WHO preferred product characteristics for bivalent Salmonella Typhi/Paratyphi A vaccine for comprehensive protection against enteric fever– key considerations and research gaps

The proportion of paratyphoid fever cases to typhoid fever cases may change due to urbanization and increased dependency on food purchased from street vendors. For containment of paratyphoid a different strategy may be needed than for typhoid, because risk factors for disease may not coincide and current typhoid vaccines do not protect against paratyphoid fever. To determine risk factors for typhoid and paratyphoid fever in an endemic area. Community-based case-control study conducted from June 2001 to February 2003 in hospitals and outpatient health centers in Jatinegara district, Jakarta, Indonesia. Enrolled participants were 1019 consecutive patients with fever lasting 3 or more days, from which 69 blood culture-confirmed typhoid cases, 24 confirmed paratyphoid cases, and 289 control patients with fever but without Salmonella bacteremia were interviewed, plus 378 randomly selected community controls. Blood culture-confirmed typhoid or paratyphoid fever; risk factors for both diseases. In 1019 fever patients we identified 88 (9%) Salmonella typhi and 26 (3%) Salmonella paratyphi A infections. Paratyphoid fever among cases was independently associated with consumption of food from street vendors (comparison with community controls: odds ratio [OR], 3.34; 95% confidence interval [CI], 1.41-7.91; with fever controls: OR, 5.17; 95% CI, 2.12-12.60) and flooding (comparison with community controls: OR, 4.52; 95% CI, 1.90-10.73; with fever controls: OR, 3.25; 95% CI, 1.31-8.02). By contrast, independent risk factors for typhoid fever using the community control group were mostly related to the household, ie, to recent typhoid fever in the household (OR, 2.38; 95% CI, 1.03-5.48); no use of soap for handwashing (OR, 1.91; 95% CI, 1.06-3.46); sharing food from the same plate (OR, 1.93; 95% CI, 1.10-3.37), and no toilet in the household (OR, 2.20; 95% CI, 1.06-4.55). Also, typhoid fever was associated with young age in years (OR, 0.96; 95% CI, 0.94-0.98). In comparison with fever controls, risk factors for typhoid fever were use of ice cubes (OR, 2.27; 95% CI, 1.31-3.93) and female sex (OR, 1.79; 95% CI, 1.04-3.06). Fecal contamination of drinking water was not associated with typhoid or paratyphoid fever. We did not detect fecal carriers among food handlers in the households. In Jakarta, typhoid and paratyphoid fever are associated with distinct routes of transmission, with the risk factors for disease either mainly within the household (typhoid) or outside the household (paratyphoid).

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. 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. 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.

Typhoid and paratyphoid fever may follow a seasonal pattern, but this pattern is not well characterized. Moreover, the environmental drivers that influence seasonal dynamics are not fully understood, although increasing evidence suggests that rainfall and temperature may play an important role. We compiled a database of typhoid, paratyphoid, or enteric fever and their potential environmental drivers. We assessed the seasonal dynamics by region and latitude, quantifying the mean timing of peak prevalence and seasonal variability. Moreover, we investigated the potential drivers of the seasonal dynamics and compared the seasonal dynamics for typhoid and paratyphoid fever. We observed a distinct seasonal pattern for enteric and typhoid fever by latitude, with seasonal variability more pronounced further from the equator. We also found evidence of a positive association between preceding rainfall and enteric fever among settings 35°–11°N and a more consistent positive association between temperature and enteric fever incidence across most regions of the world. In conclusion, we identified varying seasonal dynamics for enteric or typhoid fever in association with environmental factors. The underlying mechanisms that drive the seasonality of enteric fever are likely dependent on the local context and should be taken into account in future control efforts.

SummaryBackgroundEfforts 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.MethodsFor 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.FindingsGlobally, 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.InterpretationDespite 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.FundingBill & Melinda Gates Foundation.

Chapter 71 - Salmonella Typhi and Salmonella Paratyphi A

BackgroundTyphoid and paratyphoid fever remain important causes of morbidity worldwide. Accurate disease burden estimates are needed to guide policy decisions and prevention and control strategies.MethodsWe conducted a systematic literature review of the PubMed and Scopus databases using pre-defined criteria to identify population-based studies with typhoid fever incidence data published between 1980 and 2009. We also abstracted data from annual reports of notifiable diseases in countries with advanced surveillance systems. Typhoid and paratyphoid fever input data were grouped into regions and regional incidence and mortality rates were estimated. Incidence data were extrapolated across regions for those lacking data. Age-specific incidence rates were derived for regions where age-specific data were available. Crude and adjusted estimates of the global typhoid fever burden were calculated.ResultsTwenty-five studies were identified, all of which contained incidence data on typhoid fever and 12 on paratyphoid fever. Five advanced surveillance systems contributed data on typhoid fever; 2 on paratyphoid fever. Regional typhoid fever incidence rates ranged from <0.1/100 000 cases/y in Central and Eastern Europe and Central Asia to 724.6/100 000 cases/y in Sub-Saharan Africa. Regional paratyphoid incidence rates ranged from 0.8/100 000 cases/y in North Africa/Middle East to 77.4/100 000 cases/y in Sub-Saharan Africa and South Asia. The estimated total number of typhoid fever episodes in 2010 was 13.5 million (interquartile range 9.1–17.8 million). The adjusted estimate accounting for the low sensitivity of blood cultures for isolation of the bacteria was 26.9 million (interquartile range 18.3–35.7 million) episodes. These findings are comparable to the most recent analysis of global typhoid fever morbidity, which reported crude and adjusted estimates of 10.8 million and 21.7 million typhoid fever episodes globally in 2000.ConclusionTyphoid fever remains a significant health burden, especially in low- and middle-income countries. Despite the availability of more recent data on both enteric fevers, additional research is needed in many regions, particularly Africa, Latin America and other developing countries.

BackgroundTyphoid fever and paratyphoid fever are one of the most criticial public health issues worldwide, especially in developing countries. The incidence of this disease may be closely related to socio-economic factors, but there is a lack of research on the spatial level of relevant determinants of typhoid fever and paratyphoid fever.MethodsIn this study, we took Hunan Province in central China as an example and collected the data on typhoid and paratyphoid incidence and socio-economic factors in 2015–2019. Firstly spatial mapping was made on the disease prevalence, and again using geographical probe model to explore the critical influencing factors of typhoid and paratyphoid, finally employing MGWR model to analysis the spatial heterogeneity of these factors.ResultsThe results showed that the incidence of typhoid and paratyphoid fever was seasonal and periodic and frequently occurred in summer. In the case of total typhoid and paratyphoid fever, Yongzhou was the most popular, followed by Xiangxi Tujia and Miao Autonomous Prefecture, Huaihua and Chenzhou generally focused on the south and west. And Yueyang, Changde and Loudi had a slight increase trend year by year from 2015 to 2019. Moreover, the significant effects on the incidence of typhoid and paratyphoid fever from strong to weak were as follows: gender ratio(q = 0.4589), students in ordinary institutions of higher learning(q = 0.2040), per capita disposable income of all residents(q = 0.1777), number of foreign tourists received(q = 0.1697), per capita GDP(q = 0.1589), and the P values for these factors were less than 0.001. According to the MGWR model, gender ratio, per capita disposable income of all residents and Number of foreign tourists received had a positive effect on the incidence of typhoid and paratyphoid fever. In contrast, students in ordinary institutions of higher learning had a negative impact, and per capita GDP shows a bipolar change.ConclusionsThe incidence of typhoid and paratyphoid fever in Hunan Province from 2015 to 2019 was a marked seasonality, concentrated in the south and west of Hunan Province. Attention should be paid to the prevention and control of critical periods and concentrated areas. Different socio-economic factors may show other directions and degrees of action in other prefecture-level cities. To summarize, health education, entry-exit epidemic prevention and control can be strengthened. This study may be beneficial to carry out targeted, hierarchical and focused prevention and control of typhoid fever and paratyphoid fever, and provide scientific reference for related theoretical research.

The treatment of enteric fever

Host genetic factors are thought to contribute to susceptibility and outcome in infectious diseases. A polymorphism in a proinflammatory gene, tumor necrosis factor-alpha (TNFA - 308), was recently found to be associated with susceptibility to typhoid fever. As the observation was made in hospitalized patients, a potential confounder could be that the TNFA polymorphism is associated with the severity of established illness resulting in hospital admission rather than susceptibility to disease. We tested whether the association with TNFA - 308 is present also in typhoid fever patients enrolled in a community-based case-control study in an endemic area in Indonesia. Common polymorphisms in other proinflammatory genes were assayed as well. Samples of patients with blood culture-confirmed typhoid fever (n = 90) and paratyphoid fever (n = 26) and fever controls (n = 337) were compared with those of community controls (n = 322). In these groups, we analyzed polymorphisms in TNFA by PCR and RFLP, polymorphisms of IFNG, IL1A, IL1B, IL1R1, TNFRSF1A, CASP1, and CRP by Sequenom MassArray (San Diego, CA), and polymorphisms in IL12B and IFNGR1 by fragment length analysis. The IL1R1 polymorphisms were nearly absent in the Indonesian population. The TNFA - 308 polymorphism was not associated with typhoid fever (OR 0.35, 95% CI 0.1-1.0) in this population. The polymorphisms at TNFA - 238 or in IFNG, IL1A, IL1B, IL12B, TNFRSF1A, IFNGR1, CASP1, and CRP were also not associated with typhoid or paratyphoid fever. We conclude that polymorphisms in proinflammatory genes do not contribute to susceptibility to typhoid fever and, in view of earlier findings, suggest that the TNFA - 308 polymorphism is likely related to severity of established disease rather than to susceptibility per se.

Updating and refining estimates of typhoid fever burden for public health action.

To understand the incidence rates of both typhoid fever and paratyphoid fever in the high prevalent areas of Guizhou province so as to provide evidence for the development of programs on comprehensive intervention and effectiveness evaluation. Six townships in Pingba county were selected as intervention areas while six townships in Kaiyang county were taken as control. All hospitals and clinics were classified into A, B and C types according to its level and the capacity of the blood culture. Surveillance on typhoid and paratyphoid fever was conducted based on all population and all hospitals, clinics and county CDCs among the patients with unknown fever. In the surveillance area in those two counties, there were 12 944 blood samples from patients with unknown fever which have been tested and cultured. Among them, 200 strains of Salmonella including 16 typhoid strains, 184 paratyphoid A strains were identified, with the total positive rate as 1.55%. The positive rate before the intervention program was higher than the after. The detection rate was 1.91% in the type A hospitals. 39 strains of Salmonella have been cultured from 2039 samples which accounting for 19.50% (39/200) of the total strains. 4315 blood samples were cultured at the 'Class B' sites which isolated 82 strains of Salmonella, accounting for 41.00% (82/200), with a detection rate as 1.90%. 6590 samples were cultured at the 'Class C' sites, which identified 79 strains of Salmonella, accounting for 39.50% (79/200), with a detection rate as 1.20%. The detection rate was much higher before the use of antibiotics than after using them (P < 0.05). The annual peak time of positive detection was in spring and fall. The outbreaks or epidemics often appeared in the same places, with farmers, students as the high-risk populations. Symptoms of both typhoid and paratyphoid fever were not typical. Typhoid and paratyphoid monitoring programs which covered primary health care institutions in the high incidence area seemed to be effective in reflecting the pictures as well as the burden of both typhoid and paratyphoid.

Objective: To analyze the spatial and temporal clustering characteristics of typhoid and paratyphoid fever and its change pattern in Yunnan, Guizhou and Guangxi provinces in southwestern China in recent years. Methods: The incidence data of typhoid and paratyphoid fever cases at county level in 3 provinces during 2001-2012 were collected from China Information System for Diseases Control and Prevention and analyzed by the methods of descriptive epidemiology and geographic informatics. And the map showing the spatial and temporal clustering characters of typhoid and paratyphoid fever cases in three provinces was drawn. SaTScan statistics was used to identify the typhoid and paratyphoid fever clustering areas of three provinces in each year from 2001 to 2012. Results: During the study period, the reported cases of typhoid and paratyphoid fever declined with year. The reported incidence decreased from 30.15 per 100 000 in 2001 to 10.83 per 100 000 in 2006(annual incidence 21.12 per 100 000); while during 2007-2012, the incidence became stable, ranging from 4.75 per 100 000 to 6.83 per 100 000 (annual incidence 5.73 per 100 000). The seasonal variation of the incidence was consistent in three provinces, with majority of cases occurred in summer and autumn. The spatial and temporal clustering of typhoid and paratyphoid fever was demonstrated by the incidence map. Most high-incidence counties were located in a zonal area extending from Yuxi of Yunnan to Guiyang of Guizhou, but were concentrated in Guilin in Guangxi. Temporal and spatial scan statistics identified the positional shifting of class Ⅰ clustering area from Guizhou to Yunnan. Class Ⅰ clustering area was located around the central and western areas (Zunyi and Anshun) of Guizhou during 2001-2003, and moved to the central area of Yunnan during 2004-2012. Conclusion: Spatial and temporal clustering of typhoid and paratyphoid fever existed in the endemic areas of southwestern China, and the clustering area covered a zone connecting the central areas of Guizhou and Yunnan. From 2004 to 2012, the most important clustering area shifted from Guizhou to Yunnan. Findings from this study provided evidence for the identifying key areas for typhoid and paratyphoid fever control and prevention and allocate health resources.

Although enteric fever (typhoid and paratyphoid fevers) is a major global public health problem, comparable data on the risks of contracting travel-associated enteric fever in various regions of the world are scarce. From the Swedish database on notifiable communicable diseases, we retrieved all case records from 1997 to 2003 on typhoid and paratyphoid fevers. The data set was compared with data on travel patterns obtained from a comprehensive travel database with information from interviews with more than 16,000 Swedish residents with recent overnight travel outside Sweden. The overall risk of being notified with enteric fever after travel was 0.42 in 100,000 travelers. The highest risk for typhoid fever was seen in travelers from India and neighboring countries (41.7 in 100,000), the Middle East (5.91 in 100,000), and Central Africa (3.33 in 100,000), whereas the risk was comparatively low in East Asia (0.24 in 100,000). Almost the same risk areas stood out for paratyphoid fever: India and neighbors (37.5 in 100,000), the Middle East (3.64 in 100,000), and East Africa (3.33 in 100,000). The epidemiology of paratyphoid fever was considerably affected by a large outbreak of paratyphoid B in a Turkish tourist resort in 1999. The youngest children were at highest risk for typhoid fever (odds ratio 44.2), whereas youths ages 7 to 18 years were at highest risk for paratyphoid fever (odds ratio 9.7). Detailed risk data for enteric fever after travel could form the basis for travel advice. Vaccination against typhoid fever should always be considered for travelers to the Indian subcontinent, the Middle East, and Africa but should not routinely be given to travelers to the Malay Peninsula.

Enteric fever is caused by Salmonella enterica serovar Typhi (S. Typhi) and Salmonella enterica serovar Paratyphi (S. Paratyphi) A, B, and C. Globally, an estimated 11 to 21 million cases of typhoid and paratyphoid fever occur annually, with approximately 130,000-160,000 deaths, most of which are reported in South/Southeast Asia and sub-Saharan Africa. The antibiotic susceptibility of S. Typhi strains varies between countries within broad limits, from 3% to 97% for ampicillin, 9% to 95% for ciprofloxacin, 4% to 94% for chloramphenicol (India vs. Pakistan), and 0% to 99% for ceftriaxone (India vs. Iraq). With S. Typhi increasingly exhibiting resistance to antibiotics, vaccination becomes an essential preventive measure. Currently, three vaccines are licensed for typhoid fever: the typhoid conjugate vaccine (TCV), live-attenuated oral vaccine Ty21a (Ty21a), and Vi capsular polysaccharide vaccine (Vi-CPS). While no specific vaccine exists for paratyphoid fever, the genetic and antigenic similarities between S. Paratyphi and S. Typhi offer potential for the development of such a vaccine. Early studies show promising results, demonstrating both safety and immunogenicity in preclinical trials. Whole genome sequencing (WGS) provides a powerful tool for assigning genotypes, identifying plasmids, comparing genetic elements, and investigating molecular factors that contribute to antibiotic resistance and virulence.

Review status: Current question - no update intended. Azithromycin treatments are included in the review: Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). (Thaver D, Zaidi AKM, Critchley JA, Azmatullah A, Madni SA, Bhutta ZA. Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD004530. DOI: 10.1002/14651858.CD004530.pub3.) This latter review is being updated, and will be published in late 2011.Enteric fever (typhoid and paratyphoid fever) is potentially fatal. Infection with drug-resistant strains of the causative organism Salmonella enterica serovar Typhi or Paratyphi increases morbidity and mortality. Azithromycin may have better outcomes in people with uncomplicated forms of the disease. To compare azithromycin with other antibiotics for treating uncomplicated enteric fever. In August 2008, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, LILACS, and mRCT. We also searched conference proceedings, reference lists, and contacted researchers and a pharmaceutical company. Randomized controlled trials comparing azithromycin with other antibiotics for treating children and adults with uncomplicated enteric fever confirmed by cultures of S. Typhi or Paratyphi in blood and/or stool. Both authors independently extracted data and assessed the risk of bias. Dichotomous data were presented and compared using the odds ratio, and continuous data were reported as arithmetic means with standard deviations and were combined using the mean difference (MD). Both were presented with 95% confidence intervals (CI). Seven trials involving 773 participants met the inclusion criteria. The trials used adequate methods to generate the allocation sequence and conceal allocation, and were open label. Three trials exclusively included adults, two included children, and two included both adults and children; all were hospital inpatients. One trial evaluated azithromycin against chloramphenicol and did not demonstrate a difference for any outcome (77 participants, 1 trial). When compared with fluoroquinolones in four trials, azithromycin significantly reduced clinical failure (OR 0.48, 95% CI 0.26 to 0.89; 564 participants, 4 trials) and duration of hospital stay (MD -1.04 days, 95% CI -1.73 to -0.34 days; 213 participants, 2 trials); all four trials included people with multiple-drug-resistant or nalidixic acid-resistant strains of S. Typhi or S. Paratyphi. We detected no statistically significant difference in the other outcomes. Compared with ceftriaxone, azithromycin significantly reduced relapse (OR 0.09, 95% CI 0.01 to 0.70; 132 participants, 2 trials) and not other outcome measures. Few adverse events were reported, and most were mild and self limiting. Azithromycin appears better than fluoroquinolone drugs in populations that included participants with drug-resistant strains. Azithromycin may perform better than ceftriaxone.