Browse the corpus

Burden of Typhoid and Paratyphoid Fever in India. BACKGROUND: In 2017, more than half the cases of typhoid fever worldwide were projected to have occurred in India. In the absence of contemporary population-based data, it is unclear whether declining trends of hospitalization for typhoid in India reflect increased antibiotic treatment or a true reduction in infection. METHODS: From 2017 through 2020, we conducted weekly surveillance for acute febrile illness and measured the incidence of typhoid fever (as confirmed on blood culture) in a prospective cohort of children between the ages of 6 months and 14 years at three urban sites and one rural site in India. At an additional urban site and five rural sites, we combined blood-culture testing of hospitalized patients who had a fever with survey data regarding health care use to estimate incidence in the community. RESULTS: A total of 24,062 children who were enrolled in four cohorts contributed 46,959 child-years of observation. Among these children, 299 culture-confirmed typhoid cases were recorded, with an incidence per 100,000 child-years of 576 to 1173 cases in urban sites and 35 in rural Pune. The estimated incidence of typhoid fever from hospital surveillance ranged from 12 to 1622 cases per 100,000 child-years among children between the ages of 6 months and 14 years and from 108 to 970 cases per 100,000 person-years among those who were 15 years of age or older. Salmonella enterica serovar Paratyphi was isolated from 33 children, for an overall incidence of 68 cases per 100,000 child-years after adjustment for age. CONCLUSIONS: The incidence of typhoid fever in urban India remains high, with generally lower estimates of incidence in most rural areas. (Funded by the Bill and Melinda Gates Foundation; NSSEFI Clinical Trials Registry of India number, CTRI/2017/09/009719; ISRCTN registry number, ISRCTN72938224.).

For four prospective, closed cohorts in India (Delhi, Kolkata and Vellore (urban) and Pune (rural); Figure 1), we enrolled ~6,000 eligible children between 6 months and 13 years of age at each site between October 2017 to February 2018, and followed each child for 24 months or until their 15th birthday. These study sites were chosen for broad urban/rural and geographic representation across the country, while ensuring their ability to perform high-quality community-based research. The protocol and informed consent forms were approved by the Christian Medical College Institutional Review Board and by ethics committees at each of the sites. All children in the defined catchment area were eligible and written informed consent was obtained from the primary caregiver. A detailed study protocol, including sample size calculations, has been published (and at nejm.org) and the study registered (Clinical Trial Registry of India CTRI/2017/09/009719).11 Weekly surveillance for fever was conducted either by telephonic interviews or a home-visit, with one mandatory home-visit each month. A digital thermometer and fever diary were provided to report any acute febrile illness (AFI). An initial report of fever triggered a home, study clinic or hospital visit to assess the child. Daily visits continued until the resolution of fever, defined by three consecutive fever-free days. Physician-assigned diagnosis, clinical investigations, and treatment, including antibiotics, were recorded.

illness (AFI). An initial report of fever triggered a home, study clinic or hospital visit to assess the child. Daily visits continued until the resolution of fever, defined by three consecutive fever-free days. Physician-assigned diagnosis, clinical investigations, and treatment, including antibiotics, were recorded. For children with potential enteric fever (PEF), defined as fever for three or more consecutive days, an age-appropriate blood volume was inoculated into a BacT/ALERT® or BACTEC® bottle. Prior antibiotics were not considered a contraindication. S. typhi and S. paratyphi were isolated based on standard laboratory methods,11,12 and antimicrobial susceptibility determined following Clinical and Laboratory Standards Institute guidelines.13 The incidence rates of AFI, PEF, typhoid and paratyphoid fever were calculated per child year of observation (CYO) using survival analysis with interval censoring of periods when valid recall was unavailable. The overall incidence was adjusted for age structure at each site. We investigated the association of typhoid incidence with baseline household characteristics and location using Andersen-Gill’s proportional hazards model.14 We estimated incidence with and without adjustment for the sensitivity of blood culture (60%).8 Details of the statistical analysis are provided in Supplementary Appendix.

igated the association of typhoid incidence with baseline household characteristics and location using Andersen-Gill’s proportional hazards model.14 We estimated incidence with and without adjustment for the sensitivity of blood culture (60%).8 Details of the statistical analysis are provided in Supplementary Appendix. At six hospitals in additional locations representing different geographic and risk settings, study physicians screened hospitalized patients over 6 months old for fever and following consent, performed blood cultures (BACTEC®) between February 2018 and March 2020 (Supplementary Appendix; Figure 1). These study sites were chosen to represent geographical, urban/rural, and risk settings across India. These sites were often in regions with poor health and research infrastructure from which data are rarely obtained and the selected hospitals provided care for a significant proportion of the studied population. Further description of each site is available in the Supplementary Appendix. An independent agency conducted Healthcare Utilization Surveys in each hospital’s catchment to estimate the proportion of the population that used the surveillance hospital(s) for fever related hospitalization.14

ion of the studied population. Further description of each site is available in the Supplementary Appendix. An independent agency conducted Healthcare Utilization Surveys in each hospital’s catchment to estimate the proportion of the population that used the surveillance hospital(s) for fever related hospitalization.14 The estimated incidence of hospitalized typhoid and paratyphoid fever among children (6 months to 14 years) and older individuals (15 years plus) in the catchment population was calculated by dividing the number of culture-confirmed cases by population size, adjusting for the age-specific proportion of febrile illnesses seen at the surveillance hospital from the Healthcare Utilization Surveys (Figure S1). The catchment population was defined as the contiguous area from which 80% of hospitalizations in the previous 2 years were recorded. Incidence was adjusted further for the proportion of eligible episodes where blood cultures were not done because of non-consent and for the sensitivity of blood culture. To estimate the incidence of typhoid of all clinical severity, we divided the estimates of hospitalized typhoid fever by the proportion of typhoid fevers that required hospitalization in Tier 1 surveillance.12 This adjustment approach for hybrid surveillance studies has been previously done for enteric fever.15–17 To account for uncertainty in the adjusted estimates, we used Monte Carlo simulation that samples a range of values for each multiplier used from the Healthcare Utilization Surveys (using a beta distribution) and report the 95% uncertainty interval (Tables S7, S8).18 We performed sensitivity analyses on the blood culture sensitivity when accounting for prior antibiotic exposure (See Supplementary Appendix).

At six hospitals in additional locations representing different geographic and risk settings, study physicians screened hospitalized patients over 6 months old for fever and following consent, performed blood cultures (BACTEC®) between February 2018 and March 2020 (Supplementary Appendix; Figure 1). These study sites were chosen to represent geographical, urban/rural, and risk settings across India. These sites were often in regions with poor health and research infrastructure from which data are rarely obtained and the selected hospitals provided care for a significant proportion of the studied population. Further description of each site is available in the Supplementary Appendix. An independent agency conducted Healthcare Utilization Surveys in each hospital’s catchment to estimate the proportion of the population that used the surveillance hospital(s) for fever related hospitalization.14

A total of 24,062 children were enrolled at four sites, with 21,470 (89.2%) completing 24 months of follow-up, 1,436 (6.0%) censored at 15 years, and 1,156 (4.8%) lost to follow-up or withdrawing consent (Figure 2). Study populations were three urban poor, densely populated city catchments and a rural agrarian community across several villages (Table S1). Drinking water sources and toilet facilities varied significantly between sites (p-values <0.001); 603 (4.3%) households had access only to unimproved water,19 3189 (22.6%) used bottled water (mainly in Pune) and the remainder had access to piped water or a public tap. Water treatment was inadequate for 10,425 (73.7%) children. The majority (84.2%) of households had access to toilets, although 37.2% shared toilets with other families.

ds had access only to unimproved water,19 3189 (22.6%) used bottled water (mainly in Pune) and the remainder had access to piped water or a public tap. Water treatment was inadequate for 10,425 (73.7%) children. The majority (84.2%) of households had access to toilets, although 37.2% shared toilets with other families. We recorded 76,027 AFIs during 46,959 CYO across the four cohorts, with the highest incidence among children aged between 6 months and 4 years (2.45 episodes per CYO; Table S2). Overall incidence among children aged 6 months to 14 years old was 1.73 episodes per CYO. PEF criteria were met in 20,911 (27.5%) fevers (range 24.2–29.2% among sites), of whom 70.1% (range 67.0–75.8%) remained febrile at investigation and were eligible for a blood culture. Blood cultures were done for 86.6% (range 79.1–93.6%) of eligible PEFs and the remainder were not done because of refusal by the caregiver (7.3%) or other reasons (6.1%), mainly being outside the study area. The pre-specified blood volume was obtained for 91.0% of cultures. Antibiotics were used in 67.7% of PEFs, 38.8% before blood culture (range 22.4–64.8% across sites). Blood cultures were performed on day 4 of fever in 67.6%, on day 5 in 18.8% and on day 6 to 16 for the remainder (13.6%). The clinical diagnoses of these episodes are listed in Table S3.

s obtained for 91.0% of cultures. Antibiotics were used in 67.7% of PEFs, 38.8% before blood culture (range 22.4–64.8% across sites). Blood cultures were performed on day 4 of fever in 67.6%, on day 5 in 18.8% and on day 6 to 16 for the remainder (13.6%). The clinical diagnoses of these episodes are listed in Table S3. There were 299 culture confirmed cases of typhoid, ranging from just 4 in Pune to 146 in Vellore (Table 1). Overall incidence among children aged 6 months to 14 years per 100,000 CYO was 576 (95% confidence interval (CI): 445–734) in Delhi, 714 (568–885) in Kolkata, 35 (9–89) in Pune and 1173 (991–1379) in Vellore, after adjusting for the age-distribution of the underlying population (Figure 3). Incidence was highest among children 5–9 years old in Vellore, Kolkata and Pune sites and 10–14 years old in Delhi (Table 1; Figure S2). S. paratyphi was isolated from 33 children, giving an overall incidence of 68 (95% CI: 47–96) per 100,000 CYO after adjusting for age.

ibution of the underlying population (Figure 3). Incidence was highest among children 5–9 years old in Vellore, Kolkata and Pune sites and 10–14 years old in Delhi (Table 1; Figure S2). S. paratyphi was isolated from 33 children, giving an overall incidence of 68 (95% CI: 47–96) per 100,000 CYO after adjusting for age. The incidence of typhoid varied over time but did not show seasonality or association with wetter monsoon months (hazard ratio (HR) 0.95 (95% CI: 0.69–1.32), p=0.77; Figure S2) at any site. In the final multivariable model, the risk of typhoid was greater for children from households of greater than average size, with fewer assets and without a sanitary toilet (Table S4). Typhoid incidence was 648 (95% CI, 568 – 739) per 100,000 PYO in those without access to safe water compared to 611 (489 – 763) per 100,000 PYO in those with access to safe water. Incidence of typhoid was lower among vaccinated children, but few children were vaccinated, and this difference was not significant (HR=0.60 (95% CI: 0.28–1.27), p=0.18). The median duration of culture-confirmed typhoid fever was 9 days (interquartile range 7–11 days) and the median highest temperature was 102.8 °F (Table S5). Other than fever, common symptoms were cough (145/299), nausea or vomiting (139/299), abdominal pain (137/299) and headache (115/299) (Table S5; Figure S3). Clinical characteristics of paratyphoid were similar to typhoid. No children with typhoid or paratyphoid died although 46 (15%) and 7 (21%), respectively, were hospitalized.

fever, common symptoms were cough (145/299), nausea or vomiting (139/299), abdominal pain (137/299) and headache (115/299) (Table S5; Figure S3). Clinical characteristics of paratyphoid were similar to typhoid. No children with typhoid or paratyphoid died although 46 (15%) and 7 (21%), respectively, were hospitalized. Nearly all children with confirmed typhoid received antibiotics (296/299), mainly azithromycin (230/299) followed by cephalosporins (145/299) (Table S5). Administration of multiple antibiotics was common (160/299). Nearly all (289/294) were non-susceptible to ciprofloxacin. 15,736 (79%) of 20,022 febrile admissions between February 27, 2018, and March 31, 2020, were recruited at the six hospitals, with 8253 (53%) males, and 6120 (39%) <15 years of age (Table S6). Blood cultures were obtained from 13,264 (84%) participants, with 8.9 ml mean blood volume in adults and 3.5 ml in children. The most common pathogen was S. typhi (n=221; 1.7%), followed by Staphylococcus species (n=197; 1.5%) and Escherichia coli (n=178; 1.3%). S. paratyphi A was recovered from 54 samples (0.4%), with one S. paratyphi C. Of these, 185 S. typhi and 52 S. paratyphi A were from patients within the catchment population. In 7.8%, blood culture was performed after antibiotic initiation.

wed by Staphylococcus species (n=197; 1.5%) and Escherichia coli (n=178; 1.3%). S. paratyphi A was recovered from 54 samples (0.4%), with one S. paratyphi C. Of these, 185 S. typhi and 52 S. paratyphi A were from patients within the catchment population. In 7.8%, blood culture was performed after antibiotic initiation. After adjusting for surveillance coverage, study compliance, severity and blood culture sensitivity, the adjusted incidence of typhoid fever in children per 100,000 CYO ranged between 12 (95% Uncertainty Interval (UI): 7–20) in East Champaran and 1622 (858–3359) in Chandigarh (Table 2, Table S7). The incidence of paratyphoid per 100,000 CYO ranged between 0 at multiple rural sites and 696 (368–1439) at urban Chandigarh site (Table S8). Among those over 15 years, the adjusted incidence of typhoid fever per 100,000 person-years varied between 108 (69–177) in Karimganj and 970 (683–1420) in Chandigarh (Table S7), and for paratyphoid fever between 8 (5–13) in Karimganj and 416 (305–607) in Chandigarh (Table S8). Sensitivity analyses that adjust for blood culture sensitivity in those with prior antibiotic exposure is presented in Tables S9–S10.

varied between 108 (69–177) in Karimganj and 970 (683–1420) in Chandigarh (Table S7), and for paratyphoid fever between 8 (5–13) in Karimganj and 416 (305–607) in Chandigarh (Table S8). Sensitivity analyses that adjust for blood culture sensitivity in those with prior antibiotic exposure is presented in Tables S9–S10. The median durations of fever and hospitalization in those with typhoid fever were nine and five days, respectively. The median highest temperature recorded was 102.4°F. The median age of those hospitalized with typhoid fever was 19.4 years (IQR, 10.1 to 24.7 years), with 54.3% of cases aged between 15 and 30 years. Of the 221 patients with typhoid fever, 202 recovered without complications, 14 were referred to higher centres, four left against medical advice, and one died.

We recorded 76,027 AFIs during 46,959 CYO across the four cohorts, with the highest incidence among children aged between 6 months and 4 years (2.45 episodes per CYO; Table S2). Overall incidence among children aged 6 months to 14 years old was 1.73 episodes per CYO. PEF criteria were met in 20,911 (27.5%) fevers (range 24.2–29.2% among sites), of whom 70.1% (range 67.0–75.8%) remained febrile at investigation and were eligible for a blood culture. Blood cultures were done for 86.6% (range 79.1–93.6%) of eligible PEFs and the remainder were not done because of refusal by the caregiver (7.3%) or other reasons (6.1%), mainly being outside the study area. The pre-specified blood volume was obtained for 91.0% of cultures. Antibiotics were used in 67.7% of PEFs, 38.8% before blood culture (range 22.4–64.8% across sites). Blood cultures were performed on day 4 of fever in 67.6%, on day 5 in 18.8% and on day 6 to 16 for the remainder (13.6%). The clinical diagnoses of these episodes are listed in Table S3.

There were 299 culture confirmed cases of typhoid, ranging from just 4 in Pune to 146 in Vellore (Table 1). Overall incidence among children aged 6 months to 14 years per 100,000 CYO was 576 (95% confidence interval (CI): 445–734) in Delhi, 714 (568–885) in Kolkata, 35 (9–89) in Pune and 1173 (991–1379) in Vellore, after adjusting for the age-distribution of the underlying population (Figure 3). Incidence was highest among children 5–9 years old in Vellore, Kolkata and Pune sites and 10–14 years old in Delhi (Table 1; Figure S2). S. paratyphi was isolated from 33 children, giving an overall incidence of 68 (95% CI: 47–96) per 100,000 CYO after adjusting for age. The incidence of typhoid varied over time but did not show seasonality or association with wetter monsoon months (hazard ratio (HR) 0.95 (95% CI: 0.69–1.32), p=0.77; Figure S2) at any site. In the final multivariable model, the risk of typhoid was greater for children from households of greater than average size, with fewer assets and without a sanitary toilet (Table S4). Typhoid incidence was 648 (95% CI, 568 – 739) per 100,000 PYO in those without access to safe water compared to 611 (489 – 763) per 100,000 PYO in those with access to safe water. Incidence of typhoid was lower among vaccinated children, but few children were vaccinated, and this difference was not significant (HR=0.60 (95% CI: 0.28–1.27), p=0.18).

The median duration of culture-confirmed typhoid fever was 9 days (interquartile range 7–11 days) and the median highest temperature was 102.8 °F (Table S5). Other than fever, common symptoms were cough (145/299), nausea or vomiting (139/299), abdominal pain (137/299) and headache (115/299) (Table S5; Figure S3). Clinical characteristics of paratyphoid were similar to typhoid. No children with typhoid or paratyphoid died although 46 (15%) and 7 (21%), respectively, were hospitalized.

Nearly all children with confirmed typhoid received antibiotics (296/299), mainly azithromycin (230/299) followed by cephalosporins (145/299) (Table S5). Administration of multiple antibiotics was common (160/299). Nearly all (289/294) were non-susceptible to ciprofloxacin.

15,736 (79%) of 20,022 febrile admissions between February 27, 2018, and March 31, 2020, were recruited at the six hospitals, with 8253 (53%) males, and 6120 (39%) <15 years of age (Table S6). Blood cultures were obtained from 13,264 (84%) participants, with 8.9 ml mean blood volume in adults and 3.5 ml in children. The most common pathogen was S. typhi (n=221; 1.7%), followed by Staphylococcus species (n=197; 1.5%) and Escherichia coli (n=178; 1.3%). S. paratyphi A was recovered from 54 samples (0.4%), with one S. paratyphi C. Of these, 185 S. typhi and 52 S. paratyphi A were from patients within the catchment population. In 7.8%, blood culture was performed after antibiotic initiation.

After adjusting for surveillance coverage, study compliance, severity and blood culture sensitivity, the adjusted incidence of typhoid fever in children per 100,000 CYO ranged between 12 (95% Uncertainty Interval (UI): 7–20) in East Champaran and 1622 (858–3359) in Chandigarh (Table 2, Table S7). The incidence of paratyphoid per 100,000 CYO ranged between 0 at multiple rural sites and 696 (368–1439) at urban Chandigarh site (Table S8). Among those over 15 years, the adjusted incidence of typhoid fever per 100,000 person-years varied between 108 (69–177) in Karimganj and 970 (683–1420) in Chandigarh (Table S7), and for paratyphoid fever between 8 (5–13) in Karimganj and 416 (305–607) in Chandigarh (Table S8). Sensitivity analyses that adjust for blood culture sensitivity in those with prior antibiotic exposure is presented in Tables S9–S10. The median durations of fever and hospitalization in those with typhoid fever were nine and five days, respectively. The median highest temperature recorded was 102.4°F. The median age of those hospitalized with typhoid fever was 19.4 years (IQR, 10.1 to 24.7 years), with 54.3% of cases aged between 15 and 30 years. Of the 221 patients with typhoid fever, 202 recovered without complications, 14 were referred to higher centres, four left against medical advice, and one died.

During two years of active surveillance, the incidence of blood culture-confirmed typhoid in 3 urban Indian cohorts of children exceeds published thresholds above which routine vaccination with TCV becomes highly cost-effective.20,21 It is substantially higher than burden estimates based on mathematical models fit to hospital-reported cases22 and is comparable with the reported incidence from cohort studies conducted between 1995 and 2006.23–25 Estimated incidence in children is even higher when accounting for the low sensitivity of blood culture with the adjusted incidence ranging between 960 (742–1223) in Delhi to 1995 (1652–2298) at Vellore. These estimates are also consistent with the estimates in children in urban Chandigarh from the Tier 2 hospital-based surveillance. The high incidence of typhoid in urban India suggests that declines in reported cases from hospitals have been driven by changes in healthcare-seeking behaviour and widespread antibiotic treatment, rather than a reduction in transmission. Antibiotics are commonly available without a prescription and the number of defined daily doses used in India has increased from 3.2 to 6.5 billion per year between 2000 and 2015.26

have been driven by changes in healthcare-seeking behaviour and widespread antibiotic treatment, rather than a reduction in transmission. Antibiotics are commonly available without a prescription and the number of defined daily doses used in India has increased from 3.2 to 6.5 billion per year between 2000 and 2015.26 The apparent masking of typhoid disease by widespread use of effective antibiotics highlights the major risk posed by emerging strains of extensively drug resistant S. typhi, strengthening the argument for TCV introduction.10 Although disease incidence peaks among children aged 5–9 years, there is a significant burden from one year of age. Routine immunization with a single dose of TCV at 9 months of age following WHO recommendations would offer early protection, with a one-time catch-up immunization of children up to 15 years of age providing protection in a larger vulnerable age range.5 The estimated incidence of typhoid fever in children in rural areas was lower than in urban areas. Although urban vaccination alone may reduce incidence, rural areas continue to have moderate levels of disease, and urban migration of younger people will threaten gains achieved through an urban-only vaccination strategy. Over half the hospitalized typhoid fever episodes in rural settings were among individuals over 15 years of age indicating a substantial burden in adults that may reflect lower exposure during childhood and consequent vulnerability if they migrate to higher risk settings.

ved through an urban-only vaccination strategy. Over half the hospitalized typhoid fever episodes in rural settings were among individuals over 15 years of age indicating a substantial burden in adults that may reflect lower exposure during childhood and consequent vulnerability if they migrate to higher risk settings. The geographic heterogeneity adds complexity for immunization programs and is also an important issue elsewhere, with many rural studies in Africa and Asia reporting low incidence of S. typhi,27,28 but other rural or peri-urban sites recording relatively high incidence.29 However, the uncertainty of typhoid estimates in rural areas is larger given that the majority of rural data came from the Tier 2 study.

ortant issue elsewhere, with many rural studies in Africa and Asia reporting low incidence of S. typhi,27,28 but other rural or peri-urban sites recording relatively high incidence.29 However, the uncertainty of typhoid estimates in rural areas is larger given that the majority of rural data came from the Tier 2 study. The most administered antibiotics for PEF were azithromycin or cephalosporins (cefixime or ceftriaxone). The predominant genotype of S. typhi circulating in India (4.3.1 also called H58) remains susceptible to these antibiotics and all isolates were susceptible to ceftriaxone. Extensively drug resistant (XDR) S. typhi strains with resistance to third generation cephalosporins reported from Pakistan have not yet been isolated in India.10 However, six S. typhi isolates and eight S. paratyphi A isolates showed evidence of resistance to azithromycin. This is consistent with the emergence of azithromycin resistance elsewhere.9 The spread of S. typhi strains resistant to azithromycin and other first-line antibiotics would change typhoid treatment from oral antibiotics to needing parenteral antibiotics in an inpatient setting, risking higher rates of mortality and putting a further strain on health systems. The burden of paratyphoid was variable and lower in Tier 1 than at Tier 2 sites. The variable incidence and the observed antimicrobial resistance in S. paratyphi are of particular importance as typhoid conjugate vaccines do not protect against S. paratyphi

es of mortality and putting a further strain on health systems. The burden of paratyphoid was variable and lower in Tier 1 than at Tier 2 sites. The variable incidence and the observed antimicrobial resistance in S. paratyphi are of particular importance as typhoid conjugate vaccines do not protect against S. paratyphi Our studies had several limitations. In the active surveillance cohorts, early treatment with antibiotics may have resulted in the resolution of fever in some children meaning they were ineligible for blood culture, potentially contributing to an underestimate of the true incidence. We aimed to minimise this bias through weekly fever surveillance and early referral for blood culture. Nonetheless, 30% of PEFs were ineligible for blood culture because of defervescence, of whom 28% had received antibiotics for at least 48 hours. Prior analyses from this study on the relationship of antibiotics and culture positivity did not yield a relationship.30 We were also unable to conduct a blood culture in 13% of eligible PEFs and in 9% we did not obtain sufficient blood volumes, meaning we may have missed some episodes. The 10 study sites (4 in Tier 1 and 6 in Tier 2) were not randomly selected and thus not entirely representative of India, and therefore we do not provide a national incidence estimate. These sites were chosen to broadly reflect the geographic, urban/rural, and risk settings available in India, but achieving full representativeness was not possible given the size of the country and the intensive resources needed to conduct such studies.

a, and therefore we do not provide a national incidence estimate. These sites were chosen to broadly reflect the geographic, urban/rural, and risk settings available in India, but achieving full representativeness was not possible given the size of the country and the intensive resources needed to conduct such studies. The Tier 2 estimates on enteric fever are more uncertain than Tier 1. Estimates of typhoid incidence from hospital-based surveillance depend on accurate multipliers used to account for healthcare seeking, disease severity, blood culture administration and sensitivity which all retain significant individual uncertainty. The overall magnitude of the product of these multipliers leads to considerable uncertainty in the estimation of typhoid and paratyphoid fever incidence from hospital admission data. To address this limitation, we derived uncertainty intervals using Monte Carlo simulation and based our estimates of healthcare utilization on surveys from 5000 households at each site, which demonstrate appropriately wide intervals suggesting uncertainty.31 This hybrid surveillance methodology has been applied in infectious diseases surveillance across multiple pathogens15–17 Finally, the Tier 2 surveillance did not perform sample size calculations to inform study design.

000 households at each site, which demonstrate appropriately wide intervals suggesting uncertainty.31 This hybrid surveillance methodology has been applied in infectious diseases surveillance across multiple pathogens15–17 Finally, the Tier 2 surveillance did not perform sample size calculations to inform study design. In summary, despite improvements in water and sanitation and declining trends reported from hospitals, the burden of typhoid in urban India remains high, particularly among the poorest households. TCV introduction, in parallel with continued emphasis on safer water, sanitation and food, offers potential for reduction of an under-estimated and often overlooked infection disease in a country that carries the highest burden of typhoid.