INTRODUCTION

Hemophagocytic lymphohistiocytosis (HLH) is a critical dysregulation of the immune response in which hyperactivated lymphocytes and macrophages initiate a cascade of inflammatory processes, resulting in multisystem organ involvement [1]. This complex disorder is characterized by uncontrolled immune activation that can cause severe systemic inflammation and potentially lead to organ failure [2,3].

HLH can be categorized into two forms: primary (genetic) and secondary (acquired). Primary HLH is typically associated with genetic mutations that affect immune system regulation, such as mutations in the perforin gene. In contrast, secondary HLH can be triggered by various conditions, including infections, malignancies, autoimmune diseases, and, less commonly, severe trauma [4,5].

The diagnostic criteria for HLH, as established by the HLH-2004 protocol [6], require the patient to meet at least five of the following criteria: fever of 38.5 °C or higher, splenomegaly, cytopenias affecting two or more cell lineages, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow, low or absent natural killer cell activity, elevated ferritin levels, and elevated soluble CD25 (soluble interleukin-2 receptor) levels. Despite meaningful advances in our understanding of HLH, the condition remains challenging to diagnose and treat, especially in adults and in cases with atypical presentations [7]. Specific data on the incidence of HLH in adults are scarce; however, a nationwide study in Japan that included all age groups reported an incidence of about 1 per 800,000 individuals each year [8]. In a study conducted at a single tertiary medical center, approximately one case of adult HLH was found for every 2,000 inpatient admissions [9]. The mortality rate remains high, ranging from 26.5% to 74.8% [10], which underscores the critical importance of early recognition and aggressive management [5].

While most research has focused on HLH induced by infections or malignancies, the potential for severe trauma to act as a trigger is less well-documented. This case report aims to highlight a rare instance of HLH developing after a motorcycle accident, thus contributing to the broader understanding of this complex syndrome.

CASE REPORT

A 40-year-old man was referred to the hospital after being involved in a motorcycle accident. The patient, who had been wearing a helmet, collided with a truck traveling in the same direction. Initial assessment revealed multiple traumatic injuries, including fracture of the left seventh rib, contusion of the right lung, distal shaft fracture of the right humerus, distal shaft fracture of the left ulna, and significant hematoma (measuring 15.3×3.5×13.2 cm) in the subcutaneous layer at the posterior aspect of the L5-sacrum. These findings were confirmed by lumbar magnetic resonance imaging.

Initial laboratory evaluation indicated mild abnormalities, including a white blood cell count of 7,380/μL, a hemoglobin level of 11.0 g/dL, and a platelet count of 123,000/μL. Liver function tests showed a slightly elevated aspartate aminotransferase (AST) level at 62 IU/L, while the patient’s alanine aminotransferase (ALT) level was normal at 24 IU/L. Renal function parameters fell within normal limits, with a blood urea nitrogen level of 14.6 mg/dL and a creatinine level of 1.01 mg/dL. Levels of C-reactive protein, an initial inflammatory marker, were mildly elevated at 2.49 mg/dL.

On the 10th day of hospitalization, the patient underwent successful orthopedic surgery, which included open reduction and internal fixation for both fractures. However, by the 13th day, he developed a fever of 38.6 °C along with diarrhea. Laboratory tests revealed an elevated white blood cell count of 8,210/μL, a decrease in hemoglobin to 9.7 g/dL, and an increased platelet count of 414,000/μL. Inflammatory markers were notably elevated, with C-reactive protein rising to 8.06 mg/dL and procalcitonin reaching 0.14 ng/mL, although liver and renal function remained normal.

While the patient was receiving empiric antibiotic therapy with piperacillin/tazobactam and teicoplanin, his condition continued to evolve. By the 19th day of hospitalization, laboratory values indicated improvement in inflammatory markers, with C-reactive protein decreasing to 0.96 mg/dL and procalcitonin to 0.10 ng/mL. However, on the 20th day, the patient experienced recurrent fever, prompting an escalation of antibiotic coverage to include vancomycin and meropenems.

On the 21st day of hospitalization, the patient continued to exhibit a fever, at 38.1 °C, without an identifiable source. The peripherally inserted central catheter line was replaced, and testing for cytomegalovirus via polymerase chain reaction yielded negative results. With the fever persisting, abdominal computed tomography (CT) conducted on day 23 revealed a large, circumscribed liquefying hematoma. The hematoma extended from the deep subcutaneous space of the lower back to the lacerated bed of the medial part of the left gluteus medius muscle, showing slight resolution. Additionally, mild splenomegaly was noted. In response to these findings, a percutaneous drainage catheter was inserted into the retroperitoneal hematoma, and 75 mL of old blood was extracted and sent for culture. The culture results were negative.

On the 25th day of hospitalization, the patient experienced significant clinical deterioration, characterized by a high-grade fever exceeding 39 °C and the onset of a diffuse skin rash. Laboratory results indicated progressive pancytopenia, with the white blood cell count falling to 3,010/μL and the platelet count declining to 144,000/μL. Liver function tests revealed marked elevation, with AST and ALT levels rising to 297 IU/L and 314 IU/L, respectively.

The following day, the patient’s condition worsened further, with fever spiking to 40.6 °C. Laboratory tests indicated critical abnormalities, including severe pancytopenia (white blood cell count of 2,890/μL, platelets at 73,000/μL), marked hepatic dysfunction (AST at 644 IU/L, ALT at 699 IU/L), and notably elevated inflammatory markers, with ferritin reaching 32,901 ng/mL and interleukin 6 levels at 1,138 pg/mL. However, all prior cultures were negative, and chest CT revealed no signs of pneumonia. Further imaging studies indicated splenomegaly (12.5 cm) and bilateral axillary lymphadenopathy (Fig. 1).

Based on these findings, treatment was initiated with high-dose methylprednisolone (2 mg/kg intravenous [IV] loading dose, followed by 1 mg/kg IV every 12 hours) and IV immunoglobulin (0.33 g/kg daily for 3 days). Bone marrow biopsy performed on day 27 confirmed the diagnosis of HLH. Subsequently, treatment was modified in accordance with the HLH-2004 protocol.

Based on this protocol, treatment was adjusted to intrathecal methotrexate at a dose of 12 mg (administered via cerebrospinal fluid tapping), etoposide at 150 mg/m², cyclosporin A at 3 mg/kg, and dexamethasone at 10 mg/m² for days 1 to 14. To exclude the possibility of lymphoma, a positron emission tomography/CT scan was performed, along with additional diagnostic tests. Afterward, the patient’s fever resolved completely, and he exhibited stable vital signs.

Right inguinal lymph node biopsy revealed dermatopathic lymphadenitis. Immunohistochemistry results were positive for CD20 (B cell), CD68 (macrophage), Ki-67 (reactive pattern), and S-100 protein markers. Conversely, CD10, CD1a, CD3, and Epstein-Barr virus in situ hybridization yielded negative results. Additional autoimmune panels, including anti-double stranded DNA immunoglobulin G antibody, antineutrophil cytoplasmic antibodies quantification, and antinuclear antibody testing, were also negative.

By day 34 of hospitalization, the patient demonstrated significant clinical improvement, including the normalization of laboratory values. The white blood cell count improved to 3,400/μL, platelets stabilized at 112,000/μL, and ferritin levels decreased to 3,812.0 ng/mL. Liver function tests returned to normal, with AST at 25 IU/L and ALT at 75 IU/L. The patient was discharged on the 37th day of hospitalization and has exhibited no signs of recurrence over a 2-year follow-up period.

Ethics statement

Written informed consent for publication of the research details and clinical images was obtained from the patient.

DISCUSSION

HLH is a rare but potentially life-threatening hyperinflammatory syndrome characterized by the uncontrolled activation of lymphocytes and macrophages [1]. In this case, we present a unique scenario in which secondary HLH developed in a trauma patient following a motorcycle accident, highlighting the complex interplay between severe physical trauma and the systemic inflammatory response [4,5].

The development of HLH following severe trauma in this case provides unique insights into disease pathogenesis. Although HLH typically emerges in the context of infections, malignancies, or autoimmune disorders [4], this case highlights the potential for trauma to independently trigger immune dysregulation. The patient’s clinical course, characterized by persistent fever, cytopenias, and marked elevation of inflammatory markers, aligns with the established diagnostic criteria for HLH [6]. Notably, the patient’s ferritin level reached a peak of 32,901 ng/mL, greatly surpassing the diagnostic threshold of >10,000 ng/mL; this is indicative of severe HLH [11].

This case exemplifies the diagnostic complexity of posttraumatic HLH, the initial presentation of which can mimic that of more common postoperative complications. The progression of symptoms, from seemingly routine postoperative inflammation to full-blown hemophagocytic syndrome, underscores the importance of maintaining clinical vigilance in trauma patients who exhibit persistent inflammatory responses [7]. Initial nonspecific symptoms, such as intermittent fever and the gradual deterioration of clinical parameters, can be easily misinterpreted as posttraumatic complications or nosocomial infection. Bone marrow biopsy and subsequent immunohistochemistry were pivotal in confirming the diagnosis of HLH by revealing hemophagocytosis and characteristic lymphoid cell infiltration [12].

The treatment approach adhered to the HLH-2004 protocol, which integrates immunosuppressive and immunomodulatory therapies [2,6]. The regimen of methylprednisolone and IV immunoglobulin, coupled with vigilant monitoring, was effective in this case. The patient’s rapid clinical improvement and the lack of recurrence during the follow-up period indicate successful management of this potentially fatal condition [5].

This case provides several key insights into trauma-associated HLH. First, major physical trauma may act as an independent trigger for the development of HLH, a finding that broadens our understanding of the etiology of secondary HLH [3,13]. Second, the rapid progression from postoperative recovery to full-blown HLH underscores the need for prompt recognition and aggressive intervention [2]. Third, when faced with an unexplained persistent inflammatory state, a comprehensive diagnostic workup is essential [14]. Finally, a multidisciplinary approach is crucial in managing complex inflammatory syndromes [14].

The limitations of this case report include an incomplete understanding of the precise mechanism by which trauma precipitated HLH. Future research should aim to clarify the immunological cascade that can transform a localized traumatic injury into a systemic inflammatory response [15].

The favorable outcome in this case underscores two essential principles in the management of complex trauma patients: first, the need to consider immunological complications that extend beyond typical posttraumatic responses; and second, the benefit of systematic diagnostic evaluation in the presence of unexplained inflammatory deterioration. The successful resolution of HLH in this trauma context demonstrates the possibility of achieving positive outcomes with timely diagnosis and aggressive treatment. Clinicians should be vigilant for signs of HLH in patients exhibiting persistent fever, cytopenias, and unexplained abnormalities in inflammatory markers, especially following recent significant physical trauma [3,5].

ARTICLE INFORMATION

Author contributions

Conceptualization: JK; Investigation: all authors; Methodology: JK; Project administration: JK; Visualization: all authors; Writing–original draft: all authors; Writing–review & editing: all authors. All authors read and approved the final manuscript.

Conflicts of interest

The authors have no conflicts of interest to declare.

Funding

The authors received no financial support for this study.

Data availability

Data sharing is not applicable as no new data were created or analyzed in this study.

Fig. 1.

Coronal view of the chest computed tomography scan revealing splenomegaly (arrow) with a craniocaudal length of 12.5 cm.

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