Onset of Hemophagocytic Lymphohistiocytosis during Piperacillin-Tazobactam Therapy in Three Children with Acute Focal Bacterial Nephritis

Abstract

Hemophagoytic lymphohistiocytosis (HLH) is a rare life-threatening disorder caused by overactivation of the immune system, associated with infections, autoimmune disorders, and malignancies. The pathological hallmark of HLH is phagocytosis of blood cells and platelets by activated macrophages and histiocytes. In this report, we describe the onset of HLH in three children, aged 2, 5 and 7 years old, during the treatment of acute focal bacterial nephritis (AFBN) with an antibiotic, piperacillin-tazobactam (PIPC-TAZ). AFBN is acute localized bacterial infection of the kidney without abscess formation. PIPC-TAZ was chosen for the treatment of AFBN, because it not only has indications for complicated urinary tract infections, but also covers most of the causative bacteria of urinary tract infections, including β-lactamase-producing Escherichia coli. The clinical courses of the three patients were similar, and they were treated with PIPC-TAZ and amikacin (AMK) for AFBN. Fever went down 2 to 5 days later, and AMK was discontinued by day 6. However, fever recurred on 13 to 15 days after introduction of PIPC-TAZ therapy, even though all of the patients had no signs of recurrence of AFBN. The clinical features and laboratory tests of two patients fulfilled the criteria of HLH, whereas the other patient had initiated therapy before fulfilling the criteria. Cessation of PIPC-TAZ combined with corticosteroid therapy improved clinical symptoms. HLH of our patients was probably induced by PIPC-TAZ, as judged by the timing of the onset of HLH and the positivity of the drug-lymphocyte stimulation test. In conclusion, prolonged antibiotic therapy with PIPC-TAZ could be a cause of HLH.

Haemophagocytic lymphohistiocytosis (HLH) in an adult following treatment with trimethoprim/sulfamethoxazole

“…There is support that medication-induced HLH is related to a drug hypersensitivity reaction and prior reports have noted similarities with DRESS. However, eosinophilia is not seen in HLH and excessive CD8+T cell activation or haemophagocytosis would not be expected in DRESS 12. Prior case reports have noted quick response to therapy and relatively favourable outcomes in medication-induced HLH in comparison to more common aetiologies of HLH syndrome 10.…”

“…However, eosinophilia is not seen in HLH and excessive CD8+T cell activation or haemophagocytosis would not be expected in DRESS. 12 Prior case reports have noted quick response to therapy and relatively favourable outcomes in medication-induced HLH in comparison to more common aetiologies of HLH syndrome. 10 Our patient's rapid and lasting response to steroids alone may also be indicative of medication-induced HLH.…”

“…Medicationinduced HLH is a rare entity with few prior published case reports and even fewer associated with antibiotics. [8][9][10][11][12][13] The mechanism of the association between medications and HLH is unclear and there are no established guidelines for treatment of these patients. Patients with medication-induced HLH were not specifically included in the HLH-94 or HLH-2004 trials.…”

“…The causative agent for HLH in this patient was likely TMP/SMX given the time course from the offending agent, no use of other medications, no other significant medical history and no underlying malignancy or other systemic condition identified. Medication-induced HLH is a rare entity with few prior published case reports and even fewer associated with antibiotics 8–13. The mechanism of the association between medications and HLH is unclear and there are no established guidelines for treatment of these patients.…”