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Enteric fever is a systemic infection caused by Salmonella Typhi or Paratyphi A. In many endemic areas, these serovars co-circulate and can cause multiple infection-episodes in childhood. Prior exposure is thought to confer partial, but incomplete, protection against subsequent attacks of enteric fever. Empirical data to support this hypothesis are limited, and there are few studies describing the occurrence of heterologous-protection between these closely related serovars. We performed a challenge-re-challenge study using a controlled human infection model (CHIM) to investigate the extent of infection-derived immunity to Salmonella Typhi or Paratyphi A infection. We recruited healthy volunteers into two groups: naïve volunteers with no prior exposure to Salmonella Typhi/Paratyphi A and volunteers previously-exposed to Salmonella Typhi or Paratyphi A in earlier CHIM studies. Within each group, participants were randomised 1:1 to oral challenge with either Salmonella Typhi (104 CFU) or Paratyphi A (103 CFU). The primary objective was to compare the attack rate between naïve and previously challenged individuals, defined as the proportion of participants per group meeting the diagnostic criteria of temperature of ≥38°C persisting for ≥12 hours and/or S. Typhi/Paratyphi bacteraemia up to day 14 post challenge. The attack-rate in participants who underwent homologous re-challenge with Salmonella Typhi was reduced compared with challenged naïve controls, although this reduction was not statistically significant (12/27[44%] vs. 12/19[63%]; Relative risk 0.70; 95% CI 0.41-1.21; p = 0.24). Homologous re-challenge with Salmonella Paratyphi A also resulted in a lower attack-rate than was seen in challenged naïve controls (3/12[25%] vs. 10/18[56%]; RR0.45; 95% CI 0.16-1.30; p = 0.14). Evidence of protection was supported by a post hoc analysis in which previous exposure was associated with an approximately 36% and 57% reduced risk of typhoid or paratyphoid disease respectively on re-challenge. Individuals who did not develop enteric fever on primary exposure were significantly more likely to be protected on re-challenge, compared with individuals who developed disease on primary exposure. Heterologous re-challenge with Salmonella Typhi or Salmonella Paratyphi A was not associated with a reduced attack rate following challenge. Within the context of the model, prior exposure was not associated with reduced disease severity, altered microbiological profile or boosting of humoral immune responses. We conclude that prior Salmonella Typhi and Paratyphi A exposure may confer partial but incomplete protection against subsequent infection, but with a comparable clinical and microbiological phenotype. There is no demonstrable cross-protection between these serovars, consistent with the co-circulation of Salmonella Typhi and Paratyphi A. Collectively, these data are consistent with surveillance and modelling studies that indicate multiple infections can occur in high transmission settings, supporting the need for vaccines to reduce the burden of disease in childhood and achieve disease control. Trial registration NCT02192008; clinicaltrials.gov.

Background. Enteric fever, caused by Salmonella Typhi and Salmonella Paratyphi A, is the leading cause of bacterial febrile disease in South Asia. Methods. Individual data from 2092 patients with enteric fever randomized into 4 trials in Kathmandu, Nepal, were pooled. All trials compared gatifloxacin with 1 of the following comparator drugs: cefixime, chloramphenicol, ofloxacin, or ceftriaxone. Treatment outcomes were evaluated according to antimicrobial if S. Typhi/Paratyphi were isolated from blood. We additionally investigated the impact of changing bacterial antimicrobial susceptibility on outcome. Results. Overall, 855 (41%) patients had either S. Typhi (n = 581, 28%) or S. Paratyphi A (n = 274, 13%) cultured from blood. There were 139 (6.6%) treatment failures with 1 death. Except for the last trial with ceftriaxone, the fluoroquinolone gatifloxacin was associated with equivalent or better fever clearance times and lower treatment failure rates in comparison to all other antimicrobials. However, we additionally found that the minimum inhibitory concentrations (MICs) against fluoroquinolones have risen significantly since 2005 and were associated with increasing fever clearance times. Notably, all organisms were susceptible to ceftriaxone throughout the study period (2005–2014), and the MICs against azithromycin declined, confirming the utility of these alternative drugs for enteric fever treatment. Conclusion. The World Health Organization and local government health ministries in South Asia still recommend fluoroquinolones for enteric fever. This policy should change based on the evidence provided here. Rapid diagnostics are urgently required given the large numbers of suspected enteric fever patients with a negative culture.

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.

As a result of migrations and globalization, people may face a possible increase in the incidence of central nervous system rickettsial infections (CNS R). These diseases, caused by Rickettsia species and transmitted to humans by arthropod bites, are putatively lethal. However, the diagnosis of CNS R is challenging and often delayed due to their nonspecific clinical presentation and the strict intracellular nature of rickettsiae. Furthermore, transfer of rickettsiae to the brain parenchyma is not yet understood. The aim of this review is to analyze and summarize the features and correlated findings of CNS R in order to focus attention on these intriguing but frequently neglected illnesses. We also incorporated data on CNS infections caused by Rickettsia-related microorganisms.

Enteric fever remains a public health challenge. We analyzed data from a cluster-randomized Vi-tetanus toxoid conjugate vaccine trial to compare the epidemiology between Salmonella enterica serovars Paratyphi A, which causes paratyphoid fever, and Typhi, which causes typhoid fever. The overall incidence rate of paratyphoid fever was 27 (95% CI 23-32)/100,000 person-years (PY) and of typhoid fever was 216 (95% CI 198-236)/100,000 PY. We observed the highest incidence for both diseases in children 2-4 years of age: 72 (95% CI 41-117)/100,000 PY for paratyphoid and 887 (95% CI 715-1,088)/100,000 PY for typhoid. Lack of private toilets and safe drinking water were associated with both diseases. Prevalence of multidrug resistance was significantly higher in Salmonella Typhi (20.2%) than in Salmonella Paratyphi A (0.8%) (p<0.001). Our data suggest that integrated control measures targeting water, sanitation, and hygiene measures and bivalent vaccine targeting both pathogens are promising strategies to control both diseases.

Bacterial zoonoses are diseases caused by bacterial pathogens that can be naturally transmitted between humans and vertebrate animals. They are important causes of non-malarial fevers in Kenya, yet their epidemiology remains unclear. We investigated brucellosis, Q-fever and leptospirosis in the venous blood of 216 malaria-negative febrile patients recruited in two health centres (98 from Ijara and 118 from Sangailu health centres) in Garissa County in north-eastern Kenya. We determined exposure to the three zoonoses using serological (Rose Bengal test for Brucella spp., ELISA for C. burnetti and microscopic agglutination test for Leptospira spp.) and real-time PCR testing and identified risk factors for exposure. We also used non-targeted metagenomic sequencing on nine selected patients to assess the presence of other possible bacterial causes of non-malarial fevers. Considerable PCR positivity was found for Brucella (19.4%, 95% confidence intervals [CI] 14.2–25.5) and Leptospira spp. (1.7%, 95% CI 0.4–4.9), and high endpoint titres were observed against leptospiral serovar Grippotyphosa from the serological testing. Patients aged 5–17 years old had 4.02 (95% CI 1.18–13.70, p -value = 0.03) and 2.42 (95% CI 1.09–5.34, p -value = 0.03) times higher odds of infection with Brucella spp. and Coxiella burnetii than those of ages 35–80. Additionally, patients who sourced water from dams/springs, and other sources (protected wells, boreholes, bottled water, and water pans) had 2.39 (95% CI 1.22–4.68, p -value = 0.01) and 2.24 (1.15–4.35, p -value = 0.02) times higher odds of exposure to C. burnetii than those who used unprotected wells. Streptococcus and Moraxella spp. were determined using metagenomic sequencing. Brucellosis, leptospirosis, Streptococcus and Moraxella infections are potentially important causes of non-malarial fevers in Garissa. This knowledge can guide routine diagnosis, thus helping lower the disease burden and ensure better health outcomes, especially in younger populations.

Rift Valley fever (RVF) virus and Coxiella burnetii infections are significant public health concerns in East Africa, causing recurring outbreaks. However, the prevalence of these pathogens among febrile patients in Ethiopia remains unknown. This study aimed to determine the prevalence and associated factors of these infections among febrile patients. A multisite cross-sectional study was conducted among 415 randomly selected adult febrile patients from health facilities in Shinile and Dire Dawa, Ethiopia, between March 01, 2023, and February 28, 2024. Serum samples were tested for the presence of antibodies against RVF virus and C. burnetii infections using various Enzyme Linked Immunosorbent Assays. Polymerase Chain Reaction (PCR) was used to detect RVF virus RNA and C. burnetii DNA in blood samples. A multivariable logistic regression model was used to identify predictive factors. A p value <0.05 was considered statistically significant. Of the 402 serum samples analyzed, 21 (5.2%) tested positive for immunoglobulin G (IgG) antibodies against RVF virus, and 86 (21.4%) tested positive for C. burnetii Phase I and Phase II antibodies. No RVF virus IgM was detected. Among the C. burnetii antibodies positive sera, 6 (7.0%) were positive for Phase II IgG antibodies. No blood samples tested positive for RVF virus RNA or C. burnetii DNA. Febrile patients aged ≥35 years had significantly higher odds of RVF virus exposure (AOR: 3.1, 95% CI: 1.3-7.8). Females (AOR: 1.7, 95% CI: 1.1-2.9), rural residents (AOR: 2.4, 95% CI: 1.3-4.5), and febrile patients who disposed of dead animals (AOR: 2.6, 95% CI: 1.2-5.6) exhibited significantly higher odds of C. burnetii infection. This study reveals significant but underrecognized exposure to RVF virus (5.2%) and C. burnetii (21.4%) infections among febrile patients. Risk factors for RVF included older age, whereas C. burnetii infection was associated with females, rural residents, and exposure to dead animals. Health authorities are advised to consider these infections in the differential diagnosis of fever, implement active surveillance, and target public health interventions.

We conducted a multicenter surveillance study to identify changes in antimicrobial susceptibility patterns of Salmonella Typhi and S. Paratyphi in India since the COVID-19 pandemic began. We collected S. Typhi and S. Paratyphi isolates from blood or bone marrow culture-confirmed enteric fever cases at eight sites in seven cities across India between 2021 and 2024. We tested the antibiotic susceptibility of 1150 S. Typhi isolates and 265 S. Paratyphi isolates via disc diffusion and determined their minimum inhibitory concentrations (MICs) of ceftriaxone and azithromycin via broth dilution. We identified 18 S. Typhi isolates from Ahmedabad that were resistant to ceftriaxone, indicating a larger emergence of third-generation cephalosporin-resistant S. Typhi in Western India with a novel plasmid profile. Furthermore, we observed yearly increases in the mean, median and 90th percentile of azithromycin MICs for S. Typhi and S. Paratyphi isolates throughout India between 2021 and 2023. Finally, we found that only 0.70% of S. Typhi isolates and 1.13% of S. Paratyphi isolates exhibited susceptibility to ciprofloxacin. Our results indicate the necessity for a shift from ciprofloxacin in the treatment of enteric fever, and the importance of implementing long-term monitoring of resistance to alternative antibiotics such as azithromycin and ceftriaxone.