Towards improved detection, prevention and integrated control of scrub typhus in Central Vietnam

SUMMARY
Background
Scrub typhus is a zoonotic infectious disease caused by obligate intracellular bacteria Orientia spp, transmitted to humans by the bites of infected larval-stage trombiculid mites, which are found mainly on rodents of forests and rice fields across the Asia-Pacific region.
Scrub typhus is a severe public health problem, with one billion people at risk globally, causes illness in an estimated one million people every year, and became a leading cause of treatable non-malarial febrile illness. Case fatality reports vary widely around a median mortality of 6.0% (range 0-70%) for untreated and 1.4% (range 0-33%) for treated scrub typhus patients.
In Vietnam, after 40 years of neglect, scrub typhus (ST) is re-emerging as evidenced by expanding geographical distribution and increase in new cases. Unfortunately, both the clinical and laboratory diagnoses of ST remain challenging, even at the national hospital. Due to late diagnosis and late treatment effects, a severe case complication rate of 17% and a mortality rate of 1.2% among 251 infected and diagnosed patients was reported at the national hospital in 2003. Epidemiological and ecological information on scrub typhus is very scant in Vietnam, and there is no updated evidence on practical preventive measures and fostered case-detection.
Dengue fever (DF) has made a substantial impact over the two past decades in Vietnam and is unequivocally the leading cause of febrile illness throughout the country. Dengue incidence per 100,000 population has steadily increased from 32.5 in the year 2000 (24,434 cases) to 149.9 in 2018 (141,927 cases), at the third rank among the 28 most common communicable diseases. Because of non-specific symptoms such as high fever, headache, skin rash or myalgia are common to both ST and DF, differential diagnosis is required to decide on the treatment strategies.
The overall aim of the present PhD research was to contribute to a better understanding and improving case detection and practical prevention of scrub typhus in Vietnam. Specifically, the work aimed to i) differentiate scrub typhus from dengue fever using admission clinical manifestations and routine blood tests; ii) investigate behavioural and environmental related risk factors of scrub typhus; iii) evaluate temporal dynamics of DNA and serology-based assays and its efficacy in early diagnosis of scrub typhus in Vietnam.
Methods
First, a study including 221 and 387 confirmed acute cases of ST and DF, respectively, and use of multivariable logistic regression and classification and regression trees (CART), identified clinical and laboratory parameters differentiating ST from DF. Then in 2018/2020, a clinical hospital-based active surveillance study, and a retrospective residence-enrolment date-age-matched case-control study were conducted to investigate the risk factors of ST in Khanh Hoa, Vietnam. Finally, were used data of two hospital active surveillances of suspected ST patients that were done in Khanh Hoa in the periods of 2013-2014 and 2018-2020. The PCR, IgM ELISA, IgM rapid test (RDT) results and days of fever on admission of these patients were used to evaluate temporal dynamics of DNA and serology-based assays and their efficacies in early diagnosis of scrub typhus in Vietnam.
Results
The main variables to distinguish scrub typhus from dengue included i) the eschar; ii) regional lymphadenopathy; iii) an occupation in nature; iv) increased days of fever on admission; v) increased neutrophil count; vi) decreased ratio of neutrophils/lymphocytes; vii) increased platelet count; and viii) the higher age of patients. Sensitivity and specificity of predictions for scrub typhus based on these seven factors reached 93.7% and 99.5%, respectively, in multi. When excluding the “eschar” variable, the values dropped to 76.3% and 92.3%, respectively. Using the CART model, the corresponding values for the alternative decision tree model were 95.0% and 96.9% when including the variable “eschar” and 77.4% and 90.7% without eschar.
Several factors were significantly associated with acquisition of scrub typhus, including sitting/laying directly on the household floor (adjusted OR=4.9, 95%CI:1.6–15.1), household with poor sanitation/conditions (aOR=7.9, 95%CI:1.9–32.9), workplace environment with risk (aOR=3.0, 95%CI:1.2–7.6), observation of mice around the home always (aOR=3.7, 95%CI:1.4–9.9), and use of personal protective equipment in the field (aOR=0.4, 95%CI:0.1–1.1).
PCR buffy coat performed best from day 1 to day 6, compared to ELISA and RDT, with an overall positivity rate of 73% during this early phase. ELISA IgM and RDTs performed better after day 7 of fever, with positivity rates of 90% and 81%, respectively, in the later phase – but contributed to diagnosis from day 3 of fever. The combination of PCR buffy coat with an RDT detected 93% to 100% of all positive cases during the first 14 days of fever.
Conclusions
This work provides evidence for better understanding on fostered case-detection and practical preventive measures of scrub typhus in Vietnam. A combined package with clinical training, risk factors training, and RDTs should be implemented at primary health care level to promote accurate diagnostic for scrub typhus in the hotspot area. The findings from this study are useful for training courses at the community level, support the establishment of preventive measures, create better awareness among the public and inform regional surveillance, and promote much-needed effective public health responses against scrub typhus - this after many decades of neglect in Vietnam.