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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.

Enteric fever, caused by the human-restricted bacteria Salmonella enterica serovar Typhi (typhoid) and Salmonella enterica serovar Paratyphi A, B, and C (paratyphoid), affects persons residing in, or travelling from, areas lacking safe water, sanitation, and hygiene infrastructure. Transmission is by the faecal–oral route. A gradual fever onset over 3–7 days with malaise, headache, and myalgia is typical. Symptoms can be altered by previous antimicrobial use. Life-threatening complications can arise in the second week of untreated illness. Differentiation from other febrile illnesses is challenging. Blood or bone marrow culture remain reference standard diagnostic methods, despite the low sensitivity of blood culture. Azithromycin, ciprofloxacin (excepting cases originating in south Asia due to drug resistance), or ceftriaxone are recommended treatment options for both typhoid and paratyphoid; however, choice should be guided by local resistance patterns. Ciprofloxacin-resistant and ceftriaxone-resistant typhoid is common in Pakistan. Three vaccine types are available for prevention of typhoid disease, including the newer, more effective typhoid Vi-conjugate vaccines. Vaccination as well as water, sanitation, and hygiene measures are cornerstones of prevention.

In surveillance for typhoid fever, under-detection of cases occurs when patients with fever do not seek medical care, or seek medical care but do not receive a blood test. Missing data may result in incorrect estimates of disease incidence. We used data from an ongoing randomised clinical trial of typhoid conjugate vaccine among children in Nepal to determine if eligible patients attending our fever clinics who did not have blood taken for culture had a lower risk of disease than those who had blood drawn. We assessed clinical and demographic predictors of having blood taken for culture, and predictors of culture-positive results. Missing blood culture data were imputed using multiple imputations. During the first year of surveillance, 2392 fever presentations were recorded and 1615 (68%) of these had blood cultures. Children were more likely to have blood taken for culture if they were older, had fever for longer, a current temperature ≥38 degrees, or if typhoid or a urinary tract infection were suspected. Based on imputation models, those with blood cultures were 1.87 times more likely to have blood culture-positive fever than those with missing data. Clinical opinion on the cause of the fever may play a large part in the decision to offer blood culture, regardless of study protocol. Crude typhoid incidence estimates should be adjusted for the proportion of cases that go undetected due to missing blood cultures while adjusting for the lower likelihood of culture-positivity in the group with missing data.

Typhoid and paratyphoid fever continue to be important causes of illness and death, particularly among children and adolescents in south-central and Southeast Asia, where enteric fever is associated with poor sanitation and unsafe food and water. High-quality incidence data from Asia are underpinning efforts to expand access to typhoid vaccines. Efforts are underway to develop vaccines that are immunogenic in infants after a single dose and that can be produced locally in countries of endemicity. The growing importance of Salmonella enterica serotype Paratyphi A in Asia is concerning. Antimicrobial resistance has sequentially emerged to traditional first-line drugs, fluoroquinolones, and third-generation cephalosporins, posing patient treatment challenges. Azithromycin has proven to be an effective alternative for treatment of uncomplicated typhoid fever. The availability of full genome sequences for S. enterica serotype Typhi and S. enterica serotype Paratyphi A confirms their place as monomorphic, human-adapted pathogens vulnerable to control measures if international efforts can be redoubled.

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 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.

From 2017 through 2020 in India, weekly surveillance for blood-confirmed typhoid and paratyphoid among children showed an incidence of 576 to 1173 cases of typhoid fever per 100,000 child-years in urban sites.

Blood culture is the standard diagnostic method for typhoid and paratyphoid (enteric) fever in surveillance studies and clinical trials, but sensitivity is widely acknowledged to be suboptimal. We conducted a systematic review and meta-analysis to examine sources of heterogeneity across studies and quantified the effect of blood volume. We searched the literature to identify all studies that performed blood culture alongside bone marrow culture (a gold standard) to detect cases of enteric fever. We performed a meta-regression analysis to quantify the relationship between blood sample volume and diagnostic sensitivity. Furthermore, we evaluated the impact of patient age, antimicrobial use, and symptom duration on sensitivity. We estimated blood culture diagnostic sensitivity was 0.59 (95% confidence interval [CI], 0.54-0.64) with significant between-study heterogeneity (I2, 76% [95% CI, 68%-82%]; P < .01). Sensitivity ranged from 0.51 (95% CI, 0.44-0.57) for a 2-mL blood specimen to 0.65 (95% CI, 0.58-0.70) for a 10-mL blood specimen, indicative of a relationship between specimen volume and sensitivity. Subgroup analysis showed significant heterogeneity by patient age and a weak trend towards higher sensitivity among more recent studies. Sensitivity was 34% lower (95% CI, 4%-54%) among patients with prior antimicrobial use and 31% lower after the first week of symptoms (95% CI, 19%-41%). There was no evidence of confounding by patient age, antimicrobial use, symptom duration, or study date on the relationship between specimen volume and sensitivity. The relationship between the blood sample volume and culture sensitivity should be accounted for in incidence and next-generation diagnostic studies.

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.