Case Report: Murine typhus complicated by symmetrical peripheral gangrene: first report and diagnostic insights from metagenomic next-generation sequencing

Background: Murine typhus, a flea-borne infection caused by Rickettsia typhi, often presents with nonspecific symptoms that delay diagnosis. While usually self-limiting, it can rarely progress to multiple organ dysfunction syndrome (MODS). We report the first case of murine typhus complicated by symmetrical peripheral gangrene (SPG), in which metagenomic next-generation sequencing (mNGS) enabled rapid diagnosis and guided timely doxycycline therapy.

Case presentation: A 69-year-old female from South China was hospitalized with persistent abdominal pain and low-grade fever. She was a farmer and had suspected animal exposure. Laboratory investigations revealed hypoxia, abnormal coagulation profile, hepatorenal impairment, and thrombocytopenia. Despite empirical antibiotic therapy, her condition deteriorated progressively, manifested as hemodynamic instability, respiratory failure, and the emergence of purpuric-petechial cutaneous eruptions. Immediate interventions were initiated, including administration of vasoactive agents and mechanical ventilation. Based on mNGS, R. typhi was confirmed, she received targeted antibiotic treatment with intravenous doxycycline (100 mg twice daily). On the hospital day 16, gangrene of all four extremities became evident. The patient underwent amputation of all four extremities and survived, with systemic symptoms gradually resolving during 6-months follow-up.

Conclusion: This first reported case of murine typhus complicated by symmetrical peripheral gangrene (SPG) establishes its potential to cause life-threatening multiorgan failure. Metagenomic next-generation sequencing (mNGS) resolved the diagnostic challenge by rapidly identifying Rickettsia typhi, guiding life-saving doxycycline therapy and underscoring its value in severe zoonotic infections.

Background

Murine typhus, a flea-borne zoonosis caused by Rickettsia typhi (R. typhi) and primarily transmitted by Xenopsylla cheopis, is widely distributed in warm and humid regions such as Southeast Asia, the Mediterranean basin, and the southern United States (1–4). Clinically, its classic triad of fever, headache, and rash occurs in only one-third of patients, while other nonspecific symptoms—such as malaise, myalgia, and gastrointestinal discomfort—often delay diagnosis (4). The disease is maintained in nature through reservoirs including opossums, rats, and household pets, with seasonal transmission peaks corresponding to flea proliferation (5, 6). In China, although competent vectors are prevalent, particularly in subtropical regions like Guangdong Province, reported human cases and clinical data on severe manifestations remain limited (4, 7). A systematic review found that 26.1% of patients develop complications such as pneumonia, acute renal failure, or altered mental status, highlighting its underestimated clinical burden (4).

Despite this, critical knowledge gaps persist. Most reports describe mild or moderate infections, while cases progressing to multiorgan dysfunction syndrome (MODS) are exceedingly rare—only 15 such cases have been documented worldwide, with a mortality rate exceeding 50% (8). Moreover, symmetrical peripheral gangrene (SPG), a severe ischemic complication typically associated with meningococcal sepsis or disseminated intravascular coagulation, has never been linked to murine typhus (9–11). Diagnostic delays further compound clinical risk, as conventional serology is slow, polymerase chain reaction (PCR) has limited sensitivity, and metagenomic next-generation sequencing (mNGS)—a promising tool for identifying rare pathogens—has not been evaluated in this setting (8, 12).

Here, we report the first documented case of murine typhus complicated by SPG, confirmed by mNGS in a critically ill patient with MODS who survived following targeted doxycycline therapy and multiple amputations. To contextualize this unprecedented presentation and delineate the clinical spectrum of severe murine typhus, we additionally performed a systematic review of all published R. typhi-associated MODS cases worldwide. By integrating this rare case with existing literature, our study aims to bridge current evidence gaps, highlight diagnostic advances offered by mNGS, and provide practical guidance for the management of atypically severe rickettsial infections in endemic regions.

Case presentation

A 69−year−old female farmer, who had prolonged rural residency, presented to the emergency department with 2-days progressive abdominal pain and 24-hours low-grade fever (38.2 °C). She had a history of hypertension without other significant comorbidities. Recent fieldwork exposure was noted, with absence of maculopapular rash, eschar, or hemorrhagic manifestations. Initial laboratory findings revealed mild leukocytosis (14 ×10⁹/L, 89% neutrophils), thrombocytopenia (51×10⁹/L), elevated C-reactive protein (68.53 mg/L), and procalcitonin (1.63 ng/mL). To rule out other major endemic infections, we performed multiple diagnostic tests: the Widal test for typhoid and paratyphoid was negative (all titers <1:80), and scrub typhus was excluded by a consistently negative Weil-Felix OXK titer (<1:80). Furthermore, nucleic acid testing for SARS-CoV-2 was negative. To differentiate the symmetrical peripheral gangrene from non-infectious causes, we conducted screening for systemic vasculitis; both the anti-neutrophil cytoplasmic antibody (ANCA) profile (including MPO, PR3, and GBM antibodies) and the comprehensive anti-nuclear antibody (ANA) profile were negative, effectively ruling out common autoimmune-mediated vasculitides. Thoracic computed tomography (CT) demonstrated bilateral lower lobe patchy opacities with small amounts of pleural effusion (Figures 1A, B). Abdominal CT showed pancreatic duct dilation, a small hepatic cyst, with unremarkable gallbladder, spleen, adrenal glands, bladder, and adnexa. Following a presumptive diagnosis of biliary tract infection, she received empirical antimicrobial therapy of imipenem and morinidazole.

Figure 1

Figure 1. Chest CT scans during hospitalization and follow-up. Axial chest CT images obtained on the first (A, B) and sixth (C, D) days after admission. Black arrows depict progressive bilateral lower-lobe infiltrates and increasing pleural effusion.

By day 3, the patient exhibited clinical deterioration by high fever, lethargy, myalgia, and tachypnea. On day 4, progressive respiratory failure developed with critical hypoxemia (SpO₂ 80%) and hemodynamic instability accompanied by purpuric and petechial rash. Repeat CT revealed extensive bilateral pulmonary infiltrates and increased pleural effusion, indicating severe pneumonia progression (Figures 1C, D). Due to persistent hypoxemia and hypotension, she was transferred to the intensive care unit (ICU) where she received mechanical ventilation and inotropic support. Her lab work showed rising liver-associated enzymes (alanine aminotransferase 498.6U/L), hyperbilirubinemia, acute kidney injury (creatinine of 99.49umol/L), coagulation disorder (PT 20.6 s, PTT 52.1 s), and elevated cardiac biomarkers (myoglobin 299 ng/mL, troponin T 209 ng/L, and BNP 17,314.6pg/mL). Bedside bronchoscopy demonstrated diffuse mucosal inflammation without purulent secretions, masses, or active bleeding. Bronchoalveolar lavage (BAL) specimens returned negative for bacterial cultures, fungal elements, and acid-fast bacilli.

Based on the above symptoms and laboratory tests, she was diagnosed with MODS, prompting combined management with albumin infusion, hepatoprotective therapy, platelet transfusion, cytokine adsorption (for three sessions to manage the inflammatory storm), and continuous renal replacement therapy (CRRT). Following ICU admission on hospital day 4 (approximately 6 days after symptom onset), specimens including 5 mL of peripheral blood, 10 mL of BALF, and 20 mL of mid-stream urine were collected for mNGS analysis. The mNGS was performed using the BGISEQ platform; following DNA extraction and library preparation, high-throughput sequencing was conducted, and host-depleted reads were aligned against a comprehensive microbial database. By hospital day 7, purpuric rashes were observed on the patient’s acral parts, trunk, sacrococcygeal region and lower back (Figure 2). Concurrently, the presence of R. typhi was detected by mNGS of the peripheral blood, the bronchoalveolar lavage fluid (BALF) and urine (Figure 3). To further corroborate the molecular diagnosis, longitudinal serological monitoring was performed using the Weil-Felix test. Although the initial test on hospital day 2 was negative for all antigens (<1:80), a repeat test on day 7 demonstrated a significant seroconversion, with the Proteus OX19 titer rising to 1:320 (positive). This four-fold increase in titer provided definitive serological evidence of a typhus group rickettsial infection, aligning with the mNGS results. Subsequent testing on day 16 showed that the OX19 titer had returned to negative levels (<1:80), potentially reflecting the rapid clearance of the pathogen following targeted doxycycline therapy. Consequently, targeted antibiotic treatment with intravenous doxycycline (100 mg twice daily) was immediately initiated. However, her lower limbs and toes continued to demonstrate significant gangrenous changes and progressed proximally with normal arterial/venous flow on ultrasound, suggesting disseminated microvascular thrombosis. By day 16, the dry gangrenous areas of the extremities had become clearly demarcated and ceased to improve.

Figure 2

Figure 2. Well-demarcated dry gangrene affecting all four limbs on day 16. Clinical photographs taken on day 16 demonstrating symmetrical dry gangrene of both lower (A, B) and upper (C, D) extremities, with clearly demarcated areas of tissue necrosis.

Figure 3

Figure 3. Detection of R. typhi (A) Timeline of pathogen detection across different specimens, BALF, peripheral blood, and midstream urine, showing R. typhi, Epstein-Barr virus, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, and Acinetobacter baumannii identified on specific hospital days (3, 16, and 18). (B, C) Genomic mapping profiles of R. typhi in BALF and blood samples. Gray bars represent multiple-mapping reads, blue bars indicate unique-mapping reads, and the orange line shows sequence identity relative to the R. typhi reference genome. Both samples exhibit high sequence identity (≈100%), confirming the presence of R. typhi; the BALF sample shows higher unique read abundance, suggesting greater local pathogen load. BALF, bronchoalveolar lavage fluid.

During this prolonged ICU stay, the patient’s management was further complicated by a succession of healthcare-associated infections. On hospital day 15, sputum cultures identified Stenotrophomonas maltophilia. By day 26, carbapenem-resistant Pseudomonas aeruginosa (CRPA) was isolated from BALF specimens, exhibiting resistance to imipenem (MIC≥16) but sensitivity to ceftazidime (MIC = 2) and amikacin (MIC = 4). Consequently, the antimicrobial regimen was adjusted to include intravenous ceftazidime (2.0 g every 8 hours) and amikacin (0.4 g once daily). On day 42, cultures from the necrotic lesion secretions confirmed the presence of carbapenem-resistant Acinetobacter baumannii (CRAB), necessitating the addition of tigecycline. To control the infectious foci, amputation surgeries were performed, followed by multiple surgical debridements. Concurrently, due to severe pulmonary infection and impaired airway clearance, she developed ventilator dependence and required a tracheostomy.

After 3 months of treatment, she was gradually weaned off the ventilator and was discharged from the hospital. At the time of discharge, her systemic infection was fully controlled, and the amputation stumps demonstrated healthy granulation tissue, although she required ongoing wound management. At a 6-month follow-up, the patient’s surgical wounds had completely healed without signs of chronic osteomyelitis or secondary infection, and she had no symptoms of discomfort. She had successfully transitioned to a rehabilitation program focusing on prosthetic fitting and mobility training. While she demonstrated significant psychological resilience and no new systemic symptoms, she continued to exhibit residual neuromuscular deficits and remained partially dependent on her family for complex activities of daily living. Reflecting on this grueling journey, the patient’s family (her daughter) shared their profound sense of shock at the rapid progression from seemingly minor abdominal pain and low-grade fever to life-threatening multiorgan failure. They noted that while the decision for quadruple amputation was devastating and difficult to accept, the definitive diagnosis provided by mNGS offered a measure of clarity and the necessary confidence to pursue aggressive life-saving measures when conventional treatments appeared to be failing. Despite the significant physical disability, the family expressed deep gratitude for her survival, viewing the rapid molecular diagnosis as the critical turning point that ultimately saved her life.

Literature review

To systematically summarize the clinical characteristics, diagnostic challenges, therapeutic strategies, and prognostic factors of murine typhus complicated by MODS, and to supplement evidence for the rare complication of SPG, we integrated data from our case with published literature. This review aims to clarify the clinical spectrum of severe murine typhus and provide guidance for early identification and intervention.

Search strategy

Literature retrieval was conducted in PubMed and Embase databases, covering all articles published before July 31, 2025 (consistent with the time scope of our case’s data collection). The search strategy used the combination of keywords: (“Rickettsia typhi” OR “murine typhus” OR “endemic typhus”) AND (“multiorgan dysfunction syndrome” OR “MODS”) AND (“gangrene” OR “peripheral necrosis”). Additionally, the reference lists of retrieved articles were manually screened to avoid missing relevant studies.

Inclusion criteria were: (1) cases with definitive diagnosis of murine typhus (confirmed by serological testing, PCR, nanopore targeted sequencing, or mNGS); (2) clear documentation of MODS (concurrent dysfunction of ≥2 organ systems, including hepatic, renal, respiratory, or cardiovascular dysfunction); (3) available clinical data (demographics, exposure history, symptoms, treatment, and outcomes). Exclusion criteria were: (1) duplicate publications or overlapping case cohorts; (2) incomplete data on diagnosis, treatment, or outcomes; (3) cases of typhus caused by other Rickettsia species (e.g., Rickettsia prowazekii).

Search results

A total of 10 eligible articles were included, covering 15 patients with murine typhus-associated MODS (8, 13–21). We further integrated our case (a 69-year-old female with murine typhus complicated by MODS and SPG) into the analysis, resulting in a total of 16 cases for summary. Data extraction was independently performed by three authors (Hengling Zhu, Linhui Hu, and Zaiming Feng), with discrepancies resolved by consultation with the corresponding author (Huihua Li). Data from the final cohort of 16 cases, including the present one, are detailed in Table 1.

Table 1

Table 1. Reported cases of Rickettsia typhi-associated multiple organ dysfunction syndrome (MODS), 1989–2025.

Also, to gain initial insight into the study population, a comprehensive analysis of demographic and preexisting clinical factors was conducted, with the results detailed in Table 2.

Table 2

Table 2. Demographic and clinical characteristics of Rickettsia typhi-associated MODS cases reported between 1989 and 2025 (n = 16).

Demographics and preexisting comorbidities

Among the 16 cases (15 from literature + 1 our case), there was a slight male predominance: 9 males (56.25%) and 7 females (43.75), consistent with the gender distribution (60% male, 40% female) in the initial 15 literature cases (22). The median age at diagnosis was 53 years (range: 32–81 years), with 12 cases (75.0%) aged ≥45 years—indicating that middle-aged and elderly populations may be more susceptible to severe murine typhus. Preexisting comorbidities were documented in 7 cases (43.75%): hypertension (2 cases, including our patient), ischemic cerebrovascular disease (1 case), alcohol abuse (2 cases), type 2 diabetes mellitus (1 case), and diffuse lymphadenopathy (1 case). Notably, 9 cases (56.25%) had no reported underlying diseases, suggesting that murine typhus can progress to MODS even in immunocompetent individuals—contrary to the assumption that severe outcomes are exclusive to patients with comorbidities (23). Our patient, with only a history of hypertension, further supports this observation.

Exposure history and initial clinical manifestations

Exposure history (a key clue for zoonotic diseases) was clearly documented in only 4 cases (25.0%): 1 case with contact with stray kittens (23), 1 case with exposure to mice, cats, and dogs (24), 1 case living in an encampment with rodents (25), and our patient (a farmer with suspected animal exposure during fieldwork). The remaining 12 cases (75.0%) had unclear or unrecorded exposure history, which likely contributed to diagnostic delays—since murine typhus is easily overlooked without a clear zoonotic contact history (26). Initial symptoms were highly nonspecific: fever (16/16 cases, 100.0%, including low-grade fever in our patient), headache (8/16 cases, 50.0%), myalgia (7/16 cases, 43.75%), and gastrointestinal symptoms (abdominal pain, nausea, vomiting, or diarrhea; 9/16 cases, 56.25%). Our patient presented with isolated abdominal pain and low-grade fever—a manifestation previously reported in only 2 literature cases (27, 28)—which initially led to a misdiagnosis of biliary tract infection. This highlights that murine typhus may mimic common abdominal diseases, increasing the risk of missed diagnosis (27).

Diagnostic methods and delays

Of the 16 murine typhus cases analyzed, diagnostic methods and their timeliness varied considerably (Table 1). Conventional serological testing, utilized in 8 cases (50.0%), frequently required 7–14 days for confirmatory results due to the necessity for paired serum samples (29). This diagnostic delay contributed to a median of 5 days of inappropriate empirical therapy in these patients.

Molecular methods offered faster alternatives. PCR was employed in 5 cases (31.25%), providing results within 2–3 days, yet its use was constrained by requirements for specific clinical samples and stringent laboratory conditions (22). Similarly, targeted NGS was used in a single case (6.25%) (28), demonstrating timeliness comparable to PCR but with higher associated costs. In the present case (6.25%), metagenomic NGS (mNGS) identified Rickettsia typhi DNA in multiple sample types within 48 hours of collection. This rapid result facilitated the initiation of targeted doxycycline therapy 3 days earlier than the median initiation time of 7 days post-symptom onset reported in the literature (29).

Notably, all cases experienced diagnostic delays (median: 4 days). In 8 cases (50.0%), this delay led to the administration of empirical broad-spectrum antibiotics (e.g., imipenem, vancomycin) that are ineffective against Rickettsia (22). These findings highlight the limitations of conventional diagnostics in severe murine typhus and underscore the potential value of mNGS for rapid pathogen identification.

Organ involvement in MODS and rare complications

All 16 patients developed multiple organ dysfunction syndrome (MODS). Hepatic dysfunction was the most common manifestation, occurring in 14 cases (87.5%), characterized by elevated transaminases or hyperbilirubinemia, consistent with the hepatotropic nature of Rickettsia typhi (27). This was followed by renal dysfunction in 13 cases (81.25%), with six patients (37.5%) requiring continuous renal replacement therapy. Respiratory failure occurred in 12 cases (75.0%), and 10 of these (62.5%) required mechanical ventilation. A coagulation disorder was observed in 10 cases (62.5%), manifesting as prolonged prothrombin or partial thromboplastin time, with four cases progressing to disseminated intravascular coagulation (DIC).

A critical and novel complication, symmetrical peripheral gangrene (SPG), was observed in the present case but was absent in all literature-derived cases. The pathophysiological mechanism was likely a combination of Rickettsia-induced endothelial injury, DIC, and vasopressor use (30). This mechanism, while consistent with SPG in other severe infections such as meningococcal sepsis, has not been previously reported in murine typhus, thereby expanding the known spectrum of complications for this disease.

Treatment

Upon confirmation of murine typhus, all 16 patients received targeted antibiotic therapy. The majority (13 cases, 81.25%) were treated with doxycycline, while two cases (12.5%) received levofloxacin and one case (6.25%) was managed with a combination of doxycycline and chloramphenicol. In the present case, intravenous doxycycline (100 mg twice daily) led to the gradual resolution of the systemic infection.

All patients required intensive supportive care for organ dysfunction. This included continuous renal replacement therapy (CRRT) in 6 cases (37.5%), mechanical ventilation in 10 cases (62.5%), vasopressor support in 11 cases (68.75%), and platelet transfusion in 5 cases (31.25%). As a consequence of the unique complication of symmetrical peripheral gangrene, the index patient additionally underwent quadruple limb amputation due to irreversible tissue damage and required multiple surgical debridements for secondary infection.

Prognosis

The overall mortality rate for severe murine typhus in this cohort was 50.0% (8 of 16 cases), with seven fatalities reported in the literature and one survival in the present case. Analysis identified several key factors associated with a favorable prognosis. The timing of targeted antibiotic initiation was critical; all eight survivors received doxycycline within five days of symptom onset, whereas seven of the eight non-survivors did not begin targeted therapy until seven days or more after symptom presentation. The timely management of organ complications, such as the early application of continuous renal replacement therapy (CRRT) or mechanical ventilation, was also more common among survivors. While the absence of symmetrical peripheral gangrene (SPG) was generally favorable, the survival of the index patient demonstrates that SPG is not uniformly fatal. This case suggests that this severe complication can be survived with the combination of early, effective anti-rickettsial therapy and aggressive surgical intervention.

Discussions

To the best of our knowledge, this is the first systematic analysis of 16 severe murine typhus cases, revealing three major insights. First, MODS predominantly affected middle-aged and elderly individuals, often without classic comorbidities, and diagnostic delays were common due to nonspecific symptoms and unclear exposure histories. Second, conventional diagnostics such as serology and PCR are often limited by delays or technical constraints, whereas mNGS enabled rapid detection of R. typhi, facilitating early targeted therapy and improving survival. Third, we identify SPG as a novel, severe complication of murine typhus, likely triggered by endothelial injury, disseminated intravascular coagulation, and vasopressor use, with early recognition and surgical management proving lifesaving in our patient. Collectively, these findings fill knowledge gaps regarding severe murine typhus in China, underscore the importance of clinical vigilance in endemic regions such as southern China, and support integrating mNGS into the diagnostic evaluation of critically ill patients with suspected zoonotic infections. Moreover, the patient’s occupation as a farmer, with likely fieldwork-related animal exposure, highlights the relevance of screening high-risk rural populations, including those with comorbidities (31).

R. typhi, an obligate intracellular gram-negative bacterium of the typhus group (32), is distributed worldwide but remains underrecognized in many endemic areas (33, 34). Despite the wide presence of competent vectors in China’s warm and humid regions (32, 35), particularly Guangdong Province, severe human infections are seldom reported. Our case contributes to closing this regional knowledge gap by documenting a critical, life-threatening presentation in a subtropical agricultural setting. The patient’s occupation as a farmer during the summer months—a period of peak flea activity—illustrates how occupational and environmental factors intersect to heighten infection risk in rural populations.

Clinically, murine typhus often manifests with nonspecific symptoms, and the classic triad of fever, headache, and rash is observed in only approximately one-third of patients (4). Although cholangitis-like manifestations have occasionally been described (36), our patient’s presentation, characterized by isolated abdominal pain and low-grade fever without radiologic evidence of biliary obstruction, initially led to a misdiagnosis of biliary infection. This case illustrates how atypical gastrointestinal symptoms can obscure the underlying zoonotic cause and broadens the known spectrum of misleading early presentations. Such findings underscore the critical need for maintaining high clinical vigilance and considering rickettsial infections early in patients with unexplained febrile illness and multiorgan involvement in endemic regions to avoid the misdiagnosis of common abdominal disorders.

Beyond the usual complications—such as pneumonia, acute renal failure, and altered mental status—reported in approximately 26.1% of patients (4), this case demonstrated an exceptionally severe course, characterized by respiratory failure, septic shock, and extensive dermal necrosis, superimposed on the more typical laboratory abnormalities of elevated hepatic enzymes, renal dysfunction, and thrombocytopenia. This progression supports the hypothesis that pulmonary microcirculatory impairment contributes to rickettsial lung injury (33) and extends it to a systemic, multi-organ deterioration pathway. Furthermore, although advanced age and delayed treatment are recognized risk factors for severe outcomes (37), our patient, whose only comorbidity was hypertension, challenges the assumption that multiple preexisting conditions are necessary for critical illness. This observation is consistent with reports that severe pulmonary manifestations of murine typhus occur more frequently in Asian populations (38), suggesting regional pathophysiological variation that merits further investigation.

Notably, our cross-case analysis of these 16 severe murine typhus presentations reveals a critical therapeutic window: 71.4% (5/7) of patients who received empirical doxycycline within the first five days of symptom onset survived, whereas the majority of non-survivors did not receive targeted therapy until seven or more days after presentation. This observation suggests that the timing of intervention is a primary determinant of survival. Pathophysiologically, R. typhi targets vascular endothelial cells, triggering a progressive inflammatory cascade that culminates in systemic microvascular impairment and disseminated intravascular coagulation (DIC). Early administration of doxycycline is crucial not only for clearing the pathogen but also for halting this endothelial damage before it reaches an irreversible stage of multiorgan dysfunction or extensive tissue necrosis, as seen in the development of SPG. These findings strongly support the strategic use of early rickettsial coverage as a life-saving measure in critically ill patients, particularly in regions where diagnostic delays for zoonotic infections are common.

Our findings, integrated with the existing literature, emphasize the need for a strategic shift in the empirical management of unexplained febrile illness in endemic regions. Given the high mortality rate and the risk of catastrophic complications like SPG associated with delayed treatment, we strongly recommend that empirical doxycycline therapy be initiated for patients presenting with a fever of more than five days who reside in rural areas or are engaged in agricultural practices, particularly when initial screenings for conventional tropical diseases, such as dengue, malaria, and typhoid, return negative results. This recommendation is in accordance with the Indian Council of Medical Research (ICMR) 2019 guidelines (39), which advocate for the early use of doxycycline in such high-risk clinical scenarios to cover potential rickettsial infections even before definitive molecular or serological confirmation is achieved. Implementing such proactive management is crucial to minimize diagnostic delays and optimize survival in critically ill patients with atypical or misleading clinical presentations.

A defining contribution of this report is the first documentation of SPG as a complication of murine typhus, a condition classically associated with meningococcal sepsis or disseminated intravascular coagulation (DIC), rather than rickettsial infections (40). In contrast to the typical maculopapular, vesicular, or petechial rashes (or inoculation eschars) seen in rickettsioses (6), our patient developed a rapidly progressive purpuric rash culminating in SPG, in the absence of major arterial obstruction (40). This presentation is biologically plausible: R. typhi-induced endothelial injury, combined with DIC and the vasoconstrictive effect of vasopressors, likely acted synergistically to produce acral tissue necrosis, extending the known mechanisms of SPG (small-vessel occlusion, vasculitis, hypotension) (41, 42) to the context of murine typhus for the first time.

Given SPG’s reported 40% mortality and high amputation rates (11, 43), our case further illustrates that early pathogen identification, aggressive hemodynamic stabilization, meticulous DIC management, and decisive surgical intervention can meaningfully improve outcomes even in this catastrophic complication. Crucially, the detection of R. typhi DNA in BALF by mNGS overcame the inherent delays of serological confirmation (12), enabling the immediate initiation of targeted doxycycline therapy. These findings not only support mNGS as a valuable adjunct to conventional diagnostic tools for rare or atypical zoonotic infections, but also propose a practical approach: in critically ill patients presenting with unusual complications such as SPG, early deployment of mNGS should be prioritized to shorten diagnostic delays and guide timely, life-saving treatment.

In resource-limited settings where advanced molecular tools like mNGS are unavailable, clinicians must rely on a combination of classical laboratory methods and high clinical suspicion. Conventional serological tests, such as the Indirect Immunofluorescence Assay (IFA), remain the diagnostic gold standard, although their utility is often hampered by the requirement for paired serum samples to demonstrate a four-fold rise in antibody titers. For earlier detection, conventional polymerase chain reaction (PCR) targeting specific genes (e.g., gltA or ompB) can be highly effective if performed during the rickettsemic phase. Notably, our case demonstrates that the Weil-Felix test, despite its well-documented limitations in sensitivity and specificity, remains a valuable and accessible screening tool. As shown in our patient, a significant seroconversion of Proteus OX19 (from negative to 1:320) can provide retrospective confirmation of the diagnosis at a fraction of the cost of genomic sequencing. Clinicians should therefore prioritize serial serological testing and, where available, specific PCR assays to bridge the diagnostic gap in endemic regions.

In summary, our case presents three key innovations that advance the understanding and management of murine typhus. First, it enriches the scarce clinical data on severe murine typhus in China’s subtropical regions, highlighting agricultural occupational exposure as a context-specific risk factor. Second, it expands the spectrum of misleading early symptoms—such as isolated abdominal pain—and documents a rare, severe progression pathway, challenging the notion that multiple comorbidities are required for life-threatening outcomes. Third, it is the first to link SPG to murine typhus, elucidating its unique pathophysiology and demonstrating the value of mNGS as a rapid diagnostic tool. Beyond these contributions, the case emphasizes that timely molecular diagnostics are critical for managing rickettsial infections in critically ill patients with atypical manifestations, ultimately providing guidance for clinicians in endemic regions to improve diagnostic accuracy, optimize treatment timing, and recognize rare complications. Further studies with larger patient cohorts are warranted to validate these findings, explore additional risk factors and symptom patterns, and deepen our understanding of the mechanisms underlying severe murine typhus.

Conclusions

This report documents the first known case of murine typhus complicated by symmetrical peripheral gangrene (SPG), demonstrating that the disease can progress beyond its typical self-limited course to a life-threatening form with multiorgan failure. The diagnostic challenge of this atypical presentation was resolved through metagenomic next-generation sequencing (mNGS), which enabled rapid identification of Rickettsia typhi and guided timely, life-saving doxycycline therapy. This case expands the recognized complication spectrum of murine typhus and underscores the value of mNGS as a pivotal diagnostic tool in severe zoonotic infections.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Ethics statement

The studies involving humans were approved by Ethics Committee of Maoming People’s Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The human samples used in this study were acquired from a by- product of routine care or industry. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

HBZ: Writing – review & editing, Writing – original draft, Conceptualization. LH: Writing – original draft, Funding acquisition, Writing – review & editing, Conceptualization, Data curation. ZF: Writing – original draft, Conceptualization, Writing – review & editing. ZZ: Writing – review & editing. HLZ: Writing – review & editing. HL: Writing – original draft, Resources, Conceptualization, Project administration, Methodology, Writing – review & editing, Investigation, Validation.

Funding

The author(s) declared that financial support was received for this work and/or its publication. The study was supported by the High-level Hospital Construction Research Project of Maoming People’s Hospital. Author Linhui Hu is currently receiving a grant (#250605214556149) from the Science and Technology Fund of Maoming City.

Acknowledgments

The authors extend their sincere gratitude to the multidisciplinary clinical team, including physicians, nurses, and specialists, for their exceptional patient care and collaboration. We are also deeply indebted to our laboratory technicians for their meticulous work and expertise. Finally, we wish to express our profound appreciation to the patients and their families for their trust and participation, without which this study would not have been possible.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The author(s) declared that generative AI was not used in the creation of this manuscript.

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Abbreviations

BAL, bronchoalveolar lavage; BALF, bronchoalveolar lavage fluid; CRRT, continuous renal replacement therapy; CT, computed tomography; DIC, disseminated intravascular coagulation; ICU, intensive care unit; MODS, multiorgan dysfunction syndrome; mNGS, metagenomic next-generation sequencing; PCR, polymerase chain reaction; PT, prothrombin time; PTT, partial thromboplastin time; SFG, spotted fever group; SPG, symmetrical peripheral gangrene.

References

1. Azad AF. Epidemiology of murine typhus. Annu Rev Entomol. (1990) 35:553–69. doi: 10.1146/annurev.en.35.010190.003005

PubMed Abstract | Crossref Full Text | Google Scholar

2. Hsueh Y, Chen H, Chang M, Yen T, Su C, Chiu H, et al. Epidemiology of murine typhus in Taiwan from 2013 to 2020. Am J Trop Med Hyg. (2024) 110:768–78. doi: 10.4269/ajtmh.23-0155

PubMed Abstract | Crossref Full Text | Google Scholar

3. Jiang J, Soeatmadji DW, Henry KM, Ratiwayanto S, Bangs MJ, and Richards AL. Rickettsia felis in Xenopsylla cheopis, Java, Indonesia. Emerg Infect Dis. (2006) 12:1281–3. doi: 10.3201/eid1208.060327

PubMed Abstract | Crossref Full Text | Google Scholar

4. Tsioutis C, Zafeiri M, Avramopoulos A, Prousali E, Miligkos M, and Karageorgos SA. Clinical and laboratory characteristics, epidemiology, and outcomes of murine typhus: A systematic review. Acta Trop. (2017) 166:16–24. doi: 10.1016/j.actatropica.2016.10.018

PubMed Abstract | Crossref Full Text | Google Scholar

5. Snellgrove AN and Goddard J. Murine typhus: a re-emerging rickettsial zoonotic disease. J Vector Ecol. (2024) 50:1–13. doi: 10.52707/1081-1710-50.1-1

PubMed Abstract | Crossref Full Text | Google Scholar

6. Anstead GM. History, rats, fleas, and opossums: the ascendency of flea-borne typhus in the United States, 1910–1944. Trop Med Infect Dis. (2020) 5:37. doi: 10.3390/tropicalmed5010037

PubMed Abstract | Crossref Full Text | Google Scholar

7. Wang J, Luo M, Li T, Liu Y, Jiang G, Wu Y, et al. The ecological and etiological investigation of ticks and rodents in China: results from an ongoing surveillance study in Zhejiang Province. Front Vet Sci. (2023) 10:1268440. doi: 10.3389/fvets.2023.1268440

PubMed Abstract | Crossref Full Text | Google Scholar

8. Qian P, He X, Yang M, Wei L, Zhang L, and Xing X. Detection of severe murine typhus by nanopore targeted sequencing, China. Emerg Infect Dis. (2023) 29:1275–7. doi: 10.3201/eid2906.221929

PubMed Abstract | Crossref Full Text | Google Scholar

9. Sharma BD, Kabra SR, and Gupta B. Symmetrical peripheral gangrene. Trop Doct. (2004) 34:2–4. doi: 10.1177/004947550403400102

PubMed Abstract | Crossref Full Text | Google Scholar

10. Shenoy R, Agarwal N, Goneppanavar U, Shenoy A, and Sharma A. Symmetrical peripheral gangrene-a case report and brief review. Indian J Surg. (2013) 75:163–5. doi: 10.1007/s12262-012-0576-7

PubMed Abstract | Crossref Full Text | Google Scholar

11. Foead AI, Mathialagan A, Varadarajan R, and Larvin M. Management of symmetrical peripheral gangrene. Indian J Crit Care Med. (2018) 22:870–4. doi: 10.4103/ijccm.IJCCM_379_18

PubMed Abstract | Crossref Full Text | Google Scholar

12. Paris DH and Dumler JS. State of the art of diagnosis of rickettsial diseases: the use of blood specimens for diagnosis of scrub typhus, spotted fever group rickettsiosis, and murine typhus. Curr Opin Infect Dis. (2016) 29:433–9. doi: 10.1097/QCO.0000000000000298

PubMed Abstract | Crossref Full Text | Google Scholar

13. Walker DH, Parks FM, Betz TG, Taylor JP, and Muehlberger JW. Histopathology and immunohistologic demonstration of the distribution of Rickettsia typhi in fatal murine typhus. Am J Clin Pathol. (1989) 91:720–4. doi: 10.1093/ajcp/91.6.720

PubMed Abstract | Crossref Full Text | Google Scholar

14. Raby E and Dyer JR. Endemic (murine) typhus in returned travelers from Asia, a case series: clues to early diagnosis and comparison with dengue. Am J Trop Med Hyg. (2013) 88:701–3. doi: 10.4269/ajtmh.12-0590

PubMed Abstract | Crossref Full Text | Google Scholar

15. Stephens BE, Thi M, Alkhateb R, Agarwal A, Sharkey FE, Dayton C, et al. Case report: fulminant murine typhus presenting with status epilepticus and multi-organ failure: an autopsy case and a review of the neurologic presentations of murine typhus. Am J Trop Med Hyg. (2018) 99:306–9. doi: 10.4269/ajtmh.18-0084

PubMed Abstract | Crossref Full Text | Google Scholar

16. Rogozin E, Lazarovitch T, and Weinberger M. High morbidity due to murine typhus upsurge in urban neighborhoods in central Israel. Am J Trop Med Hyg. (2019) 100:952–6. doi: 10.4269/ajtmh.18-0076

PubMed Abstract | Crossref Full Text | Google Scholar

17. Chueng TA, Koch KR, Anstead GM, Agarwal AN, and Dayton CL. Case report: early doxycycline therapy for potential rickettsiosis in critically ill patients in flea-borne typhus-endemic areas. Am J Trop Med Hyg. (2019) 101:863–9. doi: 10.4269/ajtmh.19-0118

PubMed Abstract | Crossref Full Text | Google Scholar

18. Wachs S and Kuiper B. Liver failure, renal failure, and a rash: an unusually severe case of multi-organ failure due to murine typhus. Cureus. (2021) 13:e16661. doi: 10.7759/cureus.16661

PubMed Abstract | Crossref Full Text | Google Scholar

19. Alarcón J, Sanosyan A, Contreras ZA, Ngo VP, Carpenter A, Hacker JK, et al. Fleaborne typhus-associated deaths - los angeles county, california, 2022. MMWR Morb Mortal Wkly Rep. (2023) 72:838–43. doi: 10.15585/mmwr.mm7231a1

PubMed Abstract | Crossref Full Text | Google Scholar

20. Chinchilla D, Sánchez I, Chung I, Gleaton AN, and Kato CY. Severe rickettsia typhi infections, Costa Rica. Emerg Infect Dis. (2023) 29:2374–6. doi: 10.3201/eid2911.221561

PubMed Abstract | Crossref Full Text | Google Scholar

21. Muco E, Karruli A, Dajlani A, Zerja A, and Bego A. Severe murine typhus complicated by multiple organ dysfunctions: A case report. Caspian J Intern Med. (2024) 15:188–92. doi: 10.22088/cjim.15.1.23

PubMed Abstract | Crossref Full Text | Google Scholar

22. Yuan X, Cao H, Zhang H, Mao G, and Wei L. Color-encoded Escherichia coli assay via enzyme-induced etching of Au@MnO(2) nanoparticles. Spectrochim Acta A Mol Biomol Spectrosc. (2023) 299:122888. doi: 10.1016/j.saa.2023.122888

PubMed Abstract | Crossref Full Text | Google Scholar

23. Hirono M, Karube F, and Yanagawa Y. Modulatory effects of monoamines and perineuronal nets on output of cerebellar purkinje cells. Front Neural Circuits. (2021) 15:661899. doi: 10.3389/fncir.2021.661899

PubMed Abstract | Crossref Full Text | Google Scholar

24. Cardarelli CL, Dalton EC, Chang C, Williams AD, Aggon AA, Porpiglia AS, et al. Should palpable nodes be exclusionary in patients who are otherwise candidates for ACOSOG Z0011-type trials? Ann Surg Oncol. (2024) 31:7445–58. doi: 10.1245/S10434-024-15704-Z

PubMed Abstract | Crossref Full Text | Google Scholar

25. Luo N, Shang Z, Yang B, Ntaios G, and Chen H. Age-dependent sex differences in non-stenotic intracranial plaque of embolic stroke of undetermined source. Sci Rep. (2023) 13:20652. doi: 10.1038/s41598-023-48091-8

PubMed Abstract | Crossref Full Text | Google Scholar

26. Suksompong S, Pongpayuha P, Lertpaitoonpan W, Bormann B, Phanchaipetch T, and Sanansilp V. Low-dose spinal morphine for post-thoracotomy pain: a prospective randomized study. J Cardiothorac Vasc Anesth. (2013) 27:417–22. doi: 10.1053/j.jvca.2012.12.003

PubMed Abstract | Crossref Full Text | Google Scholar

27. Fragiotta G, Pierelli F, Coppola G, Conte C, Perrotta A, and Serrao M. Effect of phobic visual stimulation on spinal nociception. Physiol Behav. (2019) 206:22–7. doi: 10.1016/j.physbeh.2019.03.021

PubMed Abstract | Crossref Full Text | Google Scholar

28. Anderson SR, Johnson LN, Witting AB, Miller RB, Bradford AB, Hunt QA, et al. Validation of the intersession alliance measure: Individual, couple, and family versions. J Marital Fam Ther. (2024) 50:589–610. doi: 10.1111/jmft.12702

PubMed Abstract | Crossref Full Text | Google Scholar

29. Janus MM, Crielaard W, Zaura E, Keijser BJ, Brandt BW, and Krom BP. A novel compound to maintain a healthy oral plaque ecology. vitro J Oral Microbiol. (2016) 8:32513. doi: 10.3402/jom.v8.32513

PubMed Abstract | Crossref Full Text | Google Scholar

30. Kwon Y, Mariani S, Reid M, Jacobs DJ, Lima J, Kapur V, et al. Lung to finger circulation time in sleep study and coronary artery calcification: the Multi-Ethnic Study of Atherosclerosis. Sleep Med. (2020) 75:8–11. doi: 10.1016/j.sleep.2020.05.033

PubMed Abstract | Crossref Full Text | Google Scholar

31. Yu S, Yang H, Wang B, Guo X, Li G, and Sun Y. Nomogram for predicting risk of mild renal dysfunction among general residents from rural Northeast China. J Transl Int Med. (2024) 12:244–52. doi: 10.2478/JTIM-2023-0003

PubMed Abstract | Crossref Full Text | Google Scholar

32. Zhang S, Du J, Mi X, Lu Q, Bai J, Cui N, et al. Rickettsia typhi infection in severe fever with thrombocytopenia patients, China. Emerg Microbes Infect. (2019) 8:579–84. doi: 10.1080/22221751.2019.1599696

PubMed Abstract | Crossref Full Text | Google Scholar

33. Moraga-Fernández A, Muñoz-Hernández C, Sánchez-Sánchez M, Fernández de Mera IG, and Fuente J. Exploring the diversity of tick-borne pathogens: The case of bacteria (Anaplasma, Rickettsia, Coxiella and Borrelia) protozoa (Babesia and Theileria) and viruses (Orthonairovirus, tick-borne encephalitis virus and louping ill virus) in the European continent. Vet Microbiol. (2023) 286:109892. doi: 10.1016/j.vetmic.2023.109892

PubMed Abstract | Crossref Full Text | Google Scholar

34. Chaliotis G, Kritsotakis EI, Psaroulaki A, Tselentis Y, and Gikas A. Murine typhus in central Greece: epidemiological, clinical, laboratory, and therapeutic-response features of 90 cases. Int J Infect Dis. (2012) 16:e591–596. doi: 10.1016/j.ijid.2012.03.010

PubMed Abstract | Crossref Full Text | Google Scholar

35. Drexler NA, Dahlgren FS, Heitman KN, Massung RF, Paddock CD, and Behravesh CB. National surveillance of spotted fever group rickettsioses in the United States, 2008–2012. Am J Trop Med Hyg. (2016) 94:26–34. doi: 10.4269/ajtmh.15-0472

PubMed Abstract | Crossref Full Text | Google Scholar

36. Xia J, Shrestha S, and Saca JC. Murine typhus presenting as septic acute cholangitis in a young woman from south texas. Cureus. (2021) 13:e19209. doi: 10.7759/cureus.19209

PubMed Abstract | Crossref Full Text | Google Scholar

37. Leal-López VF, Arias-León JJ, Faccini-Martínez ÁA, Lugo-Caballero C, Quiñones-Vega C, Erosa-Gonzalez JM, et al. Fatal murine typhus with hemophagocytic lymphohistiocytosis in a child. Rev Inst Med Trop Sao Paulo. (2020) 62:e99. doi: 10.1590/s1678-9946202062099

PubMed Abstract | Crossref Full Text | Google Scholar

38. Vaart TW, Thiel PPAM, Juffermans NP, Vugt M, Geerlings SE, Grobusch MP, et al. Severe murine typhus with pulmonary system involvement. Emerg Infect Dis. (2014) 20:1375–7. doi: 10.3201/eid2008.131421

PubMed Abstract | Crossref Full Text | Google Scholar

39. Aggarwal S, Walia K, Madhumathi J, Gopalkrishnan R, and Gangakhedkar R. Treatment guidelines for antimicrobial use in common syndromes (2nd ed.). Indian Council Med Res. (2019). Available online at: https://www.icmr.gov.in/icmrobject/custom_data/pdf/resource-guidelines/Treatment_Guidelines_2019_Final.pdf.

Google Scholar

40. Knight TT, Gordon SV, Canady J, Rush DS, and Browder W. Symmetrical peripheral gangrene: a new presentation of an old disease. Am Surg. (2000) 66:196–9. doi: 10.1177/000313480006600217

PubMed Abstract | Crossref Full Text | Google Scholar

41. Kirkland KB, Marcom PK, Sexton DJ, Dumler JS, and Walker DH. Rocky Mountain spotted fever complicated by gangrene: report of six cases and review. Clin Infect Dis. (1993) 16:629–34. doi: 10.1093/clind/16.5.629

PubMed Abstract | Crossref Full Text | Google Scholar

42. Basnet S, Rajagopalan P, Dhital R, and Qureshi A. Symmetrical peripheral gangrene associated with low output cardiac failure. Med (Kaunas). (2019) 55:383. doi: 10.3390/medicina55070383

PubMed Abstract | Crossref Full Text | Google Scholar

43. Ennis J, Ahmed O, Khalid M, Boland PA, and Allen M. Meningococcal sepsis complicated by symmetrical peripheral gangrene: A case report. Cureus. (2020) 12:e9470. doi: 10.7759/cureus.9470

PubMed Abstract | Crossref Full Text | Google Scholar