Scrub TyphusNCT04506944
The Epidemiology of Rickettsial Infections in South India: Cohort Study
An observational study of Scrub Typhus and Spotted Fever; India, run by London School of Hygiene and Tropical Medicine at 1 site in India.
Trial summary
There is enough evidence to suggest that scrub typhus and spotted fever group rickettsioses are common causes of febrile illness in India. Serological evidence also exists for murine typhus, but is rarely tested for. Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Scrub Typhus, Spotted Fever; India, Murine Typhus
- How many people
- 32,566 participants
- Where
- 1 siteIndia
- Study dates
- 1 Aug 2020to 31 Jul 2023
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: General population cohort: all residents in scrub typhus endemic villages Serological cohort: random sample of 4000 individuals older than 10 years present at the time of the initial baseline survey visit hospital case cohort: cases of all ages attending study clinics for undifferentiated fever of at least 5 days duration
Who may be able to join
- General population cohort: residing in study villages
- serological cohort: aged 10 years or older
- Hospital cohort: all ages
Who cannot join
- None
Trial locations and contacts
1 site in 1 country.
About this study
Official title: The Epidemiology Of Scrub Typhus And Rickettsial Infections In A Highly Endemic Rural Setting In South India: Population-Based Cohort Study
There is enough evidence to suggest that scrub typhus and spotted fever group rickettsioses are common causes of febrile illness in India. Serological evidence also exists for murine typhus, but is rarely tested for. Incidence, risk factors, clinical features and molecular epidemiology of these three infections are poorly understood. Delays in disease recognition and treatment may cause thousands of preventable deaths across India.
The objectives of the research are to determine the incidence and risk factors of scrub typhus, spotted fever and murine typhus by severity, to determine clinical features of these neglected and often unrecognized infections. Further to study the effect of previous infection on incidence and severity of subsequent infections. Finally to study the association between vector parameters and scrub typhus risk.
Read more
Enrolled will be 30,000 individuals who will be followed up for the development of fever using active and passive surveillance. Active surveillance will include household screening every 3-6 weeks. Fever cases occuring in the past two months will be tested for Scrub typhus, murine typhus and spotted fever IgG/IgM. 4000 individuals will be followed up by annual serological testing to identify asymptomatic infections. Participants notifying the study team with ongoing fever will undergo blood testing for acute diagnosis of rickettsial infection (IgM, PCR). In addition, we will enroll fever cases at study clinics who are not part of the main cohort. The research includes spatial and socio-economic risk factor analysis. Rodents carrying mite larvae will be trapped to compare the intensity of mite infestation between areas of high and low risk for human scrub typhus.
The data on incidence, burden of disease and environmental determinants of scrub typhus, spotted fever and murine typhus will be used for health care planning and information campaigns for the public and medical professionals.
Read the detailed description
The aim of the cohort study is to better understand the epidemiology, sero-epidemiology and transmission of scrub typhus, murine typhus and tick-borne spotted fever. The overall focus of the work will be on scrub typhus, being the most important of the three from the public health perspective. We aim to determine the "severity pyramid" of serological, symptomatic and severe infection. The results from this study will help clinicians to understand the natural course of scrub typhus infection, health policy makers to estimate the global burden and the scope for community-based interventions, and immunologists to better understand the immunogenicity of single and repeat infections.
The specific objectives are to:
- Estimate the incidence of symptomatic and severe scrub typhus infection in the community.
- Estimate the incidence of serological (asymptomatic) scrub typhus infection.
- Estimate the effect of previous scrub typhus infection (sero-positive at baseline) on the risk of subsequent infection and disease severity (subclinical vs clinically apparent). This includes the effect of antibodies in mothers on the risk of severe infection in young children via residual maternal antibodies.
- Estimate the effect of potential risk factors such as age, gender, occupation, water/sanitation access and comorbidity on the risk of scrub typhus infection.
- Estimate the effect of spatial-temporal risk factors for scrub typhus by identifying high risk areas, accounting for human population density and land use.
- Compare the rate of rodent trappings and vector parameters of chiggers between high risk and low risk areas identified under 5).
- Estimate the disease burden associated with scrub typhus and the economic impact of scrub typhus in terms of loss of earnings and health expenditure.
- Estimate the incidence of asymptomatic and symptomatic murine typhus and spotted fever infection and explore associated socio-demographic, spatial and vector-related risk factors.
STUDY OVERVIEW
The study will be a population-based cohort study over two years (i.e. two scrub typhus seasons) in about 30,000 people living in approximately 40 villages with a sero-prevalence of at least 15% (see flow diagram above). These individuals will be followed-up through active surveillance for recent febrile illnesses (clinical cohort). For passive surveillance, participants will be encouraged to notify the study team in case of fever or come to one of 4 local study clinics. At study clinics we will also enrol fever cases who are not part of the clinical cohort, i.e. have not been enrolled prior to their fever. The study will include a smaller cohort (sero-cohort) for serological surveillance of 4000 people drawn from the 30,000 people of the clinical cohort. Longitudinal serological surveys linked to active surveillance are essential to estimate true attack rates unbiased by disease severity. The sero-cohort will consist of three annual blood testing in the same group of participants over two scrub typhus seasons (baseline, inter-season, endline).
Target population- A pilot study showed that scrub typhus infection is highly focal This makes it difficult to define a target population for the purpose of making inferences. We will define the target population in terms of the village level sero-prevalence. The aim is to correlate the incidence of scrub typhus with the sero-prevalence at village level. This will allow using the results of the study to predict the expected incidence and burden of scrub typhus in other settings with a known sero-prevalence, and eventually estimate the global burden of scrub typhus (not part of the study but a potential extension of the work). The target population for the study is therefore "villages in which the IgG sero-prevalence is at least 15%".
- Conditions
- Scrub Typhus, Spotted Fever; India, Murine Typhus
- Being tested
- No intervention
- Medical subject headings
- Scrub Typhus, Spotted Fever Group Rickettsiosis, Typhus, Endemic Flea-Borne
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
No interventionOther
No specific exposure is explored.
| Study group | Role | What they receive |
|---|---|---|
| General population | Whole population of scrub typhus endemic villages Receives: Other: No intervention | |
| hospital case population | cases recruited at study clinics who are not enrolled in general population cohort Receives: Other: No intervention | |
| Serological cohort | random subset of 4000 participants above the age of 10 drawn from general population cohort Receives: Other: No intervention |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of scrub typhus
clinically apparent infection
Measured: 2 years
Incidence of spotted fever
clinically apparent infection
Measured: 2 years
Incidence of murine typhus
clinically apparent infection
Measured: 2 years
Secondary outcomes (6)
Incidence of serological infection (scrub typhus)
measured using paired samples from sero-cohort
Measured: 2 years
Incidence of serological infection (spotted fever)
measured using paired samples from sero-cohort
Measured: 2 years
Incidence of serological infection (murine typhus)
measured using paired samples from sero-cohort
Measured: 2 years
Incidence of complicated infection (scrub typhus)
based on pre-defined complications: ARDS, shock, CNS, renal failure, myocarditis
Measured: 2 years
Incidence of complicated infection (spotted fever)
based on pre-defined complications: ARDS, shock, CNS, renal failure, myocarditis
Measured: 2 years
Incidence of complicated infection (murine typhus)
based on pre-defined complications: ARDS, shock, CNS, renal failure, myocarditis
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Aug 2020
- Study start1 Aug 2020
- Primary completion5 Aug 2022
- Study completion31 Jul 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Scrub TyphusStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 32,566 participants (actual)
Sponsor and investigators
- Lead sponsor
- London School of Hygiene and Tropical Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- Medical Research Council, Christian Medical College, Vellore, India, Mahidol Oxford Tropical Medicine Research Unit, Australian Rickettsial Reference Laboratory
- Responsible party
- Sponsor
- Investigators
- Wolf-Peter Schmidt, PhD, Principal investigator, London School of Hygiene and Tropical MedicineDaniel Chandramohan, PhD, Study chair, London School of Hygiene and Tropical Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04506944
- Sponsor's protocol ID
- MRC typhus cohort 1
- Status last verified
- Oct 2023
- First submitted
- 7 Aug 2020
- Last updated
- 5 Oct 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: de-identified case data will be made available at LSHTMs data repository
Publications
Devamani C, Alexander N, Chandramohan D, Stenos J, Cameron M, Abhilash KPP, Mangtani P, Blacksell S, Vu HTT, Rose W, Schmidt WP. Incidence of Scrub Typhus in Rural South India. N Engl J Med. 2025 Mar 13;392(11):1089-1099. doi: 10.1056/NEJMoa2408645.
PubMed 40073309
Study at a glance
From the registry record, last updated by the sponsor on 5 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Epidemiology Of Scrub Typhus And Rickettsial Infections In A Highly Endemic Rural Setting In South India: Population-Based Cohort Study
- ClinicalTrials.gov ID
- NCT04506944
- Acronym / sponsor ID
- MRC typhus cohort 1
- Conditions
- Scrub Typhus, Spotted Fever; India, Murine Typhus
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 32,566 participants (actual)
- Lead sponsor
- London School of Hygiene and Tropical MedicineUniversity, hospital or other
- Collaborators
- Medical Research Council, Christian Medical College, Vellore, India, Mahidol Oxford Tropical Medicine Research Unit, Australian Rickettsial Reference Laboratory
- Study start
- 1 Aug 2020 (actual)
- Primary completion
- 5 Aug 2022 (actual)
- Study completion
- 31 Jul 2023 (actual)
- First posted
- 10 Aug 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
There is enough evidence to suggest that scrub typhus and spotted fever group rickettsioses are common causes of febrile illness in India. Serological evidence also exists for murine typhus, but is rarely tested for. Incidence, risk factors, clinical features and molecular epidemiology of these three infections are poorly understood. Delays in disease recognition and treatment may cause thousands of preventable deaths across India.
The objectives of the research are to determine the incidence and risk factors of scrub typhus, spotted fever and murine typhus by severity, to determine clinical features of these neglected and often unrecognized infections. Further to study the effect of previous infection on incidence and severity of subsequent infections. Finally to study the association between vector parameters and scrub typhus risk.
Enrolled will be 30,000 individuals who will be followed up for the development of fever using active and passive surveillance. Active surveillance will include household screening every 3-6 weeks. Fever cases occuring in the past two months will be tested for Scrub typhus, murine typhus and spotted fever IgG/IgM. 4000 individuals will be followed up by annual serological testing to identify asymptomatic infections. Participants notifying the study team with ongoing fever will undergo blood testing for acute diagnosis of rickettsial infection (IgM, PCR). In addition, we will enroll fever cases at study clinics who are not part of the main cohort. The research includes spatial and socio-economic risk factor analysis. Rodents carrying mite larvae will be trapped to compare the intensity of mite infestation between areas of high and low risk for human scrub typhus.
The data on incidence, burden of disease and environmental determinants of scrub typhus, spotted fever and murine typhus will be used for health care planning and information campaigns for the public and medical professionals.
Detailed description
The aim of the cohort study is to better understand the epidemiology, sero-epidemiology and transmission of scrub typhus, murine typhus and tick-borne spotted fever. The overall focus of the work will be on scrub typhus, being the most important of the three from the public health perspective. We aim to determine the "severity pyramid" of serological, symptomatic and severe infection. The results from this study will help clinicians to understand the natural course of scrub typhus infection, health policy makers to estimate the global burden and the scope for community-based interventions, and immunologists to better understand the immunogenicity of single and repeat infections.
The specific objectives are to:
- Estimate the incidence of symptomatic and severe scrub typhus infection in the community.
- Estimate the incidence of serological (asymptomatic) scrub typhus infection.
- Estimate the effect of previous scrub typhus infection (sero-positive at baseline) on the risk of subsequent infection and disease severity (subclinical vs clinically apparent). This includes the effect of antibodies in mothers on the risk of severe infection in young children via residual maternal antibodies.
- Estimate the effect of potential risk factors such as age, gender, occupation, water/sanitation access and comorbidity on the risk of scrub typhus infection.
- Estimate the effect of spatial-temporal risk factors for scrub typhus by identifying high risk areas, accounting for human population density and land use.
- Compare the rate of rodent trappings and vector parameters of chiggers between high risk and low risk areas identified under 5).
- Estimate the disease burden associated with scrub typhus and the economic impact of scrub typhus in terms of loss of earnings and health expenditure.
- Estimate the incidence of asymptomatic and symptomatic murine typhus and spotted fever infection and explore associated socio-demographic, spatial and vector-related risk factors.
STUDY OVERVIEW
The study will be a population-based cohort study over two years (i.e. two scrub typhus seasons) in about 30,000 people living in approximately 40 villages with a sero-prevalence of at least 15% (see flow diagram above). These individuals will be followed-up through active surveillance for recent febrile illnesses (clinical cohort). For passive surveillance, participants will be encouraged to notify the study team in case of fever or come to one of 4 local study clinics. At study clinics we will also enrol fever cases who are not part of the clinical cohort, i.e. have not been enrolled prior to their fever. The study will include a smaller cohort (sero-cohort) for serological surveillance of 4000 people drawn from the 30,000 people of the clinical cohort. Longitudinal serological surveys linked to active surveillance are essential to estimate true attack rates unbiased by disease severity. The sero-cohort will consist of three annual blood testing in the same group of participants over two scrub typhus seasons (baseline, inter-season, endline).
Target population- A pilot study showed that scrub typhus infection is highly focal This makes it difficult to define a target population for the purpose of making inferences. We will define the target population in terms of the village level sero-prevalence. The aim is to correlate the incidence of scrub typhus with the sero-prevalence at village level. This will allow using the results of the study to predict the expected incidence and burden of scrub typhus in other settings with a known sero-prevalence, and eventually estimate the global burden of scrub typhus (not part of the study but a potential extension of the work). The target population for the study is therefore "villages in which the IgG sero-prevalence is at least 15%".
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| General population | – | Other: No interventionWhole population of scrub typhus endemic villages |
| hospital case population | – | Other: No interventioncases recruited at study clinics who are not enrolled in general population cohort |
| Serological cohort | – | Other: No interventionrandom subset of 4000 participants above the age of 10 drawn from general population cohort |
Who may qualify
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- General population cohort: all residents in scrub typhus endemic villages Serological cohort: random sample of 4000 individuals older than 10 years present at the time of the initial baseline survey visit hospital case cohort: cases of all ages attending study clinics for undifferentiated fever of at least 5 days duration
Key inclusion criteria (3 listed)
- General population cohort: residing in study villages
- serological cohort: aged 10 years or older
- Hospital cohort: all ages
Key exclusion criteria (1 listed)
- None
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| No interventionNo specific exposure is explored. | Other | General population, Serological cohort, hospital case population |
Primary outcome
Incidence of scrub typhus
Time frame: 2 years
clinically apparent infection
Incidence of spotted fever
Time frame: 2 years
clinically apparent infection
Incidence of murine typhus
Time frame: 2 years
clinically apparent infection
6 secondary outcomes
Incidence of serological infection (scrub typhus)
Time frame: 2 years
Incidence of serological infection (spotted fever)
Time frame: 2 years
Incidence of serological infection (murine typhus)
Time frame: 2 years
Incidence of complicated infection (scrub typhus)
Time frame: 2 years
Incidence of complicated infection (spotted fever)
Time frame: 2 years
Incidence of complicated infection (murine typhus)
Time frame: 2 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Oct 2023.
- Derived from this study: PubMed 40073309Devamani C, Alexander N, Chandramohan D, Stenos J, Cameron M, Abhilash KPP, Mangtani P, Blacksell S, Vu HTT, Rose W, Schmidt WP. Incidence of Scrub Typhus in Rural South India. N Engl J Med. 2025 Mar 13;392(11):1089-1099. doi: 10.1056/NEJMoa2408645.
- Individual participant dataSharing planned: Yes. de-identified case data will be made available at LSHTMs data repository
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Active, not recruitingPhase 4
Scrub Typhus Antibiotic Resistance Trial
Scrub Typhus
Active, not recruitingObservational study
Scrub Typhus Infection Induced Cardiovascular Disease
Scrub Typhus, Cardiovascular Complication
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Wolf-Peter Schmidt, PhD principal investigator
London School of Hygiene and Tropical Medicine
Daniel Chandramohan, PhD study chair
London School of Hygiene and Tropical Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Scrub Typhus and Spotted Fever; India, run by London School of Hygiene and Tropical Medicine at 1 site in India.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in India. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of scrub typhus (time frame: 2 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04506944, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Oct 2023.