Achieving Impact: Charting the Course to Meet the Challenges Ahead at the 12th International Conference on Typhoid and Other Invasive Salmonelloses.

Typhoid fever and other invasive salmonelloses remain a major public health concern, primarily in low- and middle-income countries in Asia and Africa, where transmission occurs through contaminated food or water. However, recent developments in research, policy, and implementation offer newfound optimism for prevention and control. Now, more than ever, a coordinated and multisectoral global response is needed. To chart the course to meet the challenges ahead, the Coalition against Typhoid, housed at the Sabin Vaccine Institute, virtually organized the 12th International Conference on Typhoid and Other Invasive Salmonelloses from December 7 to 9, 2021. This commentary provides an overview of the conference's significant findings, highlighting barriers and opportunities for prevention and control. Topics covered include diagnostics advancements, improved data methodologies for a better understanding of the disease burden, the incorporation of environmental surveillance and genomics, the threat of drug resistance, and the use of typhoid conjugate vaccines alongside other integrated solutions.

A nontyphoidal Salmonella serovar domestication accompanying enhanced niche adaptation.

Invasive nontyphoidal Salmonella (iNTS) causes extraintestinal infections with ~15% case fatality in many countries. However, the mechanism by which iNTS emerged in China remains unaddressed. We conducted clinical investigations of iNTS infection with recurrent treatment failure, caused by underreported Salmonella enterica serovar Livingstone (SL). Genomic epidemiology demonstrated five clades in the SL population and suggested that the international animal feed trade was a likely vehicle for their introduction into China, as evidenced by multiple independent transmission incidents. Importantly, isolates from Clade-5-I-a/b, predominant in China, showed an invasive nature in mice, chicken and zebrafish infection models. The antimicrobial susceptibility testing revealed most isolates (> 96%) in China are multidrug-resistant (MDR). Overall, we offer exploiting genomics in uncovering international transmission led by the animal feed trade and highlight an emerging hypervirulent clade with increased resistance to frontline antibiotics.

Clinical profiles and antimicrobial resistance patterns of invasive Salmonella infections in children in China.

Invasive Salmonella infections result in a significant burden of disease including morbidity, mortality, and financial cost in many countries. Besides typhoid fever, the clinical impact of non-typhoid Salmonella infections is increasingly recognized with the improvement of laboratory detection capacity and techniques. A retrospective multicenter study was conducted to analyze the clinical profiles and antimicrobial resistance patterns of invasive Salmonella infections in hospitalized children in China during 2016-2018. A total of 130 children with invasive Salmonella infections were included with the median age of 12 months (range: 1-144 months). Seventy-nine percent of cases occurred between May and October. Pneumonia was the most common comorbidity in 33 (25.4%) patients. Meningitis and septic arthritis caused by nontyphoidal Salmonella (NTS) infections occurred in 12 (9.2%) patients and 5 (3.8%) patients. Patients < 12 months (OR: 16.04) and with septic shock (OR: 23.4), vomit (OR: 13.33), convulsion (OR: 15.86), C-reactive protein (CRP) ≥ 40 g/L (OR: 5.56), and a higher level of procalcitonin (PCT) (OR: 1.05) on admission were statistically associated to an increased risk of developing meningitis. Compared to 114 patients with NTS infections, 16 patients with typhoid fever presented with higher levels of CRP and PCT (P < 0.05). The rates of resistance to ampicillin, sulfamethoxazole/trimethoprim, ciprofloxacin, and ceftriaxone among Salmonella Typhi and NTS isolates were 50% vs 57.3%, 9.1% vs 24.8%, 0% vs 11.2%, and 0% vs 9.9%, respectively. NTS has been the major cause of invasive Salmonella infections in Chinese children and can result in severe diseases. Antimicrobial resistance among NTS was more common.

Staged progression epidemic models for the transmission of invasive nontyphoidal Salmonella (iNTS) with treatment.

We develop and analyze a stage-progression compartmental model to study the emerging invasive nontyphoidal Salmonella (iNTS) epidemic in sub-Saharan Africa. iNTS bloodstream infections are often fatal, and the diverse and non-specific clinical features of iNTS make it difficult to diagnose. We focus our study on identifying approaches that can reduce the incidence of new infections. In sub-Saharan Africa, transmission and mortality are correlated with the ongoing HIV epidemic and severe malnutrition. We use our model to quantify the impact that increasing antiretroviral therapy (ART) for HIV infected adults and reducing malnutrition in children would have on mortality from iNTS in the population. We consider immunocompromised subpopulations in the region with major risk factors for mortality, such as malaria and malnutrition among children and HIV infection and ART coverage in both children and adults. We parameterize the progression rates between infection stages using the branching probabilities and estimated time spent at each stage. We interpret the basic reproduction number R0 as the total contribution from an infinite infection loop produced by the asymptomatic carriers in the infection chain. The results indicate that the asymptomatic HIV+ adults without ART serve as the driving force of infection for the iNTS epidemic. We conclude that the worst disease outcome is among the pediatric population, which has the highest infection rates and death counts. Our sensitivity analysis indicates that the most effective strategies to reduce iNTS mortality in the studied population are to improve the ART coverage among high-risk HIV+ adults and reduce malnutrition among children.

Evasion of MAIT cell recognition by the African Salmonella Typhimurium ST313 pathovar that causes invasive disease.

Mucosal-associated invariant T (MAIT) cells are innate T lymphocytes activated by bacteria that produce vitamin B2 metabolites. Mouse models of infection have demonstrated a role for MAIT cells in antimicrobial defense. However, proposed protective roles of MAIT cells in human infections remain unproven and clinical conditions associated with selective absence of MAIT cells have not been identified. We report that typhoidal and nontyphoidal Salmonella enterica strains activate MAIT cells. However, S. Typhimurium sequence type 313 (ST313) lineage 2 strains, which are responsible for the burden of multidrug-resistant nontyphoidal invasive disease in Africa, escape MAIT cell recognition through overexpression of ribB This bacterial gene encodes the 4-dihydroxy-2-butanone-4-phosphate synthase enzyme of the riboflavin biosynthetic pathway. The MAIT cell-specific phenotype did not extend to other innate lymphocytes. We propose that ribB overexpression is an evolved trait that facilitates evasion from immune recognition by MAIT cells and contributes to the invasive pathogenesis of S. Typhimurium ST313 lineage 2.

Global Action for Local Impact: The 11th International Conference on Typhoid and Other Invasive Salmonelloses.

Typhoid and other invasive salmonelloses continue to cause an estimated 14.8 million cases and > 200 000 deaths annually, largely affecting children in low- and middle-income countries. However, recent strides in global policy have paved the way for accelerated progress with prevention and control efforts. To translate these recent advancements at the global level into real impact in communities at the local level, the Coalition against Typhoid, based at the Sabin Vaccine Institute, convened the 11th International Conference on Typhoid and Other Invasive Salmonelloses in Hanoi, Vietnam, in March 2019. Here, we review the significant topics and research discussed at the conference, including diagnostics, environmental surveillance, drug resistance, burden of disease, and vaccines, as well as additional prevention and control interventions.

Salmonella enterica Serovar Panama, an Understudied Serovar Responsible for Extraintestinal Salmonellosis Worldwide.

In recent years nontyphoidal Salmonella has emerged as one of the pathogens most frequently isolated from the bloodstream in humans. Only a small group of Salmonella serovars cause this systemic infection, known as invasive nontyphoidal salmonellosis. Here, we present a focused minireview on Salmonella enterica serovar Panama, a serovar responsible for invasive salmonellosis worldwide. S Panama has been linked with infection of extraintestinal sites in humans, causing septicemia, meningitis, and osteomyelitis. The clinical picture is often complicated by antimicrobial resistance and has been associated with a large repertoire of transmission vehicles, including human feces and breast milk. Nonhuman sources of S Panama involve reptiles and environmental reservoirs, as well as food animals, such as pigs. The tendency of S Panama to cause invasive disease may be linked to certain serovar-specific genetic factors.

Multidrug Resistant Invasive Nontyphoidal Salmonella Isolated from and Masquerading Healed Tubercular Constrictive Pericarditis and Study of Virulence Markers.

Among the infectious causes of pericarditis are various bacteria, viruses, fungal and parasitic infections. The course disease may progress to a chronic constrictive pattern especially with tubercular etiology. Non-typhoidal Salmonella has rarely been reported as a cause of pericarditis. We describe here a case from which the pericardial fluid from an old case of tubercular pericarditis sent for culture to microbiology laboratory grew a Salmonella typhimurium. We studied the antibiotic resistance pattern, phage type and virulence factors playing a role in the invasive nature of the pathogen since no such study from pericardial fluid was found in the literature. The isolate was sensitive only to cephalosporins and it was untypable. It showed amplification for five fimbrial operons, three colonization factors, and other genes (pef operon), gog B(Gifsy-1 encoded effector), sseI (Gifsy-2 encoded effector), sodC ( the periplasmic [copper and zinc Cu, Zn ]-superoxide dismutase) & sopE (a guanine nucleotide exchange factors). The present case highlights the need for early detection of the exact causative agent and serovar in management, the likelihood of a different etiological agent other than the original to be kept in mind for timely management and the highly resistant pattern of non-typhoidal Salmonella (NTS) limiting the therapeutic options as in our case to only cephalosporins. The genes encoded from the NTS might be required for invasive cardiac manifestation in humans.

Control of Invasive Salmonella Disease in Africa: Is There a Role for Human Challenge Models?

Invasive Salmonella disease in Africa is a major public health concern. With evidence of the transcontinental spread of the Salmonella Typhi H58 haplotype, improved estimates of the burden of infection and understanding of the complex interplay of factors affecting disease transmission are needed to assist with efforts aimed at disease control. In addition to Salmonella Typhi, invasive nontyphoidal Salmonella are increasingly recognized as an important cause of febrile illness and mortality in sub-Saharan Africa. Human experimental oral challenge studies with Salmonella can be used as a model to offer unique insights into host-pathogen interactions as well as a platform to efficiently test new diagnostic and vaccine candidates. In this article, we review the background and use of human challenge studies to date and discuss how findings from these studies may lead to progress in the control of invasive Salmonella disease in Africa.

Invasive Salmonella Infections Among Children From Rural Mozambique, 2001-2014.

BACKGROUND: Invasive nontyphoidal Salmonella (iNTS) has emerged as a cause of bacteremia in African children and HIV-infected adults, which is associated with high mortality. Epidemiological data and burden of iNTS infections in resource-constrained settings are needed to better define preventive and curative strategies. METHODS: Blood and, if appropriate, cerebrospinal fluid, were collected from children <15 years of age with fever or severe disease admitted to the Manhiça District Hospital and cultured for NTS; isolates were then characterized. RESULTS: From January 2001 to December 2014, 41,668 of the 51,878 admitted children had a blood culture performed. Invasive NTS was isolated from 670 (1.6%) specimens collected from 41,668 patients; 69 (10.3% died). Salmonella enterica subspecies enterica serovar Typhi or Salmonella enterica subspecies enterica serovar Paratyphi A or C were only isolated in 14 (0.03%) patients. A total of 460 of 620 (74.2%) NTS isolates serotyped were Salmonella enterica subspecies enterica serovar Typhimurium (45% [116/258] of which were multilocus sequence type 313). The incidence of iNTS was 61.8 (95% confidence interval, 55.4-68.9) cases per 100,000 child-years, being highest among infants (217.7 cases/100,000 child-years). The incidence of iNTS declined significantly (P < .0001) over time, but the case fatality ratio remained constant at approximately 10%. Antimicrobial resistance of iNTS against most available antimicrobials has steadily increased, with a predominance of multidrug-resistant strains. CONCLUSIONS: The decreasing but still high incidence of iNTS, its high associated case fatality ratio, and the common detection of multidrug-resistant strains call for a need to improve treatment and prevention strategies for iNTS.