Rickettsiae are Gram-negative, obligate intracellular bacteria transmitted by arthropod vectors, causing zoonotic diseases with natural endemic foci.1Rickettsia japonica, a member of the spotted fever group rickettsiae (SFGR), is primarily transmitted by ixodid tick bites and causes Japanese spotted fever (JSF).2 The classical clinical triad of JSF comprises fever, rash, and eschar.3 However, early manifestations are often nonspecific, necessitating differentiation from other febrile illnesses, particularly severe fever with thrombocytopenia syndrome (SFTS). The first human case of R. japonica infection in China was reported in Anhui Province in 2013, and sporadic cases have since been identified in Zhejiang, Henan, and Hubei Provinces.4–6 Nevertheless, comprehensive epidemiological surveillance data on rickettsial diseases in China remain limited. In this retrospective case series, we analyzed five patients with R. japonica infection confirmed by mNGS in Yichang, western Hubei Province, to delineate clinical features that facilitate early recognition and guide targeted treatment.

Rickettsial infections exhibit summer–autumn seasonality correlating with arthropod vector proliferation, and establishing outdoor exposure as a major risk factor.8 Fever and rash are characteristic clinical features, often accompanied by nonspecific symptoms such as headache and myalgia.9 Previous studies have reported incidence rates of approximately 88%–99% for fever, 94% for rash, and 44%–66% for eschar.3 Although JSF generally has a favorable prognosis, serious complications – including disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), and multiple organ failure – have been documented.10 In recent years, sporadic cases of JSF in regions such as Zhejiang, Henan, and Hubei, China, have included severe manifestations such as multiorgan failure.5,6,11

In the present cohort, all cases occurred during the summer–autumn period and were associated with documented outdoor exposure. The universal presence of fever and rash underscores their diagnostic utility in raising early clinical suspicion. Notably, one patient with chronic HBV infection developed multiorgan failure, potentially attributable to: (1) HBV-related immunosuppression (impaired T-cell immunity), (2) diagnostic delay (five days post-symptom onset), and (3) initial β-lactam therapy, which was ineffective against obligate intracellular pathogens.

Rickettsia species primarily invade vascular endothelial cells, resulting in increased capillary permeability, microvascular hemorrhage, and platelet consumption.12 These pathophysiological processes may precipitate severe complications, including acute respiratory distress syndrome (ARDS) and multiorgan failure.13 In this study, several findings supported the pathogenic mechanism of endothelial injury, including elevated D-dimer (indicating microthrombosis), elevated CRP (suggestive of vasculitis), and a non-blanching hemorrhagic rash (characteristic of microvascular damage). Given the potential risk of pulmonary complications, chest CT imaging was performed to evaluate lung involvement.

As an unbiased broad-pathogen detection tool, mNGS plays a critical role in diagnosing JSF.4,14 This study utilized two platforms: (1) Q-mNGS, which employs PCR-free library preparation with spike-in internal standards to calculate pathogen load via the Quantitative Index (e.g., Case 4 had a Q-index of 6730.85), thereby reducing analytical bias in low-biomass microbial samples.15 (2) MetaCAP-mNGS, which applies probe enrichment to enhance sensitivity for detecting low-abundance pathogens.16 Given the substantial symptom overlap between R. japonica, SFTSV, and other infections,17 mNGS provides critical value for differential diagnosis. No SFTSV nucleic acid was detected in this cohort. Integration with clinical data allowed definitive exclusion of SFTSV infection. Notably, the sensitivity of mNGS for detecting obligate intracellular pathogens remains suboptimal, primarily due to the low microbial DNA burden in early-phase plasma/CSF samples compounded by the overwhelming host nucleic acid background.18,19 These technical limitations may consequently result in false-negative interpretations or low-coverage sequencing results. Thus, the presence of at least one species-specific read was considered clinically significant if the following criteria were fulfilled: (1) clinical features were consistent with rickettsial disease, (2) exposure history aligned with endemic regions, and (3) alternative diagnoses were excluded.20 In Cases 2 and 4, despite low mNGS read counts (17 and 27 reads), JSF was diagnosed based on the following criteria: (a) characteristic clinical presentation (fever, rash, and eschar), (b) exposure in endemic areas, (c) pathogen identification by mNGS, and (d) defervescence within 48–72h after the initiation of doxycycline therapy.

Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit and is the first-line therapy for JSF. The recommended regimen is 100mg twice daily for 5–7 days, continued for three days after defervescence.21 In this study, two patients did not respond adequately to initial fluoroquinolones or β-lactams, but all achieved defervescence within five days (median, 72h) after initiation of doxycycline, without adverse events. Therefore, early initiation of doxycycline is strongly recommended in cases of suspected or clinically diagnosed JSF, provided there are no contraindications.

This study was not supported by any specific research funding or financial grants.

All authors declare no competing financial or non-financial interests relevant to this study.