Brucella melitensis infection complicated by secondary hemophagocytic lymphohistiocytosis, meningitis, and multiorgan damage: a case report and literature review

Abstract

Background

Brucellosis is one of the most widespread zoonotic diseases globally. Of the twelve known Brucella species that affect mammals, Brucella melitensis is the most significant cause of human infection. Others include B. abortus, B. suis, and B. canis, with transmission occurring via unpasteurized dairy, direct animal contact, or occupational exposure (veterinarians, farmers, and laboratory workers). Although hemophagocytic lymphohistiocytosis (HLH) and neurological complications are known sequelae of brucellosis, their simultaneous occurrence with multiorgan failure is rarely reported.

Case presentation

A 59-year-old female was admitted with dizziness and fatigue for more than 20 days, accompanied by fever and lethargy for 3 days. An epidemiological history revealed that the patient had close contact with goats, which was considered a key risk factor. On physical examination, the patient appeared lethargic, with petechiae on the skin and mucous membranes, oral blood blisters, gingival bleeding, and splenomegaly. Laboratory results revealed significantly increased ferritin levels, decreased fibrinogen levels, pancytopenia, and elevated transaminase levels. Bone marrow aspiration confirmed the presence of hemophagocytes. Cerebrospinal fluid (CSF) examination supported a diagnosis of meningitis. Blood cultures grew Brucella melitensis, and metagenomic next-generation sequencing (mNGS) of CSF revealed a large number of B. melitensis-specific nucleic acid sequences. Chest computed tomography (CT) revealed bilateral pulmonary infiltrates. The patient was ultimately diagnosed with B. melitensis infection complicated by HLH, meningitis, and multiorgan dysfunction. The patient was treated with ceftriaxone sodium, doxycycline, rifampicin, glucocorticoids, and supportive therapy. Following treatment, her consciousness improved, the fever subsided, the total platelet count rose, and liver enzyme levels gradually decreased. The patient was discharged in stable condition. At the 2-month follow-up, the patient remained in remission with normal haematological indicators, no recurrent fever, and stable neurological function.

Conclusions

This case reflects the severe nature of brucellosis when atypical multiorgan involvement is present and highlights the diagnostic challenges and the importance of early and standardized treatment. Maintaining a high level of clinical suspicion and achieving an early definite diagnosis are key to improving treatment outcomes and prognosis. In addition, this case report helps expand the known spectrum of clinical complications related to brucellosis.

Background

Brucellosis is a zoonotic infectious disease caused by bacteria from the genus Brucella, and it is still one of the most widespread zoonoses around the world [1]. Epidemiological data indicate that the incidence of brucellosis has been consistently increasing, with an estimated 2.1 million new human infections occurring worldwide each year [2, 3]. Brucellosis remains endemic in the Mediterranean Basin and the Middle East (Syria, Iraq, and Iran). In China, it is prevalent primarily in pastoral and rural areas, with a clear trend of geographical expansion and distinct spatiotemporal patterns. The number of reported cases increased from 8 in 1950 to a historical peak of 69,767 in 2021, while the incidence rate increased from 0.002/100,000 to 4.949/100,000 during the same period [4]. It is especially common in parts of China where animal husbandry is intensive [5]. Transmission to humans usually occurs through contact with bodily fluids from infected animals or the consumption of food products contaminated by those animals [6]. Although the main causative pathogen of human brucellosis in China is B. melitensis and Brucella species tend to be host-specific, there is growing evidence of cross-species transmission [7, 8]. Previous studies have demonstrated that Brucella species can invade a variety of physiological systems, including the musculoskeletal, gastrointestinal, circulatory, and nervous systems, leading to complex clinical manifestations [9]. The disease poses serious risks to public health but also leads to significant economic losses in many regions. Meningitis is the most common neurological complication, although it occurs in fewer than 5% of cases [10]. HLH, characterized by a cytokine storm, widespread inflammation, and multiorgan failure, is an extremely rare complication of Brucella infection [11]. Because the clinical manifestations of brucellosis vary significantly and are not exclusive to this disease, diagnosis can be difficult, often leading to prolonged health issues [12]. To the best of our knowledge, there are scarce reports of meningitis, HLH, and multiorgan dysfunction occurring simultaneously due to a Brucella infection. In this report, we present the case of a 59-year-old female from Gansu Province, China, who developed meningitis, HLH, and multiorgan dysfunction after being infected with Brucella, along with a review of the relevant literature.

Case presentation

A 59-year-old female farmer with no significant prior medical history was treated at our institution. The patient presented with dizziness and fatigue for 20 days, followed by fever and drowsiness for the past 3 days. About three weeks before her admission, the patient began experiencing dizziness and fatigue unexpectedly—these clinical signs worsened with any physical activity. No specific treatment was administered before admission. Three days before her admission to the hospital, the patient began experiencing fevers and excessive sleepiness, with a maximum recorded temperature of 38.0 °C. The symptoms persisted despite the treatment the patient received at her local hospital, leading to her referral to our facility for more comprehensive evaluations. Her medical history included no remarkable records of surgery, trauma, or blood transfusion, and she did not have any known hypersensitivity to drugs or food. Notably, the patient reported exposure to goats over a long period, allowing us to make an epidemiological connection. At admission, the patient presented with the following clinical signs: temperature 37.8℃, pulse 96 beats/min, respiratory rate 22 breaths/min, and blood pressure 109/69 mmHg. The patient was cooperative but appeared lethargic. Physical examination revealed scattered nonblanching purpuric lesions on both legs, blood blisters on the oral mucosa and tongue, mild gingival bleeding, coarse breath sounds with scattered purulent rales in both lower lung fields, and splenomegaly (49 mm thick and 159 mm long on abdominal ultrasound). No neck stiffness was noted, and the remainder of the neurological examination was unremarkable.

Bilateral pulmonary infiltrates were observed on chest computed tomography (CT) (Fig. 1). Cranial CT revealed demyelination of the cerebral white matter as well as calcification of the choroid plexus and pineal gland. The patient did not receive additional neurological examinations, such as magnetic resonance imaging (MRI) of the brain or electroencephalography (EEG), because of financial limitations. A summary of the admission laboratory results is provided in Table 1. Notable abnormalities included pancytopenia, hyperferritinemia, hypofibrinogenemia, elevated liver enzymes, and coagulopathy. All autoantibody screens (ANA, anti-dsDNA, and ANCA) and serologic tests for HIV, Epstein‒Barr virus, and syphilis were negative. With a clinical presentation of fever, pancytopenia, splenomegaly, coagulopathy, and an extremely high level of ferritin, HLH was highly suspected. The patient fulfilled five of the eight HLH-2004 diagnostic criteria (fever, splenomegaly, cytopenias affecting ≥ 2 lineages, hyperferritinemia, and hypofibrinogenemia) [13]. Empirical therapy was initiated with intravenous ceftriaxone for potential infection, dexamethasone for immunomodulation, and glycyrrhizinate for hepatoprotection. Fibrinogen concentrate and fresh frozen plasma were administered to treat coagulopathy.

Fig. 1.

Chest CT examination after admission. The arrow indicates pulmonary infiltration lesions

Table 1.

Laboratory data and infection work-up on admission

Items	Result	Reference value
ESR (mm/h)	6	0–20
WBC (× 109/L)	2.23	3.50–9.50
NEU (× 109/L)	1.41	1.80–6.30
PLT (× 109/L)	14	125–350
Hb (g/L)	112	115–150
ALB(g/L)	31.90	40.00–55.00
ALT (U/L)	51.00	7.00–40.00
AST (U/L)	131.90	13.00–35.00
LDH (U/L)	661.60	120.00-250.00
CRP (mg/L)	8.46	0.00–6.00
FER (ng/ml)	> 1500.00	12.00-135.00
PCT (ng/ml)	0.16	< 0.10
Autoantibody	Negative	Negative
HIV, EB-virus and Syph	Negative	Negative
HBsAg (IU/ml)	<0.05	≤ 0.05
HBsAb (mIU/ml)	<2.00	<10.00
HBeAg (IU/ml)	<0.050	<0.10
HBeAb (IU/ml)	1.38	<0.15
HBcAb (IU/ml)	>25.00	<0.35
APTT (Sec)	41.08	22.00–38.00
FIB (g/L)	1.06	2.00–4.00
TT (Sec)	26.2	14.0–21.0
D-Dimer (ug/ml)	5.18	0.00–1.00
FDP (ug/ml)	22.76	0.00–5.00
AT-Ⅲ (%)	66.0	75.0-125.0
T3 (nmol/l)	0.49	1.10–2.10
T4 (nmol/l)	84.79	70.00-152.00
TSH (uIU/ml)	0.41	0.75–5.60

Abbreviations: ESR – Erythrocyte Sedimentation Rate; WBC – White Blood Cell Count; NEU – Neutrophil Count; PLT – Platelet Count; Hb – Hemoglobin; ALB – Serum Albumin; ALT – Alanine Aminotransferase; AST – Aspartate Aminotransferase; LDH – Lactate Dehydrogenase; CRP – C-Reactive Protein; FER – Serum Ferritin; PCT – Procalcitonin; HIV – Human Immunodeficiency Virus; EB virus – Epstein-Barr Virus; Syph – Syphilis Serology; HBsAg – Hepatitis B Surface Antigen; HBsAb – Hepatitis B Surface Antibody; HBeAg – Hepatitis B e Antigen; HBeAb – Hepatitis B e Antibody; HBcAb – Hepatitis B Core Antibody; APTT – Activated Partial Thromboplastin Time; FIB – Fibrinogen; TT – Thrombin Time; FDP – Fibrin Degradation Products; AT-Ⅲ – Antithrombin Ⅲ; T3 – Triiodothyronine; T4 – Thyroxine; TSH – Thyroid-Stimulating Hormone

On the third day of her hospitalization (November 13), the patient developed neck stiffness and became increasingly drowsy. Blood cultures were positive for B. melitensis (Fig. 2), confirming a diagnosis of Brucella meningitis. Lumbar puncture was performed to collect CSF, which was clear and colourless. The CSF findings were consistent with those of meningitis, and the detailed results, including all reference ranges, are presented in Table 3. Serological testing for Brucella antibodies was performed using the Rose Bengal Plate Agglutination Test, which was positive. This result was further confirmed by a standard tube agglutination test which yielded a positive IgM result. Metagenomic next-generation sequencing (mNGS) of the CSF identified Brucella species with 99% confidence, and 7,465 sequence reads corresponded to this bacterium. Bone marrow aspiration revealed a hypercellular marrow with active haematopoiesis and depleted iron stores, along with the presence of hemophagocytes (see Fig. 3). The level of soluble interleukin-2 receptor (sCD25) was elevated at 1623 U/mL, further supporting the diagnosis of HLH. Detailed follow-up laboratory results can be found in Tables 2 and 3.

Fig. 2.

A. Morphology of Brucella melitensis observed on direct smear Gram stain under microscopic examination at 10 × 100 magnification, from a blood agar plate. B. Colony morphology of Brucella melitensis on blood agar plates after 48 h of incubation at 35 °C with 5% CO₂

Table 3.

Cerebrospinal fluid (CSF) examination results

Laboratory Parameters	Unit	Nov 13	Nov 25	Jan 5	Reference Range
Color	-	Colorless	Colorless	Colorless	None
Transparency	-	Clear	Clear	Clear	None
Coagulability	-	Non-coagulable	Non-coagulable	Non-coagulable	None
RBC Count	× 106/L	12	10	26	None
WBC Count	× 106/L	10	8	4	0–15
CSF Chloride	mmol/L	118.03	123.50	130.07	120.00-132.00
CSF Glucose	mmol/L	1.57	2.48	3.46	2.50–4.50
CSF LDH	U/L	47.20	25.70	20.40	10.00–25.00
CSF Protein	g/L	1.71	0.91	0.38	0.08–0.43

Abbreviations: CSF - Cerebrospinal Fluid

Fig. 3.

Bone marrow cytology examination showing hemophagocytic cells (C and D)

Table 2.

Follow-up records of patients’ laboratory examinations

Date	WBC (× 10^9/L)	PLT (× 10^9/L)	Hb (g/L)	ALT (U/L)	AST (U/L)	LDH (U/L)	CRP (mg/L)	PCT (ng/ml)	FIB (g/L)	D-Dimer (ug/ml)	FDP (ug/ml)	FER (ng/ml)
Nov 10	2.23	14	112	51.00	131.90	661.60	8.46	0.16	1.06	5.18	22.76	> 1500.00
Nov 11	2.37	73	101	76.30	204.80	-	-	0.09	1.16	15.32	35.00	-
Nov 13	2.79	85	103	89.90	154.10	512.30	5.92	-	1.30	17.19	57.27	-
Nov 17	2.67	59	103	58.00	74.10	393.40	4.3	-	-	2.23	-	-
Nov 18	3.06	136	108	-	-	-	-	-	-	1.44	-	-
Nov 21	3.36	154	122	43.20	34.80	-	-	-	-	1.18	-	-
Nov 30	2.51	101	111	15.60	15.50	-	-	-	-	-	-	-
Dec 10	5.08	123	129	15.00	18.20	-	-	-	-	-	-	-
Jan 5	5.6	155	151	15.10	18.50	205.9	0	-	2.32	1.15	1.00	68.46

The final diagnosis was brucellosis complicated by secondary HLH, meningitis, and multiorgan dysfunction that affected the haematologic, hepatic, and respiratory systems. Following a comprehensive evaluation, negative autoantibody screens helped rule out primary autoimmune causes. The patient’s body weight, measured after clinical stabilization, was 57.5 kg (above the 45 kg threshold for adult fixed dosing). The treatment regimen was modified according to the 2023 Chinese Guidelines for the Diagnosis and Treatment of Brucellosis. Accordingly, all drugs were administered at the standard adult fixed doses recommended by the relevant clinical guidelines, without conversion to a per-kilogram dose [14]. The revised treatment plan included intravenous ceftriaxone (2 g every 12 h) for one month, oral doxycycline (100 mg every 12 h) for four months, and oral rifampicin (600 mg once daily) for four months. To improve penetration into the central nervous system (CNS) and manage intracranial infection, we added intravenous levofloxacin (500 mg once daily) for one month [15, 16]. For immunomodulation, we administered a single intravenous dose of immunoglobulin (IVIG, 5 g). The patient also received intravenous dexamethasone 10 mg once daily for 12 days. The dosage was reduced to 8 mg once daily for 7 days and subsequently tapered to 6 mg once daily until discharge. Upon discharge, the patient was switched to oral prednisone, starting at 40 mg once daily. We tapered the dose by 5 mg every two weeks until complete cessation. Because her D-dimer level remained elevated, subcutaneous enoxaparin sodium (6000 IU) once daily for five days was prescribed as an anticoagulant. Cerebral edema was managed with intravenous mannitol (125 mL of 20% solution every 12 h), and intravenous diammonium glycyrrhizinate (150 mg once daily) was added for hepatoprotection.

Recovery was evident from steady clinical improvement. As of November 14, the patient was afebrile. Clinical signs such as dizziness and fatigue, along with the neurological symptoms, had also resolved. By November 30, the patient exhibited no nervous system-related symptoms. Follow-up laboratory tests demonstrated significant improvement (Tables 2 and 3). Upon discharge, the patient was prescribed an outpatient regimen consisting of oral medications (doxycycline, rifampicin, levofloxacin, and prednisone at their previous dosages) and intravenous ceftriaxone (2 g every 12 h for one month, as originally planned).

On December 10, 2025, complete blood tests were performed as a baseline assessment. On January 5, 2026, the patient remained asymptomatic and presented with a normal mental status. Haematological profiles, coagulation indices, liver enzymes, and ferritin levels returned to normal. No abnormalities were found in CSF analysis, indicating recovery from neurobrucellosis. (Tables 2 and 3). Long-term observation revealed no further recurrences.

Discussion

In this report, we provide detail of a case of B. melitensis infection complicated by the rare triad of secondary HLH, meningitis, and multiorgan injury. This case provides valuable clinical insights for managing critically ill patients with similar conditions.

The causative agent in this case was Brucella melitensis, a gram‑negative bacterium of the genus Brucella [17]. These bacteria have the ability to evade host immune defences, colonize and replicate inside macrophages, and trigger both innate and adaptive immune responses through virulence factors such as lipopolysaccharide (LPS), all of which lead to systemic immune dysregulation [18]. In this case, the patient’s prolonged exposure to goats was the most likely cause of her infection. The bacteria spread through her bloodstream (haematogenous spread), invading several organs, including the lungs, liver, and CNS, leading to systemic illness [19]. In the lungs, Brucella species enter the alveolar epithelial cells and interstitial macrophages, which cause interstitial inflammation and exudation [20]—this is consistent with the bilateral infiltrates observed on the CT scan of the chest of the patient. Bacterial growth in the liver leads to direct cell damage. This is reflected in the elevated liver enzyme levels and splenomegaly observed in the patient [21]. HLH was a major driver of deterioration. Repeated antigenic stimulation overactivates macrophages and T cells, with excessive IFN-γ, IL-6, and TNF-α production. This cytokine storm causes fever, cytopenias, hyperferritinemia, hypofibrinogenemia, and hemophagocytosis [22, 23]. Our patient met five HLH-2004 diagnostic criteria. Mechanistically, Brucella drives massive macrophage/dendritic cell activation, prompting T cells to secrete IFN-γ while suppressing NK cytotoxicity, impairing pathogen clearance and creating a positive feedback loop that amplifies inflammation [24].

The clinical course was further complicated by the development of neurological involvement. On the third day of therapy, the patient developed nuchal rigidity and somnolence. CSF analysis confirmed Brucella meningitis. Although meningitis is a common manifestation of neurobrucellosis, its incidence is low, ranging from 3% to 5% [25, 26]. Moreover, the simultaneous occurrence of Brucella infection, HLH, and multiorgan dysfunction is exceptionally rare [27]. The pathogenesis of this combined condition appears to involve a synergistic interaction between direct Brucella invasion and compromise of the blood–brain barrier (BBB) [28]. During bacteraemia, Brucella triggers inflammation of the vascular endothelium. The cytokine storm associated with HLH worsens this endothelial damage, increasing BBB permeability and allowing pathogen translocation into the CNS. Once inside the CNS, Brucella targets the meninges and brain parenchyma, initiating an inflammatory response [29]. The patient’s CSF profile—elevated protein, hypoglycorrhachia, and mild pleocytosis—was consistent with Brucella meningitis, although the relatively modest leukocyte count could have easily led to underdiagnosis. This pathological process likely explains why the patient experienced a rapid clinical decline later in her disease course [30].

The main difficulty in managing this case was the complexity of diagnosis. First, the patient presented with nonspecific clinical signs, including dizziness and fatigue [31]. Moreover, pancytopenia, markedly elevated ferritin, coagulopathy [32], bilateral pulmonary infection, hepatic failure, and multisystem damage co-occurred, complicating the early diagnosis of brucellosis [33]. The emergence of neurological impairments three days after treatment necessitated differentiation from viral encephalitis, tuberculous meningitis, autoimmune encephalitis, and haematological malignancies, which further complicated the diagnostic process [34].

Based on this therapeutic experience, several essential strategies for achieving a conclusive diagnosis in other cases have been identified [35]. In endemic areas, a comprehensive history of livestock exposure is imperative. Diagnosis can be accelerated by early and extensive laboratory screening, including tests for HLH markers, blood cultures, and CSF mNGS. Selecting the most suitable pathogen detection procedures is essential, as CSF culture positivity for B. melitensis is notoriously low (under 15%). Here, mNGS was used to detect high concentrations of B. melitensis-specific sequences in the CSF, which greatly reduced the time to diagnosis relative to that of traditional blood culture and allowed timely therapeutic changes [36].

For this patient, an integrated management strategy was used, combining “aetiological treatment, complication control, and organ protection.” This approach focused on advancing antimicrobial therapy and suppressing abnormal immune responses simultaneously—both critical to her recovery. The antimicrobial regimen followed the principles of “targeted coverage and BBB penetration.” Antibiotics with good CNS penetration (ceftriaxone, doxycycline, rifampicin, and levofloxacin) were used, and to provide immunomodulation (dexamethasone and IVIG) and organ support (anticoagulation, mannitol infusion, and hepatoprotection). The patient responded positively, and the clinical signs, as well as laboratory parameters, returned to normal at a follow-up after two months, which validates the safety and effectiveness of this diagnostic and treatment method [37]. Several limitations should be acknowledged. This was a single-center study. Genetic testing in the context of HLH was not performed, and the follow-up period was brief (only two months). Long-term follow-up is necessary to determine the possible neurological consequences. Future research will involve collaboration with medical institutions in the surrounding pastoral areas to identify more similar cases, investigate the underlying pathogenesis, optimize treatment options, and monitor long-term outcomes, thereby contributing to the clinical practice evidence base.

Conclusions

Brucellosis complicated by secondary HLH, meningitis, and multiorgan dysfunction is rare but severe. Early clinical signs like fever and cytopenias are non-specific, making diagnosis challenging. In endemic areas, inquire about livestock exposure in patients with unexplained fever and cytopenias. Severe systemic inflammation or rapid deterioration should raise suspicion for HLH, necessitating prompt recognition. Diagnostic measures include checking ferritin and sCD25 levels, blood cultures, and CSF for mNGS if neurological symptoms arise. Antibiotic treatment alone is insufficient; a combination of BBB-penetrating antibiotics and immunomodulatory therapy effectively addresses both the infection and the hyperinflammatory state. With timely diagnosis and coordinated management, critically ill patients can recover. Clinicians should be vigilant for this life-threatening complication of severe brucellosis.

Abbreviations

HLH

Hemophagocytic lymphohistiocytosis

mNGS

Metagenomic next-generation sequencing

CT

Computed tomography

CBC

Complete blood count

IVIG

Intravenous immunoglobulin

sCD25

Soluble interleukin-2 receptor

LPS

Lipopolysaccharide

TNF-α

Tumor necrosis factor-α

IL-6

Interleukin-6

IFN-γ

Interferon-γ

NK

Natural killer

sIL-2R

Soluble interleukin-2 receptor

BBB

Blood-brain barrier

Author contributions

Yiqun Li: Conceived and designed the study, collected and analyzed the clinical and laboratory data, drafted the initial manuscript. Xinmei Chen: Participated in the clinical diagnosis and treatment of the patient, provided professional advice on infectious diseases, and revised the manuscript. Juanqiang Wang: Assisted in collecting clinical data and sorting out laboratory test results, participated in the discussion of the treatment plan. Mingxi Yang: Conducted literature review and sorted out relevant academic materials, participated in the revision of the discussion part. Correspondence: Caixia Zhang: Supervised the study design and clinical diagnosis and treatment process, revised the manuscript critically for important intellectual content, finalized the manuscript, and is responsible for the integrity of the work. All authors read and approved the final manuscript.

Funding

No funding was received.

Data availability

All data generated or analyzed during this study are included in the published article (and its supplementary information files). The clinical and laboratory data supporting the conclusions of this study are presented in the main text and Tables 1, 2 and 3 of the manuscript, with imaging findings (chest CT, blood culture, bone marrow cytology) shown in the relevant figures. All raw data are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

There is no ethical/legal conflict involved in the article.

Consent for publication

Written informed consent for publication was obtained from the patient.

Competing interests

The authors declare no competing interests.