Causes of Fever in Bangladeshi Patients

Background:

The clinical features and prevalence of tropical rickettsial illnesses such as murine and scrub typhus in Bangladesh are unknown. Following testing for malaria, patients with undifferentiated fever are frequently treated empirically for typhoid or diagnosed clinically with a viral fever. Since murine and scrub typhus are common causes of fever in other countries in the region, it is likely they are prevalent in Bangladesh. Murine and scrub typhus may be treated cheaply and effectively with doxycycline.

Primary aim:

- Describe the clinical features of scrub and murine typhus in Bangladeshi patients

Secondary aims:

* Assess the proportion of patients screened for malaria having rickettsial illnesses
* Understand the pathophysiology of severe scrub typhus and murine typhus
* Prospective evaluation of rapid diagnostic tests for scrub and murine typhus

Methods:

Scrub typhus and murine typhus rapid tests will be introduced to CMCH in conjunction with existing malaria testing facilities. Consenting febrile adult patients who have had malaria and typhus rapid tests and meeting the entry criteria will be enrolled. Samples will be saved for serology and real time polymerase chain reaction (PCR) testing for O. tsutsugamushi and Rickettsia spp. A thorough history and examination will be undertaken. Hemodynamic status will be assessed by ultrasound upon enrolment. Patients will be followed up for outcome and a second sample will be taken for convalescent serological testing on day 14 where possible.

Analysis The proportion of patients screened for malaria with an acute febrile illness due to scrub typhus and murine typhus will be calculated. The clinical features of scrub and murine typhus, malaria and patients negative for these conditions will be compared. Healthy subject samples will be used to provide normal ranges. The sensitivity and specificity of the rapid tests will be assessed as compared to the gold standard of PCR and serology combined.

Proposed activities:

The primary objective of this study are to assess the clinical features of patients with scrub or murine typhus infections presenting to CMCH. The proportion of cases screened for malaria and typhus who are diagnosed with scrub and murine typhus during the study period will be calculated, and the data made available for future empiric treatment guideline preparation.

Rapid antibody-based tests for scrub typhus and murine typhus will be made available for physicians to request alongside malaria testing in CMCH. Consenting febrile patients admitted to CMCH will be enrolled and history and clinical examination recorded. A sample will be taken for reference diagnostic testing at a later stage (including indirect fluorescent antibody (IFA) and real time PCR for scrub typhus and Rickettsia spp.)16. Samples will also be taken for testing of markers of pathophysiology (endothelial dysfunction neutrophil activation, cell death, cytokines). Where an eschar is found, the scab will be removed for real time-PCR. Where possible, patients will be invited back for a follow up 14 days after enrolment and a sample collected for paired serology assayed by IFA testing. Ultrasound based hemodynamic assessment will be performed to assess volume status and evidence of cardiac dysfunction.

The results of the ultrasound based hemodynamic assessment will be used to provide baseline information on patients with O. tsutsugamushi and Rickettsia spp. infection and other infections. This information may be used to plan further studies on the fluid management of these conditions.

Study design:

This is an observational study with no intervention. Febrile patients admitted to CMCH who have had malaria film and scrub typhus and murine typhus rapid test will be screened for enrolment. If patients meet the entry criteria, they will be enrolled after written informed consent has been given. Enrolled patients will then undergo study procedures (blood tests, physical examinations, follow-up).

Overall Description of study Participants:

The target population of this study is consenting adult patients who have had malaria and typhus rapid tests meeting the eligibility criteria admitted in CMCH. All study patients must meet the applicable inclusion and exclusion criteria.

During the study period, we aim to prospectively recruit consecutive patients until 300 patients are enrolled for whom there are paired admission and convalescent samples.

Data obtained from the malaria patients and patients without malaria or typhus will be used as comparator groups for the patients with typhus. The data from the 300 consecutive patients will be used to prospectively assess the sensitivity and specificity of the typhus diagnostic tests.

In addition, 30 healthy subjects with no recent history of fever will be recruited to provide control samples for the blood and plasma assays.

The total sample size is therefore estimated to be 330 (300 with paired serology and 30 healthy subjects).

Eligibility Criteria:
Patients

Inclusion Criteria:

1. Admitted to CMCH
2. Have had malaria and typhus rapid tests
3. Age≥12 years old
4. Febrile or history of fever for \<3 weeks.
5. Written informed consent from patient or attending adult (for patient who lacks capacity) or parent (for those below 18)

Exclusion Criteria:

* Consent refused, or no adult (≥18 years) relative or guardian present to give consent in the case the patient lacks capacity to give consent.

Healthy subjects Inclusion

1. No known acute or chronic medical conditions
2. Asymptomatic
3. No febrile illness in the last 2 weeks
4. Age≥12 years old
5. Written informed consent from patient or parent (for those below 18)

Exclusion criteria:

1. Consent refused, or no adult (≥18 years) relative or guardian present to give consent in the case the patient is under 18 years.