Analysis of the Epidemiological Characteristics and Risk Factors for Severe Progression of Scrub Typhus in the Dali Region of China

Introduction

Scrub typhus, also known as tsutsugamushi disease or bush typhus, is an acute zoonotic infectious disease with natural foci, primarily caused by Orientia tsutsugamushi. In addition, it can be attributed to Candidatus Orientia chuto, Candidatus O. chuto-like organisms, and Candidatus Orientia chiloensis [1,2]. The disease is transmitted to humans via the bite of larval trombiculid mites (chiggers) [3]. It can evade the host immune system and propagate/disseminate through the lymphatic and hematogenous systems, causing systemic symptoms such as fever, headache, myalgia, rash, and lymphadenopathy. The infection can involve multiple organs, including the skin, lymphatic system, liver, central nervous system, cardiovascular system, and respiratory system. Severe cases can develop complications, including multi-organ dysfunction syndrome, meningitis, and even fatal outcomes.

It is reported that approximately 1 billion individuals worldwide are at risk of scrub typhus infection, with at least 1 million annual cases and 150 000 fatalities globally [4–6]. In recent years, the incidence of scrub typhus has demonstrated an upward trend [1], posing a severe threat to global public health security [7]. Recent studies [8] have revealed a marked increase in scrub typhus incidence in China from 2006 to 2023, with geographic expansion from the southwest, south, and east regions toward the central-northern areas, although cases remain predominantly clustered in Yunnan Province. This disease continues to pose a significant public health challenge in China. Most of Yunnan Province falls within subtropical zones, particularly Dali Prefecture, where warm, humid climates and complex topography provide ideal conditions for trombiculid mite proliferation.

In most cases, the clinical course of scrub typhus is not severe, and patients generally respond well to antibiotic therapy. The mortality rate of scrub typhus is approximately 12.7% [9]. However, if the disease is not promptly diagnosed and treated, it can progress to a severe form and cause serious complications. Patients can die due to the severe illness or these complications [10], with the mortality rate soaring as high as 30% [11]. Moreover, at present, there is still a lack of unified diagnostic criteria for severe scrub typhus. The existing relevant reports base the diagnosis primarily on manifestations such as dysfunction in the heart, kidneys, central nervous system, respiratory system, and digestive system of patients. However, the numerous diagnostic items involved make it difficult for clinicians to make accurate assessments when dealing with critically ill patients. Therefore, it is of the utmost importance to screen for risk factors that can lead to progression to a severe disease case in patients with scrub typhus during the early stage of their hospital admission and to implement precise risk-stratification management to reduce the mortality rate of patients with scrub typhus. Hence, in this study, we aimed to explore the epidemiological characteristics of scrub typhus in the Dali region and identify early predictive risk factors for its progression to a severe condition, providing a theoretical reference for the local prevention and treatment of scrub typhus.

Material and Methods

ETHICS:

This study was approved by the Ethics Committee of the First Affiliated Hospital of Dali University (DFY20241123001). As this study was a retrospective study, the Ethics Committee granted a waiver of informed consent for the patients. All research procedures involving human participants were conducted in accordance with the 1964 Helsinki Declaration and its later amendments or similar ethical standards.

DATA SOURCE:

This study included a total of 459 patients with scrub typhus diagnosed at the First Affiliated Hospital of Dali University in Dali Prefecture from January 1, 2015, to December 31, 2024.

GEOGRAPHIC LOCATION AND ECONOMIC STATUS OF THE GEOGRAPHICAL REGION:

Dali is situated between 98°52′ and 101°03′ east longitude and 24°41′ and 26°42′ north latitude. Geographically, it falls within the subtropical zone, characterized by a warm and humid climate, along with complex and diverse topography. The local economy is predominantly driven by agriculture and tourism, with rapid agricultural development and significant contributions from the tourism sector.

COLLECTION OF CASE DATA:

Epidemiological data of patients with scrub typhus were collected through the hospital information system. The information collected included demographic characteristics: age, sex, onset time, address, ethnicity, occupation, and history of fieldwork; clinical characteristics: fever, chill, headache, abdominal pain, cough, expectoration, muscular stiffness, asthenia, poor appetite, nausea, vomiting, splenomegaly, lymphadenectasis, and location of eschar; laboratory data: white blood cell count, absolute neutrophil count (Neu), absolute lymphocyte count, absolute monocyte count, absolute eosinophil count (Eos), absolute basophil count (Bas), red blood cell count, hemoglobin, platelet count (PLT), total bilirubin, direct bilirubin, indirect bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, γ-glutamyl transpeptidase, albumin, blood urea nitrogen (BUN), creatinine, uric acid, blood potassium, blood sodium, blood calcium, total cholesterol, triglycerides, prothrombin time, activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, C-reactive protein (CRP), hematuria, and urine protein. Results of chest X-ray or computed tomography, electrocardiogram, and the treatment plan and prognosis were also collected from the hospital information system.

INCLUSION AND EXCLUSION CRITERIA:

The study was conducted in accordance with the “Technical Guidelines for the Prevention and Control of Scrub Typhus (Trial)” [12] issued by the Chinese Center for Disease Control and Prevention in 2009, and included 58 (12.64%) clinically diagnosed cases and 401 (87.36%) laboratory-diagnosed cases. Patients who met the following 3 criteria were defined as clinically diagnosed cases: (1) field exposure history 1 to 3 weeks prior to symptom onset; (2) fever with skin rash or lymphadenopathy; and (3) typical eschars or ulcers. Laboratory-diagnosed cases were defined as those meeting any of the following criteria: (1) a positive Weill-Felix test; (2) a positive indirect immunofluorescence antibody assay; (3) a positive PCR; and (4) confirmation of an isolated pathogen.

The exclusion criteria were as follows: (1) hospitalization duration less than 24 hours; and (2) incomplete or missing clinical data.

DEFINITIONS:

The characteristic eschar refers to a localized skin manifestation following trombiculid mite (chigger mite) bites, wherein the bitten area initially presents with hyperemia and edema, leading to the formation of small papules. Subsequently, these papules progress into small vesicles, with central necrosis and hemorrhage occurring within the vesicles, ultimately resulting in the development of a round- or oval-shaped black scab (eschar).

Liver injury was defined as elevation of serum ALT more than twice the upper normal limit, taken as 40 IU/L [13].

For the diagnosis of severe scrub typhus, patients must have met at least 1 of the following criteria [14,15]: (1) central nervous system: impaired consciousness, convulsions, or stroke; (2) respiratory system: chest imaging showing bilateral pulmonary infiltrates, along with at least 1 of the following: oxygenation index 250 mmHg or lower, respiratory rate 30 breaths/min or higher, or requirement for mechanical ventilation; (3) circulatory system: myocarditis, myocardial ischemia, or new-onset arrhythmia; (4) renal system: serum creatinine level of 177 μmol/L or higher; (5) septic shock; (6) peptic ulcer; (7) requirement for admission to the intensive care unit during hospitalization; and (8) death. Other patients were defined as having mild scrub typhus.

STATISTICAL ANALYSIS:

Data analysis and graphical visualization were performed using SPSS 26.0 and GraphPad Prism 9.0 statistical software. For comparisons of continuous variables between the 2 groups, the t test or Mann-Whitney U test was applied, while categorical variables were compared using the χ² test or Fisher exact probability method. Logistic regression analysis was used to screen for risk factors associated with the severe progression of scrub typhus, and the Bonferroni multiple correction method was used to control for false positives resulting from multiple testing. The statistical significance threshold was set at α=0.05.

Results

DEMOGRAPHIC CHARACTERISTICS:

This study included a total of 459 scrub typhus cases from Dali Prefecture, with 191 male patients (41.61%) and 268 female patients (58.39%) (Figure 1A). The age distribution ranged from 14 to 89 years, with disease onset predominantly occurring between July and October (Figure 2). Patients were primarily from Dali City (36.82%), Weishan Yi and Hui Autonomous County (14.81%), Midu County (9.15%), Eryuan County (7.41%), and Nanjian County (7.19%) (Table 1). Ethnically, the patient cohort consisted mainly of Bai (41.61%), Han (40.74%), Yi (13.07%), Hui (3.05%), and Lisu (0.65%) nationalities (Figure 1B). Farmers constituted the largest occupational group, accounting for 321 cases (67.9%) (Figure 1C).

COMPARISON OF CLINICAL CHARACTERISTICS BETWEEN PATIENTS IN THE SEVERE SCRUB TYPHUS GROUP AND MILD SCRUB TYPHUS GROUP:

The mild scrub typhus group and severe scrub typhus group had statistically significant differences (P<0.05) in terms of age, cough, expectoration, concurrent liver injury, length of hospital stay, and prognosis (Table 2).

COMPARISON OF LABORATORY PARAMETERS BETWEEN PATIENTS IN THE SCRUB TYPHUS GROUP AND MILD SCRUB TYPHUS GROUP:

Statistically significant differences (P<0.05) were observed between the severe and mild scrub typhus groups in terms of laboratory parameters, including CRP, APTT, TT, fibrinogen, total bilirubin, direct bilirubin, ALT, AST, albumin, BUN, creatinine, uric acid, sodium, calcium, total cholesterol, triglycerides, Neu, Eos, PLT, creatine kinase, lactate dehydrogenase, and α-hydroxybutyrate dehydrogenase, hematuria, and proteinuria (Table 3).

UNIVARIATE LOGISTIC REGRESSION ANALYSIS FOR SEVERE SCRUB TYPHUS:

By applying univariate logistic regression analysis to the statistically significant indicators identified through comparison between the severe and mild scrub typhus groups, it was found that age, CRP, APTT, TT, fibrinogen, total bilirubin, direct bilirubin, ALT, AST, albumin, BUN, creatinine, uric acid, sodium, calcium, total cholesterol, triglycerides, Neu, PLT, lactate dehydrogenase, α-hydroxybutyrate dehydrogenase, combined liver injury, cough, expectoration, hematuria, and urine protein level were risk factors for severe scrub typhus (P<0.05) (Table 4).

MULTIVARIATE LOGISTIC REGRESSION ANALYSIS FOR SEVERE SCRUB TYPHUS:

After excluding indicators with collinearity from those showing statistical significance in the univariate logistic regression analysis, multivariate logistic regression analysis revealed that BUN over 7.3 mmol/L (P=0.040, OR [95% CI]: 1.12 [1.09–1.22]), PLT of 71×109/L or lower (P=0.036, OR [95% CI]: 0.98 [0.98–0.99]), and combined liver injury (P=0.033, OR [95% CI]: 2.70 [1.49–4.90]) were risk factors for severe scrub typhus (Table 5). When these 3 indicators were used in combination, the area under the receiver operating characteristic curve (AUC) was 0.81, with a 95% CI of 0.75–0.86 (Figure 3).

Discussion

LIMITATIONS:

This study has certain limitations. First, because the diagnostic criteria in this study were based on the Technical Guidelines for Scrub Typhus Prevention and Control (Trial Implementation) issued by the Chinese Center for Disease Control and Prevention in 2009, laboratory diagnosis still relied on the Weil-Felix test. This assay demonstrates relatively low sensitivity and specificity, which can lead to misdiagnosis or underdiagnosis of scrub typhus, potentially resulting in data gaps. Second, in this study, we analyzed only the risk factors for the progression of scrub typhus to a severe state and did not conduct an analysis on the prognosis of scrub typhus. Third, as a single-center retrospective study, its conclusions may not fully reflect the actual epidemiological characteristics of scrub typhus in Dali Prefecture. Fourth, internal and external validation were not conducted in this study. Given these constraints, future large-sample multicenter studies are needed to provide more comprehensive and reliable theoretical evidence for scrub typhus prevention and control in the Dali region.

Conclusions

The incidence of scrub typhus in the Dali region is concentrated from July to October, predominantly affecting female patients in rural areas. Elevated BUN levels over 7.3 mmol/L, decreased PLT of 71×109/L or lower, and concurrent liver injury are identified as risk factors for the progression of scrub typhus to a severe state. During the epidemic season of scrub typhus, increasing health education among high-risk populations, including raising people’s awareness of self-protection against fever, can mitigate the risk of scrub typhus infection.