D1.392 - Drug-Induced Hypersensitivity Syndrome Associated with β-Lactams and Hemophagocytic Lymphohistiocytosis: Overlapping Disorders or a Causal Relationship?

Background

Hemophagocytic lymphohistiocytosis (HLH) is a severe, potentially life-threatening hyperinflammatory syndrome, most commonly secondary to infections, malignancies, or autoimmune diseases, and only rarely drug-induced. Diagnosis is particularly challenging in patients with severe infections receiving prolonged antibiotic therapy due to clinical and laboratory overlap with sepsis and drug-induced hypersensitivity reactions. Beta-lactam antibiotics (BLA) have been exceptionally reported as potential triggers.

Case report

A 47-year-old man with type 1 diabetes mellitus was admitted for traumatic osteomyelitis of the first toe of the left foot. He was initially treated with amoxicillin–clavulanate, followed by ceftriaxone and cloxacillin, and subsequently piperacillin–tazobactam and cefazolin for approximately two weeks. During hospitalization, he developed fever, diarrhea, generalized non-pruritic maculopapular rash, behavioral changes, and progressive systemic deterioration. Clinical evaluation, laboratory tests, extensive microbiological studies, and bone marrow aspirate were performed. Diagnosis was established using the HLH-2004 criteria. Clinical and laboratory evolution after BLA withdrawal and initiation of systemic corticosteroids was assessed. A subsequent allergological work-up, including lymphocyte transformation tests (LTT) for BLA, was performed.

Results

Table 1 shows laboratory findigs during the evolution of HLH. Bone marrow aspirate revealed hypocellularity with intense macrophage activation and diffuse hemophagocytosis; malignancy and active infection were excluded. The patient fulfilled the required 5/8 HLH-2004 diagnostic criteria (fever, cytopenias, hypertriglyceridemia, hyperferritinemia, and hemophagocytosis), confirming secondary HLH. After discontinuation of beta-lactams and corticosteroid treatment, progressive clinical and laboratory improvement was observed. LTTs were positive for ceftriaxone and cefuroxime, and negative for cefazolin, piperacillin–tazobactam, and amoxicillin–clavulanate.

Conclusions

Drug-induced hypersensitivity reactions may trigger secondary HLH in patients with severe infections. Positive LTTs support a delayed T-cell–mediated mechanism, potentially sustaining immune activation and macrophage overactivation characteristic of HLH. Prolonged BLA exposure combined with infectious stimuli may precipitate an exaggerated immune response, suggesting an overlap between drug-induced hypersensitivity syndrome and HLH, or HLH as a severe consequence of hypersensitivity. Early recognition of drug-induced HLH and specialized allergological evaluation are essential to improve outcomes and guide future antibiotic therapy.