Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome whose main pathophysiological mechanism is an abnormal and exaggerated immune response triggered by infectious, metabolic, neoplastic, or rheumatologic conditions, leading to a hyperinflammatory state mediated by excessive cytokine release, also known as a cytokine storm, which accounts for the clinical manifestations [1].

Two main forms of HLH have been described: primary and secondary. The latter is most commonly triggered by viral agents such as Epstein–Barr virus, cytomegalovirus, and SARS-CoV-2, as well as bacterial infections including Mycobacterium tuberculosis, Salmonella typhi, and Brucella spp., in addition to rheumatologic and oncohematologic diseases [2].

The initial clinical signs of HLH resemble those of severe infection and include fever, cytopenias, organomegaly, and varying degrees of organ dysfunction. These features are encompassed within the diagnostic criteria established by the Histiocyte Society HLH-2004 protocol, which also includes the detection of hemophagocytosis in bone marrow, cerebrospinal fluid, or lymph nodes.

Treatment is fundamentally aimed at suppressing the hyperinflammatory response generated by immune dysregulation. This approach is based on the HLH-2004 recommendations, which include initial therapy with dexamethasone, etoposide, and cyclosporine, and intrathecal methotrexate in cases with neurological involvement. This induction phase is followed by continuation therapy intended to maintain disease remission. Supportive therapy targeting the underlying cause and, when indicated, intravenous immunoglobulin is also recommended [3].

We report the case of a 14-year-old adolescent with no significant past medical or surgical history who presented to the emergency department with a three-week history of persistent fever reaching 40 °C, poorly responsive to antipyretics, without a clear source or circadian pattern. The fever was associated with multiple episodes of food- related vomiting, weight loss, chills, and jaundice.

The patient had initially been treated at another healthcare facility with a diagnosis of leptospirosis (IgM 30.5 U/mL) and received third-generation cephalosporins without clinical improvement. On admission, physical examination revealed marked generalized pallor, signs of mild dehydration, and systemic inflammatory response.

Given the persistent febrile syndrome, an extensive diagnostic workup was initiated. Laboratory tests revealed bicytopenia on complete blood count (leukopenia 4,390×10³/µL and normocytic hypochromic anemia with hemoglobin 9.4 g/dL, hematocrit 28.7%, MCV 85.4 fL, MCH 32.8 pg), mildly elevated liver enzymes (AST 177 U/L, ALT 166 U/L, GGT 471 U/L), elevated acute-phase reactants (CRP 58 mg/L), and increased LDH levels (483 U/L). Renal function was preserved. Autoimmune studies including ANA by indirect immunofluorescence, anticardiolipin antibodies, and anti-β2-glycoprotein IgG and IgM were within normal limits.

Abdominal ultrasound showed a normal liver, a distended gallbladder with biliary sludge, hilar lymphadenopathy, and splenomegaly. Abdominal computed tomography revealed visceromegaly, gallbladder distension, splenomegaly, and multiple retroperitoneal and mesenteric lymphadenopathies. Chest computed tomography demonstrated bilateral axillary lymphadenopathy.

As part of a multidisciplinary approach, the patient was evaluated by the Pediatric Hematology service due to bicytopenia. Peripheral blood smear revealed atypical lymphocytes, activated lymphocytes, segmented neutrophils with toxic granulations, and an absolute neutrophil count of 1,280/µL. Based on these findings, a bone marrow aspirate was performed, showing a hypercellular and heterogeneous marrow with megakaryocytes, hemophagocytosis (++), plasma cells, and adequate maturation of the erythroid and myeloid lineages (Figures 1 and 2). Bone marrow culture was positive for Salmonella spp.

In the context of persistent fever and evidence of hemophagocytosis on bone marrow aspirate, secondary hemophagocytic lymphohistiocytosis due to Leptospira/Salmonella coinfection was suspected. The patient fulfilled six diagnostic criteria for HLH: fever, splenomegaly, bicytopenia (leukopenia and anemia), hypofibrinogenemia (<1.5 g/L; value: 100 mg/dL), hyperferritinemia (>500 µg/L; value: 1,250 ng/L), and hemophagocytosis in bone marrow. Other conditions such as HIV infection, hepatitis A and B, cytomegalovirus, Epstein Barr virus infection, and tuberculosis were ruled out.

Treatment following the HLH-2004 protocol was initiated, consisting of dexamethasone at a dose of 10 mg/m²/day for two weeks, followed by gradual tapering every two weeks. The patient became afebrile within 72 hours of treatment initiation and completed 14 days of hospitalization with favorable clinical evolution, no complications, and normalization of laboratory parameters, including acute-phase reactants and organ function. The patient was discharged with a tapering corticosteroid regimen and scheduled for outpatient follow-up.

Figure 1: Bone marrow aspirate image demonstrating hemophagocytosis.

Figure 2: Bone marrow aspirate image showing a macrophage phagocytosing a blood cell.

Secondary hemophagocytic lymphohistiocytosis (HLH) triggered by bacterial infections is an uncommon entity in the pediatric population. Over time, several bacterial pathogens have been identified as being commonly associated with the development of HLH, including Mycobacterium tuberculosis, Salmonella typhi, Rickettsia spp., and Brucella spp. These microorganisms induce an immune-mediated cytotoxic response driven by Th1 lymphocytes, leading to activation of natural killer (NK) cells and macrophages, which in turn release proinflammatory cytokines responsible for the systemic hyperinflammatory state that characterizes the pathophysiology of this disease [5].

Lepe-Zuniga in a study published in Mexico in 2020, identified Salmonella infection as a cause of HLH in a small proportion of cases, reporting 3 patients out of a cohort of 31, with Epstein–Barr virus (EBV) infection being the most frequently implicated pathogen [5]. These findings are consistent with other studies that establish EBV as the leading causative agent of HLH [3]. However, we found no bibliographic references or published case reports describing Leptospira infection as a causative factor of HLH, nor reports addressing bacterial coinfection as a predisposing infectious condition for this syndrome.

Although Theran-Leon reported a case of pulmonary aspergillosis and chronic granulomatous disease coinfection in a patient diagnosed with HLH [6], this scenario differs from our case, as our patient was previously healthy. The initial clinical manifestations in our patient were nonspecific and were initially attributed to leptospirosis; however, despite pathogen-directed therapy, no clinical improvement was observed, and fever persisted for 21 days. This clinical course prompted an expanded evaluation for fever of unknown origin.

As described by Galan-Gomez persistent fever lasting more than 19 days in association with elevated inflammatory markers justifies initiating a diagnostic workup for HLH [8]. In this context, and upon fulfilling the diagnostic criteria established by the Study Group of the Histiocyte Society in the HLH-2004 protocol [5], including the presence of hemophagocytosis on bone marrow aspirate (Figures 1 and 2), a definitive diagnosis was established and treatment was initiated. This aligns with the findings of García- Tevera et al., who emphasize that HLH diagnosis is often complex and delayed [6]; in our case, the diagnosis was established during the third week after symptom onset.

Once HLH is diagnosed, immediate initiation of therapy is essential to suppress the hyperinflammatory state, eliminate antigen-presenting cells involved in the infection, and reduce ongoing antigenic stimulation [9]. As stated in multiple treatment guidelines, immunosuppression constitutes the cornerstone of specific therapy, as the prognosis without treatment is fatal [8].

In this case, first-line treatment with dexamethasone, as recommended by the Histiocyte Society HLH-2004 protocol, was administered in conjunction with targeted antimicrobial therapy for both identified bacterial pathogens. Clinical improvement was observed within 72 hours of treatment initiation. Under these circumstances, etoposide was not included in the therapeutic regimen, primarily due to elevated liver enzymes at diagnosis and the documented favorable response to corticosteroid monotherapy. This approach contrasts with a case series published in Spain in 2016 by Hernandez-Jimenez et al., which highlighted the use of corticosteroid monotherapy in 16 of 18 patients, with limited use of etoposide and cyclosporine in only 2 of 18 cases [9]. Although an associated mortality rate of 40% was reported in that series, deaths were attributed to underlying neoplastic conditions, which were not present in our case [10-18].

Given the favorable response to both antimicrobial therapy and corticosteroid monotherapy, bacterial coinfection was identified as the triggering factor for HLH in this patient.

Although secondary HLH due to bacterial infections is rare in the pediatric population, it may be triggered by uncommon coinfections such as leptospirosis and salmonellosis, adding diagnostic complexity. Early recognition and timely initiation of appropriate treatment are key determinants in preventing severe complications, reducing mortality, and preserving both short- and long-term quality of life.

Vargas Caiza: Preparation of original drafts. Delgado Macias: Writing – conceptualization. Ramirez Ruiz and Campoverde Coronel: Review and validation.

Ethical Statement

This clinical case is presented anonymously, ensuring protection of the patient’s identity and confidentiality. Informed consent was obtained from the patient’s legal representative, and the right to privacy was respected at all times.

Data Availability Statement

The data are not publicly available due to patient confidentiality but may be made available upon reasonable academic request to the corresponding author.

Conflict of Interest

The authors declare no conflicts of interest.

Funding

The authors received no financial support for the conduct of this study.

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