosquito-borne diseases and significantly impact public health. We evaluated the safety and immunogenicity of AGS-v PLUS, a mosquito salivary peptide vaccine, in healthy adults 18-50 years old. METHODS: We conducted a randomized, double-blind, placebo-controlled Phase 1 study of AGS-v PLUS administered subcutaneously on Days 1 and 22 at the Center for Vaccine Development and Global Health, Baltimore, MD, USA. Participants were block randomized 1:1:1:1:1 to two doses saline placebo, two doses AGS-v PLUS, AGS-v PLUS/ISA-51 and saline placebo, two doses AGS-v PLUS/ISA-51, or two doses AGS-v PLUS/Alhydrogel. Primary endpoints were safety (all participants receiving ≥1 injection) and antibody and cytokine responses (all participants with day 43 samples), analysed by intention to treat. FINDINGS: Between 26 August 2019 and 25 February 2020, 51 participants were enrolled and randomized, 11 into the single dose AGS-v PLUS/ISA-51 group and ten in other groups. Due to COVID-19, 15 participants did not return for day 43 samplings. Participants experienced no treatment-emergent or serious adverse events. All solicited symptoms in 2/10 placebo recipients and 22/41 AGS-v PLUS recipients after dose one and 1/10 placebo recipients and 22/41 AGS-v PLUS recipients after dose two were mild/moderate except for one severe fever the day after vaccination (placebo group). Only injection site pain was more common in vaccine groups (15/51 after dose 1 and 11/51 after dose 2) versus placebo. Compared to placebo, all vaccine groups had significantly greater fold change in anti-AGS-v PLUS IgG and IFN-É£ from baseline. INTERPRETATION: AGS-v PLUS had favourable safety profile and induced robust immune responses. Next steps will determine if findings translate into clinical efficacy against mosquito-borne diseases. FUNDING: UK Department of Health and Social Care.

Complications and mortality of non-typhoidal salmonella invasive disease: a global systematic review and meta-analysis.

BACKGROUND: Non-typhoidal salmonella can cause serious, life-threatening invasive infections involving the bloodstream and other normally sterile sites. We aimed to systematically review the prevalence of complications and case-fatality ratio (CFR) of non-typhoidal salmonella invasive disease to provide contemporary global estimates and inform the development of vaccine and non-vaccine interventions. METHODS: We did a global systematic review and meta-analysis of studies investigating the complications and mortality associated with non-typhoidal salmonella invasive disease. We searched Embase, MEDLINE, Web of Science, and PubMed for peer-reviewed, primary research articles published from database inception up to June 4, 2021, with no restrictions on language, country, date, or participant demographics. Only studies reporting the proportion of complications or deaths associated with non-typhoidal salmonella invasive disease, confirmed by culture of samples taken from a normally sterile site (eg, blood or bone marrow) were included. We excluded case reports, case series, policy reports, commentaries, editorials, and conference abstracts. Data on the prevalence of complications and CFR were abstracted. The primary outcomes were to estimate the prevalence of complications and CFR of non-typhoidal salmonella invasive disease. We calculated an overall pooled CFR estimate and pooled CFR stratified by UN region, subregion, age group, and by serovar when available with a random-effects meta-analysis. A risk-of-bias assessment was done, and heterogeneity was assessed with Cochran's Q Test, I2, and τ2. This study was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, and is registered with PROSPERO, CRD42020202293. FINDINGS: The systematic review returned a total of 8770 records. After duplicates were removed, 5837 titles and abstracts were screened, yielding 84 studies from 35 countries after exclusions. Of these included studies, 77 (91·7%) were hospital-based and 66 (78·6%) were located in Africa or Asia. Among 55 studies reporting non-typhoidal salmonella disease-associated complications, a total of 45 different complications were reported and 1824 complication events were identified among 6974 study participants. The most prevalent complication was septicaemia, occurring in 171 (57·2%) of 299 participants, followed by anaemia in 580 (47·3%) of 1225 participants. From 81 studies reporting the CFR of non-typhoidal salmonella invasive disease, the overall pooled CFR estimate was 14·7% (95% CI 12·2-17·3). When stratified by UN region, the pooled CFR was 17·1% (13·6-21·0) in Africa, 14·0% (9·4-19·4) in Asia, 9·9% (6·4-14·0) in Europe, and 9·6% (0·0-25·1) in the Americas. Of all 84 studies, 66 (78·6%) had an overall high risk of bias, 18 (21·4%) had a moderate risk, and none had a low risk. Substantial heterogeneity (I2>80%) was observed in most (15 [65·2%] of 23) CFR estimates. INTERPRETATION: Complications were frequent among individuals with non-typhoidal salmonella invasive disease and approximately 15% of patients died. Clinicians, especially in African countries, should be aware of non-typhoidal salmonella invasive disease as a cause of severe febrile illness. Prompt diagnoses and management decisions, including empiric antimicrobial therapy, would improve patient outcomes. Additionally, investments in improving clinical microbiology facilities to identify non-typhoidal salmonella and research efforts towards vaccine development and non-vaccine prevention measures would prevent non-typhoidal salmonella invasive disease-associated illness and death. FUNDING: EU Horizon 2020 research and innovation programme.

Median Arcuate Ligament Syndrome is Effectively Relieved with Minimally Invasive Surgery.

Objective: Median arcuate ligament (MAL) syndrome is a constellation of symptoms related to compression of the celiac artery trunk. Minimally invasive release of the ligament has been shown to improve these symptoms. This study describes one institution's experience with this procedure and reports on outcomes of minimally invasive release and patient quality of life. Methods: We performed a retrospective chart review of all patients who underwent minimally invasive release of the MAL at our institution. Patients were mailed a survey consisting of the 36-Item Short Form and Visick questionnaires. If surveys were not returned after one month, patients were called and asked to complete them over the phone. Demographic and pre- and postoperative data were collected and analyzed. Results: Eleven patients underwent a laparoscopic MAL release from January 1, 2015 to January 31, 2020. Most patients, 73%, reported epigastric pain as their primary symptom for a median of 18 months. All cases were successfully completed laparoscopically, with only one intraoperative complication. Mean hospital length of stay was 1.4 d. At the time of survey completion, the mean weight change was 2.3 kg. Additional interventions for resolution of symptoms and celiac artery stenosis were required for two patients. Surveys were completed by eight patients. A mean Visick score of 1.8 showed resolution or improved symptoms for all patients. SF-36 scores were highest for physical functioning, emotional well-being, and social functioning health areas. Conclusions: Minimally invasive release of the MAL is a safe and effective surgery for patients suffering from MALS. Symptoms improved after adequate release of the ligament, with minimal morbidity and additional postoperative procedures needed.

Typhoid Conjugate Vaccines: Advancing the Research and Public Health Agendas.

The disease burden of typhoid fever remains high in endemic areas in Asia and Africa, especially in children. Recent clinical trials conducted by the Typhoid Vaccine Acceleration Consortium show typhoid conjugate vaccine (TCV) to be safe, immunogenic, and efficacious at preventing blood culture-confirmed typhoid fever in African and Asian children. Pakistan, Liberia, and Zimbabwe recently introduced TCV through campaigns and routine childhood immunizations, providing protection for this vulnerable population. It is essential to continue this momentum while simultaneously filling data gaps-including typhoid complications-to inform decision-making on TCV introduction. A multidisciplinary approach including surveillance, water, sanitation, and hygiene investments, and large-scale TCV introduction is needed to decrease the burden and mortality of typhoid fever.

Safety and Efficacy of a Typhoid Conjugate Vaccine in Malawian Children.

BACKGROUND: Typhoid fever caused by multidrug-resistant H58 Salmonella Typhi is an increasing public health threat in sub-Saharan Africa. METHODS: We conducted a phase 3, double-blind trial in Blantyre, Malawi, to assess the efficacy of Vi polysaccharide typhoid conjugate vaccine (Vi-TCV). We randomly assigned children who were between 9 months and 12 years of age, in a 1:1 ratio, to receive a single dose of Vi-TCV or meningococcal capsular group A conjugate (MenA) vaccine. The primary outcome was typhoid fever confirmed by blood culture. We report vaccine efficacy and safety outcomes after 18 to 24 months of follow-up. RESULTS: The intention-to-treat analysis included 28,130 children, of whom 14,069 were assigned to receive Vi-TCV and 14,061 were assigned to receive the MenA vaccine. Blood culture-confirmed typhoid fever occurred in 12 children in the Vi-TCV group (46.9 cases per 100,000 person-years) and in 62 children in the MenA group (243.2 cases per 100,000 person-years). Overall, the efficacy of Vi-TCV was 80.7% (95% confidence interval [CI], 64.2 to 89.6) in the intention-to-treat analysis and 83.7% (95% CI, 68.1 to 91.6) in the per-protocol analysis. In total, 130 serious adverse events occurred in the first 6 months after vaccination (52 in the Vi-TCV group and 78 in the MenA group), including 6 deaths (all in the MenA group). No serious adverse events were considered by the investigators to be related to vaccination. CONCLUSIONS: Among Malawian children 9 months to 12 years of age, administration of Vi-TCV resulted in a lower incidence of blood culture-confirmed typhoid fever than the MenA vaccine. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT03299426.).

Complications and mortality of typhoid fever: A global systematic review and meta-analysis.

OBJECTIVES: Updated estimates of the prevalence of complications and case fatality ratio (CFR) among typhoid fever patients are needed to understand disease burden. METHODS: Articles published in PubMed and Web of Science from 1 January 1980 through 29 January 2020 were systematically reviewed for hospital or community-based non-surgical studies that used cultures of normally sterile sites, and hospital surgical studies of typhoid intestinal perforation (TIP) with intra- or post-operative findings suggestive of typhoid. Prevalence of 21 pre-selected recognized complications of typhoid fever, crude and median (interquartile range) CFR, and pooled CFR estimates using a random effects meta-analysis were calculated. RESULTS: Of 113 study sites, 106 (93.8%) were located in Asia and Africa, and 84 (74.3%) were non-surgical. Among non-surgical studies, 70 (83.3%) were hospital-based. Of 10,355 confirmed typhoid patients, 2,719 (26.3%) had complications. The pooled CFR estimate among non-surgical patients was 0.9% for the Asia region and 5.4% for the Africa region. Delay in care was significantly correlated with increased CFR in Asia (r = 0.84; p<0.01). Among surgical studies, the median CFR of TIP was 15.5% (6.7-24.1%) per study. CONCLUSIONS: Our findings identify considerable typhoid-associated illness and death that could be averted with prevention measures, including typhoid conjugate vaccine introduction.

Morbidity and Mortality of Typhoid Intestinal Perforation Among Children in Sub-Saharan Africa 1995-2019: A Scoping Review.

BACKGROUND: Typhoid fever incidence and complications, including intestinal perforation, have declined significantly in high-income countries, with mortality rates <1%. However, an estimated 10.9 million cases still occur annually, most in low- and middle-income countries. With the availability of a new typhoid conjugate vaccine licensed for children and recommended by the World Health Organization, understanding severe complications, including associated mortality rates, is essential to inform country-level decisions on introduction of this vaccine. This scoping review summarizes over 20 years of the literature on typhoid intestinal perforation in sub-Saharan Africa. METHODS: We searched EMBASE, PubMed, Medline, and Cochrane databases for studies reporting mortality rates due to typhoid intestinal perforation in children, under 18 years old, in sub-Saharan Africa published from January 1995 through June 2019. RESULTS: Twenty-four papers from six countries were included. Reported mortality rates ranged from 4.6-75%, with 16 of the 24 studies between 11 and 30%. Thirteen papers included postoperative morbidity rates, ranging from 16-100%. The most documented complications included surgical site infections, intra-abdominal abscesses, and enterocutaneous fistulas. High mortality rates can be attributed to late presentation to tertiary centers, sepsis and electrolyte abnormalities requiring preoperative resuscitation, prolonged perforation-to-surgery interval, and lack of access to critical care or an intensive care unit postoperatively. CONCLUSIONS: Current estimates of mortality related to typhoid intestinal perforation among children in sub-Saharan Africa remain unacceptably high. Prevention of typhoid fever is essential to reduce mortality, with the ultimate goal of a comprehensive approach that utilizes vaccination, improvements in water, sanitation, and hygiene, and greater access to surgical care.

Bilateral lower extremity ischemia due to a retained umbilical artery catheter in a preterm neonate.

The use of umbilical artery catheters is common in Neonatal Intensive Care Units, especially in low and very low birth weight neonates. Rarely, these can break or fracture, leading to a retained fragment, which can embolize or cause thrombosis. We pre sent a case of a very low birth weight, premature neonate, 940 grams, with a retained umbilical artery catheter that led to bilateral lower extremity ischemia. A laparotomy with aortotomy was per formed for retrieval of the catheter. Chronic occlusion of the aorta with collateralization is a long-term complication associated with this case.