Rhabdomyolysis, Hemophagocytic Lymphohistiocytosis and Neurobrucellosis: An Unusual Triad in a Paediatric Patient

1. Introduction

Brucellosis remains an important zoonotic infection in endemic regions and may involve multiple organ systems. Neurological involvement represents one of the most severe complications; however, neurobrucellosis is uncommon in children, reported in only 0.5%–1% of paediatric brucellosis cases. While brucellosis primarily presents with non‐specific systemic symptoms, when neurological involvement does occur, it most frequently manifests as meningitis or meningoencephalitis. In the absence of cerebrospinal fluid (CSF) confirmation, diagnosis of neurological involvement may rely on clinical and radiological findings. Among systemic complications, endocarditis remains the most clinically significant and serious complication of brucellosis, although it is rare in the paediatric population [1].

Hemophagocytic lymphohistiocytosis (HLH) is a life‐threatening hyperinflammatory condition characterised by uncontrolled immune activation, cytopenias, coagulopathy, hyperferritinemia and multiorgan dysfunction. Although most frequently associated with rheumatologic and viral diseases, infection‐triggered HLH has been reported in association with brucellosis only in limited case series and sporadic reports, highlighting its rarity and diagnostic challenge [2, 3].

Rhabdomyolysis is another severe but uncommon complication of systemic inflammation and may aggravate renal and metabolic dysfunction. While infectious rhabdomyolysis is well recognised, cases associated with brucellosis are exceptional [4].

The simultaneous occurrence of probable neurobrucellosis, HLH and rhabdomyolysis in a paediatric patient has rarely been reported. We describe a child with this unusual triad leading to severe encephalopathy and multiorgan failure, highlighting the importance of early recognition of infection‐associated hyperinflammation.

2. Case Presentation

A 16‐year‐old male was referred to our clinic due to encephalopathy and multiple organ failure. According to the history obtained, the patient was found unconscious on the bank of the Meriç River. History revealed that he had been walking for 3 days trying to cross the border, had limited food and water intake during this period and drank river water before losing consciousness and being found by border patrol officers. The patient was intubated at the first medical centre due to unconsciousness. Laboratory tests revealed metabolic acidosis, elevated renal function parameters, increased creatine kinase (CK) levels, coagulopathy and thrombocytopenia, suggesting multiple organ failure. He was referred to our paediatric intensive care unit (PICU) for possible dialysis requirement. No information could be obtained regarding his past medical or family history.

On admission to our unit, physical examination revealed a poor general condition and unconsciousness with a Glasgow Coma Scale (GCS) score of 9. His blood pressure was 107/63 mmHg (mean: 85 mmHg), heart rate 128 bpm, body temperature 37°C and respiratory rate 38/min. Pupils were dilated with preserved light reflex. Heart sounds were distant, and diffuse crackles were heard bilaterally on lung auscultation. The liver was palpable 5 cm below the costal margin. Multiple lacerations were present all over the body. Hemorrhagic crusted lesions were noted on the soles of the feet, and fungal infection was observed on toenails. Laboratory results were as follows: haemoglobin 14.5 g/dL, leukocytes 14 290/mm³, platelets 36 000/mm³, glucose 120 mg/dL, BUN 50 mg/dL, creatinine 4.27 mg/dL, uric acid 21.6 mg/dL, sodium 141 mmol/L, potassium 3.89 mmol/L, chloride 109 mmol/L, calcium 7.7 mg/dL, phosphorus 3.2 mg/dL, magnesium 2.65 mg/dL, aspartate aminotransferase (AST) 1468 U/L, alanine aminotransferase (ALT) 550 U/L, lactate dehydrogenase (LDH) 2287 U/L, CK 81186 U/L, ferritin 14 854 μg/L, C‐reactive protein 30 mg/L, procalcitonin 199 μg/L, troponin T 654 ng/L and pro‐BNP 16123 ng/L. Coagulation studies showed a prothrombin time of 26.2 s, INR 2.27, aPTT 33.9 s and fibrinogen 147 mg/dL. Arterial blood gas analysis revealed pH 7.24, pCO₂ 39.5 mmHg, lactate 1.9 mmol/L and bicarbonate 16 mmol/L. ECG demonstrated ST‐segment changes, and chest X‐ray showed infiltrative opacities consistent with pulmonary edema. Cranial MRI revealed restricted diffusion in the right frontobasal white matter, and T2 WI‐FLAIR showed increased signal intensity in this region and both thalami (Figure 1a–d). The patient was started on broad‐spectrum antibiotics (vancomycin, meropenem, doxycycline and azithromycin) and N‐acetylcysteine infusion. Due to anuria, a dialysis catheter was placed and continuous renal replacement therapy (CRRT) was initiated. Renal ultrasonography revealed increased parenchymal echogenicity consistent with grade 3 renal parenchymal disease. Echocardiography showed systolic dysfunction with an ejection fraction (EF) of 38%, and milrinone infusion was started. When hypotension developed, adrenaline and noradrenaline infusions were added. Bone marrow aspiration revealed hemophagocytosis, and together with hyperferritinemia, hypofibrinogenemia and elevated AST, the patient was diagnosed with HLH, fulfilling the HLH‐2004 diagnostic criteria [5]. Plasma exchange therapy was performed, followed by administration of 1 g methylprednisolone. Severe dehydration, prolonged physical stress and poor nutritional status likely played a substantial contributory role in disease severity.

FIGURE 1.

Initial axial brain MRI demonstrates two focal areas of diffusion restriction in the deep white matter of the right frontal lobe on DWI (a) and ADC maps (b) (curved red arrows). Corresponding FLAIR (c) and T2‐weighted (d) images show hyperintensity in the same region and in both thalami (yellow arrows). At 2‐week follow‐up, interval progression of frontal lobe hyperintensities is observed (curved red arrow) (e, f). New FLAIR hyperintense foci appear in the right parietal subcortical and periventricular white matter (curved yellow arrows) and in both cerebellar hemispheres (red arrows), not present previously, consistent with probable neurobrucellosis (g, h). At 8 weeks, complete resolution of prior signal abnormalities is demonstrated; however, compared with previous examinations, there was prominence of the lateral ventricles (yellow arrows) and hemispheric cortical sulci (red arrows) consistent with atrophy (i–l).

On the second day of hospitalisation, CK increased to 125 003 U/L and ferritin to 31 642 μg/L. After three sessions of plasma exchange therapy, coagulopathy and thrombocytopenia improved. As anuria and elevated CK persisted, CRRT was continued. When ferritin decreased to 2182 μg/L, the patient received pulse steroid therapy for 5 days, then tapered to 2 mg/kg/day. Laboratory findings are presented in Table 1. On the Day 8, Brucella was isolated from the initial blood culture. The Brucella agglutination test was positive at a titre of 1/1280. A detailed prior medical and exposure history could not be obtained, as the patient was unconscious at presentation and had not been with his family during the preceding 3 months; therefore, the exact timing and route of Brucella infection remain unclear.

TABLE 1.

Changes in biochemical, haematological findings of the patient.

Variables	On admission	12th h	24th h	36th h	48th h	60th h	72th h	HD 4	HD 5	HD 6	HD 7	HD 14	HD 21	HD 28
WBC count, ×103/μL (3.8–10)	14.3	24.0	19.9	27.1	30.5	32.3	34.4	30.4	25.3	17.2	18.8	11.7	6.9	13.6
Neutrophil, ×103/μL (1.78–5.38)	12.3	18.9	18.3	25.2	27.9	29.9	31.5	27.7	22.8	14.7	15.9	10.7	4.2	9.9
Lymphocyte, ×103/μL (0.8–4)	1.4	4.0	6.2	1.1	1.3	1.3	1.6	1.2	1.3	1.1	0.8	0.5	1.1	1.8
Hemoglobulin, g/dl (11–16)	14.5	12.5	12.0	13.2	12.9	11.9	11.1	10.7	9.4	9.1	8.9	8.2	8.7	9.7
Platelets, ×103/μL (100–400)	36.0	27.0	112.0	123.0	134.0	119.0	103.0	94.0	103.0	108.0	128.0	136.0	143.0	135.0
BUN, mg/dL (8–24)	50.4	41.8	32.0	30.2	29.7	32.2	32.3	31.9	30.9	31.7	34.5	70.3	33.5	56.9
Creatinine, mg/dL (0.70–1.2)	4.3	3.0	3.5	3.6	3.4	3.6	2.9	3.4	2.3	1.9	1.7	2.2	1.7	3.6
Total bilirubin, mg/dL (< 1.2)	0.7	0.9	1.1	1.1	4.4	6.5	6.0	5.4	5.0	4.5	4.2	2.6	3.0	1.1
AST, U/L (< 33)	1468.0	1916.0	2911.0	4139.0	5703.0	6132.0	4273.0	2670.0	1324.0	682.0	483.0	103.0	108.0	42.0
ALT, U/L (< 37)	550.0	1121.0	1716.0	2686.0	4010.0	4833.0	4075.0	3010.0	1412.0	1060.0	695.0	122.0	114.0	27.0
Uric acid, mg/dL (3.4–7)	21.6	10.9	8.2	8.1	5.4	3.5	—	—	1.0	1.1	1.5	3.0	—	5.8
CK, U/L (< 270)	81186.0	70369.0	85606.0	109143.0	125003.0	111471.0	86970.0	60069.0	36940.0	10305.0	10302.0	2438.0	465.0	156.0
ALP, U/L (82–331)	154.0	123.0	192.0	183.0	192.0	—	—	—	183.0	—	161.0	167.0	—	353.0
LDH, U/L (135–225)	2287.0	2233.0	—	4808.0	5337.0	4962.0	—	2018.0	1351.0	982.0	906.0	708.0	—	401.0
Sodium, mmol/L (132–141)	141.0	139.0	146.0	146.0	144.0	139.0	135.0	135.0	134.0	143.0	137.0	136.0	136.0	132.0
Potassium, mmol/L (3.5–5.1)	3.9	3.5	2.8	3.5	3.9	4.0	4.3	4.3	4.6	4.1	3.8	4.3	3.7	4.4
Total protein, g/dL (6–8)	6.8	5.8	6.0	7.4	7.0	7.3	7.3	7.6	7.0	7.5	7.6	5.6	5.5	5.5
Albumin, g/dL (3.2–4.5)	3.6	3.6	3.5	4.2	4.3	4.4	4.4	4.7	4.4	4.4	4.4	3.1	2.9	2.7
CRP, mg/L (< 5)	28.8	28.7	37.0	58.4	58.1	45.0	31.5	24.6	13.1	7.2	13.8	48.1	74.1	64.9
Procalcitonin, ng/mL (< 0.5)	199.2	146.6	115.0	133.7	120.7	128.0	> 100.0	> 100.0	40.7	16.2	19.1	17.6	1.8	2.2
PT, s (10.5–14.5)	26.2	18.7	25.7	30.0	21.4	19.9	16.8	15.7	13.4	15.4	12.5	13.7	13.2	13.4
PT INR (0.8–1.2)	2.4	1.6	2.3	2.7	1.9	1.8	1.5	1.4	1.1	1.3	1.1	1.2	1.1	1.1
aPTT, s (21–35)	33.9	40.2	62.1	64.4	29.9	40.5	37.4	36.0	37.7	84.6	25.2	43.4	65.2	27.7
Fibrinogen, mg/dl (170–420)	147.0	163.0	199.0	266.0	320.0	338.0	345.0	366.0	303.0	298.0	314.0	687.0	900.0	778.0
Pro BNP, ng/L (< 125)	16123.0	20073.0	10299.0	15931.0	19614.0	18624.0	15645.0	10297.0	4116.0	2885.0	2235.0	33525.0	10285.0	3840.0
Ferritin, μg/L (14–152)	14854.0	6491.0	31632.0	25572.0	18931.0	14765.0	9537.0	5016.0	2666.0	2182.0	1477.0	707.8	540.7	963.7
Troponin T, ng/L (< 14)	654.7	427.3	522.8	665.2	545.8	782.5	1121.0	879.7	412.2	262.3	235.5	470.1	4023.0	9426.0

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; CK, creatine kinase; CRP, C‐reactive protein; HD, hospital day; INR, international normalized ratio; LDH, lactate dehydrogenase; PT, prothrombin time; WBC, white blood cell.

On follow‐up MRI in the second week, progression of frontal lobe hyperintensities was demonstrated. Additionally, newly developed FLAIR hyperintense foci were identified in the right parietal subcortical and periventricular white matter as well as in both cerebellar hemispheres, which had not been evident on the prior examination (Figure 1e–h). Based on the clinical picture of encephalopathy and MRI findings, probable neurobrucellosis was considered. The patient was treated with ceftriaxone for 6 weeks and doxycycline plus rifampicin for 12 weeks. On Day 10, the patient experienced two episodes of cardiac arrest, requiring approximately 15 min of resuscitation. The cardiac arrest on hospital Day 10 was presumed to be secondary to underlying myocardial dysfunction in the setting of severe multiorgan failure. On Day 12, adrenaline and noradrenaline infusions were discontinued. Echocardiography revealed improvement of EF to 46%, leading to discontinuation of milrinone and initiation of digoxin and enalapril therapy. The patient required dialysis for a total of 52 days. Due to repeated extubation failures, tracheostomy was performed on Day 57. On MRI performed 8 weeks after the initial study, complete resolution of the previously reported signal changes was demonstrated. Nevertheless, interval development of mild cerebral parenchymal atrophy was noted compared with earlier imaging (Figure 1i–l). The patient was weaned from mechanical ventilation on Day 80 and maintained on spontaneous breathing through the tracheostomy with supplemental oxygen. He was discharged on Day 126 of hospitalisation. Forty‐five days after discharge from the PICU, the patient no longer required tracheostomy support, and successful decannulation was performed. The patient returned to his home country with his family. Three months later, he was able to sit independently and feed himself without assistance. He continues to receive physical rehabilitation. At his most recent follow‐up, he is able to feed himself and perform personal hygiene independently, can speak actively and comprehend spoken language and is able to ambulate with assistive walking devices. Rehabilitation is ongoing to achieve fully independent ambulation. The patient's follow‐up course is presented in Figure 2.

FIGURE 2.

Timeline of the clinical course showing key clinical events, diagnostic milestones, therapeutic interventions and outcomes during hospitalisation and follow‐up. CK, creatine kinase; CRRT, continuous renal replacement therapy; HLH, Hemophagocytic lymphohistiocytosis; MRI, Magnetic resonance imaging; MV, mechanical ventilation; PICU, paediatric intensive care unit.

3. Discussion

We report an adolescent with brucellosis complicated by concurrent probable neurobrucellosis, HLH and massive rhabdomyolysis, resulting in profound multiorgan dysfunction.

Brucellosis in children most commonly presents with prolonged fever, malaise, arthralgia, hepatosplenomegaly and laboratory findings such as anaemia, leukopenia or thrombocytopenia and elevated inflammatory markers. Hepatic involvement with transaminase elevation is also frequently reported [1]. In our patient, hepatomegaly, thrombocytopenia, markedly elevated transaminases and systemic inflammatory markers were consistent with typical paediatric brucellosis. However, unlike the usual subacute and non‐specific presentation seen in children, our case was characterised by acute encephalopathy and rapidly progressive multiorgan dysfunction, reflecting an unusually severe and complicated disease course. Although endocarditis represents the most frequent cardiac manifestation of brucellosis, isolated myocarditis remains an exceptionally rare complication. Abid et al. reported that cardiac involvement occurs in approximately 1%–2% of brucellosis cases, with myocarditis accounting for only a very small fraction of these patients, often in the absence of concomitant endocarditis [6]. Similarly, Salehi et al. emphasised the rarity of Brucella myocarditis and highlighted the role of cardiac magnetic resonance imaging in detecting myocardial inflammation and ventricular dysfunction [7]. In our patient, elevated troponin levels together with reduced EF and left ventricular systolic dysfunction suggested significant myocardial injury. While Brucella infection may have contributed to this cardiac involvement, sepsis‐related cardiomyopathy and systemic factors, including prolonged dehydration and physiological stress, likely also played a role. Therefore, distinguishing direct inflammatory myocardial involvement from sepsis‐related cardiomyopathy remains clinically challenging. Although brucellosis likely played a significant role in triggering hyperinflammation and contributing to the clinical course, the overall presentation should be interpreted within a multifactorial framework rather than a direct causal relationship. Severe dehydration, prolonged physical stress and poor nutritional status may have substantially contributed to rhabdomyolysis, metabolic derangements and progression to multiorgan failure. Therefore, rather than a direct causal chain, these findings likely reflect the combined effects of infection and critical systemic stress.

HLH represents a severe hyperinflammatory response that may complicate infectious diseases, including brucellosis. Although it is more frequently described in association with rheumatologic and viral conditions, infection‐triggered HLH secondary to Brucella species has been reported only sporadically [3]. In these cases, the clinical presentation may overlap with severe sepsis, making early recognition challenging. In our patient, marked hyperferritinemia, thrombocytopenia, hypofibrinogenemia, elevated transaminases and hemophagocytosis in bone marrow examination supported the diagnosis of HLH. The presence of overwhelming systemic inflammation together with confirmed brucellosis suggests that uncontrolled immune activation likely contributed substantially to the rapid progression to multiorgan failure. Differentiating HLH from severe sepsis remains a major diagnostic challenge in such cases. Although HLH and severe sepsis share several clinical and laboratory features, certain findings may aid in differentiation. Extremely elevated ferritin levels (often > 10 000 μg/L), hypofibrinogenemia, and evidence of hemophagocytosis are more suggestive of HLH, whereas sepsis is more commonly associated with markedly elevated procalcitonin levels and a predominant infectious trigger. In addition, persistent cytopenias and lack of response to standard antimicrobial therapy may further support the diagnosis of HLH. However, in critically ill patients, these conditions frequently overlap, and HLH may be triggered by severe infection itself, making clinical distinction challenging and necessitating a high index of suspicion [2, 3, 5, 8].

Rhabdomyolysis is an uncommon but potentially severe complication of systemic infections and may result in acute kidney injury and metabolic disturbances. Although viral pathogens are more frequently implicated, bacterial causes including Brucella species have been reported in isolated cases. The underlying mechanism remains incompletely understood and is likely multifactorial, involving direct muscle invasion, toxin‐mediated injury, severe systemic inflammation, or prolonged dehydration and tissue hypoxia [4]. In our patient, extremely elevated CK levels and persistent anuria requiring prolonged renal replacement therapy indicated severe muscle injury. Given the history of prolonged physical exertion, limited fluid intake and systemic inflammatory response, rhabdomyolysis in this case was likely multifactorial, with both infection‐related and non‐infectious contributors rather than being solely attributable to Brucella infection.

While the simultaneous occurrence of probable neurobrucellosis, HLH and rhabdomyolysis is indeed a rare clinical triad, the key clinical implication extends beyond the rarity of the triad. Our findings underscore that in endemic regions, brucellosis must be a key differential diagnosis for paediatric patients presenting with hyperferritinemic multiorgan failure and neurological involvement. The rapid progression from a seemingly non‐specific febrile illness to critical multi‐system dysfunction—including encephalopathy and significant biochemical markers like extreme hyperferritinemia—should prompt immediate screening for Brucella species. Early diagnostic suspicion is the cornerstone for initiating targeted antimicrobial therapy and managing the associated hyperinflammatory response, which are crucial for improving survival in such high‐acuity cases.

One limitation of this report is the absence of CSF analysis due to severe coagulopathy and hemodynamic instability, which precluded lumbar puncture. Therefore, the diagnosis of neurobrucellosis was based on clinical findings, neuroimaging, positive blood culture and serologic testing rather than CSF confirmation. Accordingly, the diagnosis of neurobrucellosis in this case should be considered probable rather than definitive. In addition, given the severity of systemic inflammation and multiorgan dysfunction, it is difficult to determine the relative contribution of direct central nervous system infection versus systemic hyperinflammatory processes to the neurological manifestations. As a single‐case report, our findings cannot be generalised.

In conclusion, this case highlights that paediatric brucellosis can manifest as a severe, life‐threatening hyperinflammatory state with significant neurological involvement. Beyond the documentation of an unusual clinical triad, the critical lesson for clinicians is to maintain a high index of suspicion for brucellosis in children from endemic areas who present with hyperferritinemic multiorgan failure and neurological manifestations. Recognising this clinical pattern early and implementing a multidisciplinary management approach is essential to mitigate severe complications and ensure favourable long‐term outcomes in these complex patients.

Funding

The authors have nothing to report.

Ethics Statement

The authors declare that the research presented in this manuscript adheres to the ethical principles outlined by institutional guidelines. As this study is a case report, formal approval from an ethics committee was not required according to local regulations. Written informed consent was obtained from the patient's family for publication of this case report. All procedures involving human participants were conducted in accordance with the ethical standards of the institution and the Declaration of Helsinki (1964), as revised in 2013. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.