Scrub typhus, a potentially life-threatening disease with an enormous incidence in the Asia–Pacific Rim, remains remarkably neglected [
12]. Outdoor work is the high-risk occupation associated with scrub typhus [
13]. The typical clinical manifestation of scrub typhus is an eschar at the site of mite feeding. Depending on the geographic area and research area, an eschar is found in 1% and 97% of patients, respectively, and is generally considered a key clinical feature [
14]. Patients without an eschar are difficult to diagnose. The current patient, an urban dweller with a history of field work, was previously in good health. Unfortunately, the patient was not diagnosed in a timely manner because scrub typhus was not among the differential diagnoses considered by the clinicians given the rarity of scrub typhus in our region and the lack of typical clinical features; therefore, tests such as specific serologies and NAATs were not ordered. Additionally, her main symptoms were urinary, which are rarely reported in cases of scrub typhus. Only Shu et al. [
15] and Bhattarai et al. [
16] have reported UTIs associated with scrub typhus. The mechanism of urinary involvement in scrub typhus may be that
O. tsutsugamushi induces vasculitis [
17]. High D-dimer levels may occur because
O. tsutsugamushi mainly attacks endothelial cells, which have procoagulant and proinflammatory properties [
18]. The coagulation system is activated, and the resulting thrombin converts soluble fibrinogen to fibrin monomer, leading to increase in D-dimer levels [
11]. The laboratory diagnosis of scrub typhus includes serologic tests, NAATs, and tissue biopsies. Indirect immunofluorescence assay (IFA) requires the availability of fluorescence microscopes and professional testing personnel, neither of which is usually available in endemic areas [
19]. The Weil–Felix agglutination test has poor sensitivity and specificity due to the lack of species identification techniques. Moreover, cross-reactions between
O. tsutsugamushi and other pathogens, such as those associated with dengue, malaria, typhoid, influenza and leptospirosis, should be noted [
19]. Real-time polymerase chain reaction (Q-PCR) presents 97% sensitivity and 100% specificity for the diagnosis of scrub typhus [
19]. However, laboratories in many countries, including China, have not routinely performed this diagnostic test, and PCR can be applied when an eschar is present. However, it is difficult to suspect and determine in advance a diagnosis of scrub typhus if there are no typical clinical manifestations. The biosafety risks caused by tissue biopsy samples from scrub typhus patients make it impossible to analyse these samples in BSL-2 laboratories [
5].
NGS, a revolutionary development in first-generation sequencing methods, can simultaneously sequence hundreds of thousands to millions of DNA molecules with high throughput and short detection cycles [
20]. mNGS can detect all pathogens in samples even when small amounts of pathogens are present [
20]. Due to its high sensitivity, short detection cycle, and cost-effectiveness considerations, mNGS might be a potential diagnostic method that can partially replace traditional detection methods [
20]. However, the use of NGS has rarely been reported in the case of scrub typhus presenting as a UTI. To the best of our knowledge, another case of
O. tsutsugamushi infection detected by mNGS in a patient with atypical manifestations was reported by Wu et al. [
21]. In our case report,
O. tsutsugamushi was confirmed to be the pathogen on Day 13 of illness (20th March), and doxycycline treatment was demonstrated to be effective. In this case, the protocol of mNGS in our hospital refers to the information provided by Blauwkamp et al. [
22]. mNGS detected trace pathogens in an accurate and rapid manner to save considerable time, thereby effectively avoiding the aggravation of the patient's condition and the chronic migration of the disease and even eliminating severe DIC. The results of mNGS directly affected the patient’s care, ultimately resulting in a satisfying outcome.
mNGS is likely a valuable method to diagnose scrub typhus, especially in complicated cases with atypical features. It is worth noting that the cost of mNGS, the practicality of using the method in underdeveloped areas with limited resources, potential limitations and obstacles in the clinical application of NGS, and the utility of NGS in overall clinical cases of scrub typhus warrant further research.
In summary, we used mNGS to diagnose a case of scrub typhus in a febrile patient without an eschar but with a UTI and high D-dimer levels. mNGS may be a useful method for identifying the pathogen responsible for infections without typical clinical symptoms. In the diagnosis of acute febrile patients with atypical clinical features, clinicians should consider atypical pathogens, such as O. tsutsugamushi, in patients with UTIs.