Scrub Typhus Meningoencephalitis With Concurrent Brucellosis in Rural Nepal: Diagnostic Challenges With Negative PCR in a Low‐Resource Setting

ABSTRACT

Scrub typhus is an important cause of acute febrile illness in Nepal and can rarely present with meningoencephalitis and multiorgan involvement. We report a 32‐year‐old female farmer from rural Nepal who presented during the monsoon season with high‐grade fever, myalgia, vomiting, and an eschar following an unidentified forest bite. She developed meningismus, hypotension, mild acute respiratory distress syndrome, and transaminitis. Cerebrospinal fluid showed lymphocytic pleocytosis and elevated protein, while bacterial culture, acid‐fast staining, and GeneXpert were negative. Serum scrub typhus IgM was positive, whereas Brucella abortus IgM was borderline positive. CSF PCR for both pathogens was negative. Based on the characteristic eschar, clinical presentation, CSF findings, epidemiological exposure, and exclusion of alternative diagnoses, scrub typhus meningoencephalitis was considered the most likely diagnosis. She improved with doxycycline‐based therapy and achieved complete neurological recovery. This case highlights the challenges of diagnosing scrub typhus in resource‐limited settings despite negative PCR.

Key Clinical Message

Scrub typhus can rarely cause meningoencephalitis and multiorgan dysfunction, with diagnosis complicated by limited diagnostic resources. We report a 32‐year‐old Nepalese farmer with scrub typhus meningoencephalitis, mild ARDS, and transaminitis despite negative CSF PCR. Positive Brucella IgM further complicated diagnosis. She achieved complete neurological recovery following doxycycline‐based therapy.

Scrub typhus meningoencephalitis with concurrent Brucellosis.

1. Introduction

Scrub typhus a vector‐borne disease caused by Orientia tsutsugamushi is a serious public health problem in the Asia‐Pacific and Australia, known as Tsutsugamushi Triangle. It threatens one billion people globally, and causes illness in one million people each year [1, 2]. Nepal lies within the Tsutsugamushi Triangle, where scrub typhus accounts for about 12.2% to 19.31% of acute undifferentiated febrile illnesses [3]. The illness is common, especially during the rainy season between July and November, peaking during August with the highest prevalence in Bagmati Province, where Kathmandu is located and has a rising global prevalence of around 24.93% [3, 4].

Our case report describes a female farmer who developed scrub typhus meningoencephalitis complicated by mild acute respiratory distress syndrome (ARDS) and hepatic dysfunction. The diagnostic evaluation was complicated by a borderline positive Brucella IgM titer, raising initial suspicion for neurobrucellosis. This case underscores the diagnostic confusion which can occur during the evaluation of acute febrile illness and CNS infections in resource‐limited settings, the significant neurological and respiratory manifestations of scrub typhus, and the use of empiric doxycycline therapy in the treatment of acute febrile illness.

2. Case History and Examination

A 32‐year‐old woman from rural Nepal presented during the rainy season (August) to the emergency department (ED) of a tertiary infectious disease center with a 10‐day history of high‐grade fever, myalgia, and vomiting. Before the illness, she was apparently healthy with no known significant past medical history. She was a non‐smoker and did not consume alcohol. The fever was relapsing and remitting, with a maximum recorded temperature of 103°F–104°F, and was associated with chills and rigors. Further, she reported an unidentified bite to the gluteal region 10 days earlier while cutting grass in the forest. On presentation to the ED, she had multiple episodes of projectile vomiting.

On examination, the patient was slightly drowsy but oriented, with a Glasgow Coma Scale score of 15/15. She had mild photophobia, neck rigidity, and positive Kernig and Brudzinski signs. A well‐defined eschar was noted on the right gluteal region (Figure 1). Her temperature was 101°F, pulse rate was 65 beats/min, respiratory rate was 16/min, and blood pressure was 90/60 mmHg. Abdominal examination revealed mild periumbilical tenderness without rebound tenderness or organomegaly. She was admitted to the intensive care unit (ICU) because of clinical deterioration with worsening hypotension.

FIGURE 1.

Typical eschar suggestive of scrub typhus. [Description: Painless black necrotic crusted ulcer measuring 15 mm with an erythematous halo at the right buttock suggestive of a chigger bite.]

3. Differential Diagnosis

Considering the acute febrile illness with meningeal signs, altered sensorium, thrombocytopenia, transaminitis, and an eschar following forest exposure, scrub typhus meningoencephalitis was strongly considered. Other differential diagnoses included tuberculous meningitis, cerebral malaria, leptospirosis, Japanese encephalitis, dengue encephalopathy/encephalitis, enteric fever with encephalopathy, and viral encephalitis, particularly herpes simplex encephalitis. Brucellosis was also considered during the subsequent evaluation.

4. Investigations

Baseline laboratory investigations showed hemoglobin 10.28 g/dL, total leukocyte count 6900/mm³ (neutrophils 22%, lymphocytes 63%, monocytes 14%, eosinophils 1%), and platelet count 1.08 × 10⁵/mm³. Liver function tests showed total/direct bilirubin 0.64/0.2 mg/dL, ALP 414 U/L, and SGOT/SGPT 119.46/90.82 U/L. Renal function tests showed urea 37.08 mg/dL and creatinine 0.70 mg/dL, while serum sodium and potassium were 136 and 3.9 mmol/L, respectively. ESR was 35 mm/h, CRP was 38 mg/L, and procalcitonin was 0.36 ng/mL. Initial arterial blood gas analysis showed pH 7.45, pCO₂ 29 mmHg, pO₂ 85 mmHg, HCO³⁻ 20.2 mmol/L, and a P/F ratio of 236 mmHg, suggestive of mild ARDS. On Day 3 of hospitalization, she developed an oxygen requirement of 6 L/min via face mask to maintain a target SpO₂ > 95%.

An urgent non‐contrast CT scan of the head was performed and was grossly normal. Subsequently, lumbar puncture was performed. Cerebrospinal fluid (CSF) analysis revealed a total leukocyte count of 30/mm³, with 10% polymorphs and 90% mononuclear cells. CSF glucose was 46.8 mg/dL, protein was 150 mg/dL, ADA was 15.7 U/L, and LDH was 44 U/L. CSF Gram staining showed 1–2 pus cells per high‐power field, with no epithelial cells or microorganisms. CSF culture showed no growth after 48 h of incubation at 37°C. CSF AFB staining and GeneXpert were negative respectively.

Further evaluation revealed a positive scrub typhus IgM antibody and positive Brucella abortus IgM antibody at a titer of 1:80. CSF PCR for scrub typhus and Brucella was negative. The differential diagnoses, including tuberculous meningitis, cerebral malaria, leptospirosis, Japanese encephalitis, dengue encephalopathy/encephalitis, enteric fever with encephalopathy, and viral encephalitis, particularly herpes simplex encephalitis, were evaluated and excluded based on the clinical presentation, CSF findings, neuroimaging, and relevant microbiological and serological investigations. Ultrasonography of the abdomen and pelvis was unremarkable, with no evidence of hepatobiliary, renal, gynecological, or other intra‐abdominal pathology requiring surgical intervention. ECG demonstrated sinus bradycardia.

Based on the clinical presentation and laboratory findings, a diagnosis of scrub typhus meningoencephalitis with concomitant brucellosis was made.

5. Treatment

The patient was initially managed in the ICU with empirical intravenous meropenem, doxycycline, gentamicin, and acyclovir, along with supportive care. Following the diagnostic confirmation of scrub typhus meningoencephalitis with concomitant brucellosis, antimicrobial therapy was de‐escalated to doxycycline and gentamicin, and the other empirical agents were discontinued. Her clinical condition, including hypotension and respiratory status, was closely monitored during her ICU stay.

After clinical stabilization and improvement, she was discharged with a prolonged antimicrobial regimen consisting of ceftriaxone for 4 weeks, along with doxycycline and rifampicin for 12 weeks. She was transferred to a local hospital for completion of the remaining course of antibiotics.

6. Outcome and Follow‐Up

The patient showed steady clinical improvement during hospitalization, with resolution of fever, vomiting, hypotension, and neurological symptoms. She had a total hospital stay of 10 days and was discharged in a clinically stable condition to a local hospital for completion of the remaining antimicrobial therapy. At the 3‐month follow‐up, she had achieved complete neurological recovery, with normalization of laboratory parameters and no residual neurological deficits.

7. Discussion

Scrub typhus remains an underrecognized cause of acute febrile illness, particularly in endemic regions, and diagnosis largely depends on maintaining a high index of clinical suspicion supported by appropriate laboratory testing [5]. Clinically, scrub typhus typically begins after a 6–21 day incubation period (average ~10 days) with nonspecific symptoms such as fever, headache, myalgia, rash, gastrointestinal upset, lymphadenopathy, and the characteristic eschar [5, 6]. In severe or untreated cases, it can progress to life‐threatening complications, including pneumonitis or ARDS, acute renal failure, hepatitis, myocarditis, meningoencephalitis or encephalitis, septic shock, disseminated intravascular coagulation (DIC), and multi‐organ dysfunction [7].

Age ≥ 60 years, absence of an eschar, WBC count > 10,000/mm³, and serum albumin ≤ 3.0 g/dL are key predictors of poor outcomes [7]. Mortality in scrub typhus can reach up to 30% in cases with multi‐organ failure or neurological involvement [6]. Early recognition of these markers is crucial for timely treatment and for reducing complications and deaths [7].

Scrub typhus meningoencephalitis arises from endothelial injury, perivasculitis, and microinfarctions induced by O. tsutsugamushi [8]. Neurological presentations may include severe headache, confusion, seizures, cranial neuropathies, or, as in this patient, classic meningismus. Recent reports have further emphasized the broad and occasionally atypical neurological spectrum of scrub typhus, highlighting the importance of considering scrub typhus in patients presenting with acute febrile illness and neurological manifestations [9, 10].

The CSF picture of scrub typhus typically demonstrates lymphocytic pleocytosis and elevated protein with normal glucose, closely paralleling tuberculous meningitis [8]. The rapid response to doxycycline is an important distinguishing feature. Delayed recognition often contributes to diagnostic uncertainty and delays in initiating appropriate treatment.

Scrub typhus diagnosis remains challenging due to nonspecific symptoms in tropical regions, limited access to diagnostic testing such as PCR and indirect immunofluorescence assay (IFA),  and antigenic diversity reducing the performance of serological assays. While indirect IFA is the current gold standard, its availability is limited by cost and technical demands. Weil–Felix is widely used but is not reliable due to its low sensitivity, poor specificity, and cross‐reactivity with Proteus antigens. While PCR offers early, specific detection, is not widely accessible and sometimes could not yield the result as in our case. Thus, there is a clear need for rapid, affordable, point‐of‐care diagnostics [11].

In Nepal, scrub typhus is most commonly diagnosed using IgM ELISA. Treatment for scrub typhus consists of prompt antimicrobial therapy. Doxycycline remains the treatment of choice because of its rapid bacteriostatic activity against Orientia tsutsugamushi . Azithromycin is an effective alternative in patients with contraindications to doxycycline, such as pregnant women and young children, while chloramphenicol may be used in selected settings.

A major diagnostic challenge arose due to the positive Brucella IgM titer (1:80) in our patient. However, the presence of a typical scrub typhus together with negative PCR results for both scrub and brucella, favored the clinical diagnosis of scrub typhus meningits. However, we could not exclude neurobrucellosis with absolute certainty; therefore, multiple antibiotics were used to provide coverage for both infections.

Brucellosis is an endemic zoonotic condition that occurs due to consumption of unpasteurized milk and exposure to infected animal products. Brucella primarily attacks the reticuloendothelial system (RES) involving the lymph nodes, liver, spleen, and bone marrow [12]. Brucellosis is diagnosed with the help of either serology, blood cultures, or Brucella antibody titers IgM or IgG. A standard serum agglutination test (SAT) titer ≥ 1:320 or a 2‐mercaptoethanol (2‐ME) titer of ≥ 1:80 together with clinical signs and symptoms suggestive of brucellosis is considered diagnostic [13].

Brucella isolation and culture of tissues or body fluids is generally not utilized due to it being more time consuming, higher risk of contamination and having lower sensitivity during later stages of disease [14, 15]. However, in the context of a resource limited setting such as Nepal, patients usually present late and have a high likelihood of potential background exposure. Thus, clinicians greatly rely on ELISA Brucella IgM/IgG along with the clinical context, despite its comparatively lower sensitivity and specificity than SAT [15, 16, 17]. Brucella IgM can be falsely positive due to many factors, including rheumatoid factor, cross‐reactivity with other co‐infections, connective tissue disorders, syphilis, and tuberculosis [18].

In Nepal, brucellosis is primarily diagnosed using the Rose Bengal test, Standard Tube Agglutination test (SAT), and ELISA for Brucella‐specific IgM and IgG antibodies. Blood cultures are available in tertiary care centers but have limited sensitivity, while PCR is confined to specialized laboratories and is not routinely available in clinical practice. Solely using Brucella IgM/IgG could lead to overdiagnosis and unwarranted management of brucellosis. Therefore, clinicians should interpret brucellosis diagnostic results cautiously and in conjunction with the appropriate clinical context, particularly in high‐risk endemic regions where false‐positive results and suspected co‐infections may occur.

Treatment for brucellosis consists of prolonged combination antimicrobial therapy to eradicate the intracellular organism and reduce the risk of relapse. For uncomplicated disease, the preferred regimen is doxycycline plus rifampin for 6 weeks, or doxycycline for 6 weeks combined with gentamicin for 7–14 days or streptomycin for 2–3 weeks [17].

Our patient responded rapidly, consistent with the literature documenting dramatic improvement within 48 h of doxycycline initiation.

8. Conclusion

This case highlights the complexities of diagnosing causes of acute febrile illnesses and CNS infections in tropical regions, where clinical symptoms, possible exposures, and laboratory findings may overlap while diagnostic testing may be limited. Negative PCR assays do not exclude scrub typhus or brucellosis and may occur due to low bacterial load, delayed presentation, or prior partial treatment. The presence of an eschar, CSF profile suggestive of aseptic meningitis, and compatible serology are crucial for diagnosis. Early recognition and timely initiation of combination antimicrobial therapy remain vital for favorable neurological outcomes in dual infections.

Author Contributions

Pashupati Pokharel: conceptualization, writing – original draft, writing – review and editing, project administration. Diwash Rai: writing – original draft, writing – review and editing, validation. Milan Bajracharya: writing – review and editing, supervision. Abhikshya Basnet: writing – original draft, writing – review and editing. Bimal Sharma Chalise: writing – review and editing, supervision, visualization. Arati Baskota: writing – original draft, writing – review and editing. Andrew B. Trotter: writing – review and editing, supervision, validation, visualization.

Funding

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient for the publication of this case report.

Conflicts of Interest

The authors declare no conflicts of interest.

Pokharel P., Rai D., Bajracharya M., et al., “Scrub Typhus Meningoencephalitis With Concurrent Brucellosis in Rural Nepal: Diagnostic Challenges With Negative PCR in a Low‐Resource Setting,” Clinical Case Reports 14, no. 10 (2026): e73650, 10.1002/ccr3.73650.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.