Roxane Labrosse’s research while affiliated with CHU Sainte-Justine and other places

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.

Background: Rituximab is a chimeric monoclonal antibody used in various pathologies involving CD20-positive cells. While it is usually well tolerated, infusion-related reactions are frequent but usually mild. Severe reactions such as anaphylaxis and serum sickness nevertheless can occur. Rituximab-induced serum sickness (RISS) is a rare delayed hypersensitivity reaction that may be unrecognized, as it can be confused with severe infection or in some circumstances with primary disease flare-up. We aim to extend our knowledge about severe infusion related reactions to rituximab in children, focusing on RISS and anaphylaxis. Objectives: Our study objective was to study severe reactions to rituximab by evaluating all children and adolescents who received rituximab in our center. Methods: Children and adolescents who received rituximab between 2014 and 2021 at CHU Sainte-Justine, a tertiary and leading pediatric center in Quebec, Canada, were included in the study. Data was collected retrospectively from our electronic medical records in CHU Ste-Justine. The diagnostic criteria proposed by the World Allergy Organization in 2020 were used to classify patients in the anaphylaxis subgroup. Patients with RISS were included if they developed fever and at least rash and/or arthralgia, starting 1 to 30 days following rituximab infusion, and if no other confirmed diagnosis explained symptoms. The study was approved by local Institutional Review Board. Results and discussion: 1534 rituximab infusions in 391 patients were analyzed. A severe infusion reaction to rituximab occurred in 14 patients (3.6%); none resulted in death. Rituximab was prescribed for an auto-immune disease in 61% of cases. Seven patients presented with RISS (1.8%); all were treated for an auto-immune disease including 4 for immune thrombocytopenia (ITP). Mean time from rituximab to RISS was 9 days (ranging from 6 to 12 days). All RISS patients but one presented with the classical triad of fever, rash and arthralgia. Increased C-reactive protein or sedimentation rate was documented in all patients, and decreased complement in 83%. Three patients required admission to intensive care unit due to hemodynamic instability. Patients received corticosteroids and/or intravenous immunoglobulins; mean duration of RISS was 4 days (ranging from 3 to 6 days). Rituximab was reinfused after RISS in one patient; she presented an immediate anaphylactoid reaction after which rituximab was permanently discontinued. Patients who received lower doses of rituximab were less likely to present RISS compared to patients who received higher doses (risk ratio 0.14, CI 0.03-0.74, p=0.016). Although few ITP patients developed RISS, RISS was associated with a greater chance of achieving partial or complete ITP remission (risk ratio 3, CI 1.47-6.14, p=0.033). Such possible association was not observed in other diseases. Seven patients developed severe anaphylaxis (1.8%), 3 of them reacted after the first dose (42.8%). Five of them were able to receive further rituximab infusion, using desensitization protocols. Conclusion: RISS is a rare hypersensitivity reaction in children. To this day, our study is the first to report more than 3 patients in a pediatric setting. RISS in children seems to be more frequent when rituximab is administered for an autoimmune condition, especially ITP. Although the classic triad of fever, rash and arthralgia appears more frequent in children than in adults, RISS should be considered in the differential diagnosis of any suggestive symptom developing within 30 days of infusion. Presence of biological inflammation and/or low serum complement can further support the diagnosis. In all patients, evolution was favorable within a few days with steroids. However, in contrast with anaphylaxis, RISS should be considered as a contraindication for further rituximab therapy.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplant for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase I/II clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral (SIN-LV) vector expressing the human WAS cDNA under the control of a 1.6kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All subjects were alive and well with sustained multi-lineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections and bleeding diathesis was universal. Immune function was consistently improved despite sub-physiological levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity post-GT, despite similar percentages of WASp-expressing cells and gene marking as those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), IL-10 producing regulatory B cells (Bregs), and transitional B cells. Recovery of the Breg compartment, along with Tregs, thus appears to be protective against development of autoimmunity post-GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered with ClinicalTrials.gov (NCT01410825).

Rituximab is used for a number of indications in pediatric nephrology, including the prevention of relapse in steroid-dependent nephrotic syndrome (SDNS). Clinical efficacy of rituximab is dependent on B-cell depletion, delayed reconstitution of B cells is protective of relapse in SDNS [1], and repeat courses of rituximab for SDNS or calcineurin inhibitor–dependent nephrotic syndrome decreases the risk of relapse [2], but may increase the risk of rituximab-associated adverse effects including hypogammaglobulinemia and infusion reactions [3]. In children, duration of B-cell depletion is highly variable across individuals [4]. It would therefore be helpful to predict the duration of B-cell depletion and, thus, optimize the administration scheme. However, the reasons for prolonged B-cell depletion after rituximab therapy are understudied. In this retrospective study, we included all patients followed in pediatric nephrology at CHU Sainte-Justine who were treated with rituximab between March 2006 and July 2022 for nephrological indication. We used the term “infusion” for each infusion of rituximab, and the term “course” for each course of treatment which can consist of one to four infusions over a period of 1–4 weeks. We collected clinical data from the medical record, including age, sex, body surface area, indication, and doses and dates of rituximab treatment and concomitant immunosuppressive medications. Peripheral blood immunophenotyping was routinely assessed at repeated occasions after rituximab courses, allowing estimation of the duration of B-cell depletion which was defined as the time between the last rituximab infusion of the course and the first detection of CD20⁺ cells in the peripheral blood. Descriptive characteristics are shown as medians [interquartile range (IQR)] or n (%) and were compared using a Mann–Whitney U test or a Fisher’s exact test. Probabilities of maintaining CD20⁺ cells depletion were calculated using the Kaplan–Meier method, and hazard ratios (HR) with 95% confidence intervals (95% CI) were calculated using a Cox proportional hazards models with mixed effects, using patient ID as a random effect, which was performed unadjusted and with adjustment for rituximab dose as a fixed effect. The Cox proportional hazards assumption was met. Analyses were performed using the survival and the coxme packages of R version 3.6.3. Ethical approval for chart review was obtained from the Sainte Justine Hospital ethical research committee (approval number 2020-2729). Patient consent was not required for this study.