HLH-like Hypersensitivity Reaction Secondary to Prolonged Piperacillin/Tazobactam: A Case Series

Background Prolonged (>10 days) use of intravenous (IV) piperacillin/tazobactam has been associated with a risk of developing hemophagocytic lymphohistiocytosis (HLH) syndrome. However, clinical and biological descriptions of this rare complication are lacking in the literature, such as management guidelines. Objectives and Methods We describe a series of five children who presented with an HLH-like hypersensitivity reaction after prolonged use of IV piperacillin/tazobactam therapy between February 2024 and October 2024 in a single pediatric tertiary center. Results Five patients aged between 6 and 15 years received IV piperacillin/tazobactam for various bacterial infections. The reaction occurred between 7 and 19 days after the start of therapy. While initial infections were well controlled, all patients presented with a reoccurrence of high fever, malaise, and a maculopapular rash in 4 of them. All developed biological abnormalities with elevated ferritin (range: 913-124895 µg/L), LDH (range: 565-3130 U/L), liver enzymes (ALT range: 113-363 U/L), and severe neutropenia (range: 0.1-0.4 x 109/L). Eosinophils were normal in 4/5 and mildly elevated (0.8 x 109/L) in 1/5. Increased HLADR+ CD8+ T cell frequency was observed in 3/3 patients tested (range: 25-30%). Investigations for classical secondary HLH triggers were negative. Piperacillin/tazobactam discontinuation led to resolution of fever and associated symptoms within 24 hours in all patients. All biological features resolved within a few days. Only one child received a short course of steroids for severe pruritus and myalgia. One patient reported a similar reaction after a previous course of 14 days of piperacillin/tazobactam therapy, 1.5 years earlier. Four patients were evaluated in allergology: 1/4 reacted to intradermal testing for piperacillin/tazobactam. Patch tests and one dose provocation challenge were negative (tested in 4 and 2 patients, respectively). Conclusion We provide further evidence that prolonged use of IV piperacillin/tazobactam may be associated with hypersensitivity reactions reminiscent of HLH (although only 1/5 formally fulfilled HLH-2004 criteria). We propose the term of HLH-like hypersensitivity reactions. Usual allergy testing is not useful to the diagnosis. Spontaneous resolution of symptoms can be expected after discontinuation of piperacillin/tazobactam. Clinicians should be aware of this rare disorder to avoid overtreatment or unnecessary investigations.