Delayed B cell reconstitution and maturation with hypogammaglobulinemia in the setting of in utero exposure to rituximab

Abstract

A four-month-old female presented to the Immunology Clinic for second opinion of immune globulin replacement. She was born at 36 weeks gestation and was small for gestational age. Pregnancy was complicated by in utero exposure to Rituximab. Mom was diagnosed with Stage IV Diffuse large B cell lymphoma at approximately 12 weeks of pregnancy. Treatment for Stage IV Diffuse large B cell lymphoma included rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride. Rituximab was continued until 34 weeks gestation. Newborn SCID screen was negative. Flow cytometry on day of life 1 (Table 1) revealed normal T cell populations with undetectable CD19 B cells. IgG was 915 mg/dL, IgA < 5, and IgM < 5. Repeat flow cytometry and immunoglobulins at one month of life revealed: undetectable CD19 B cells, IgG 402 mg/dL. Following birth, she developed recurrent respiratory tract infections including PICU admission secondary to respiratory failure in the setting of adenovirus and human rhinovirus/enterovirus bronchiolitis. At two months of age, IgG decreased to 299 mg/dL and B cells were still undetectable. Prophylactic IVIG was started at 3 months of age. Repeat laboratory evaluation at 4 months of age revealed the following: IgG 510 mg/dL, IgA < 5, and IgM 39 mg/dL, and recovery of CD19 B cells at 1482/mm3. At 5 months of age, B cell phenotyping was performed which revealed low class switched memory B cells. In the setting of low class switched memory B cells, IVIG therapy was continued. Patient did well clinically while on IVIG therapy. Class switched memory B cells normalized at 16 months of age and IVIG was discontinued. Patient did well off IVIG therapy, and at 30-month follow-up, continued to do well without need for IVIG replacement.Table 1Laboratory Study TrendTestDay of life 11 month old2 months oldIVIG started at 3 months old4 months old5 months old16 months old30 months oldAbsolute CD3 cells/mcL Reference Range (1484–5327 cells/mcL)4,183NA5,6436,8895,2744,6323,030Absolute CD4 cells/mcL Reference Range (733–3181 cells/mcL)3,204NA4,4805,0583,8213,1051,850Absolute CD8 cells/mcL Reference Range (370–2555 cells/mcL)979NA1,1051,6571,3461,310999Absolute CD19 cells/mcL Reference Range (370–2306 cells/mcL)<1NA<11,4821,5761,603958Absolute CD16CD56 cells/mcL Reference Range (43–526 cells/mcL)223NA175262187434601IgG mg/dl Reference Range (295–1156 mg/dL)915402299510886626717IgA mg/dL Reference Range (27–246 mg/dL)<5<5<5<515<1<1IgM mg/dL Reference Range (37–184 mg/dL)<5<5<539555397CD27+IgM-IgDcells/mcL Reference Range (5.2–74.2 cells/mcL)NANANANA1.011.113.5In utero exposure of Rituximab can lead to temporary absence ofC19 B cells and transient hypogammaglobulinemia. Despite numeric B cell reconstitution, the maturation of B cells may lag behind. Comprehensive B cell immunophenotyping will help decipher the optimal duration of supplemental immunoglobulin therapy. Frequent monitoring of B cell numbers and immunoglobulins are important and can help guide decision in immune globulin replacement.