Ledipasvir/Sofosbuvir Eradicates Hepatitis C in an Immunodeficient STAT3-GOF Patient

Abstract

To the Editor: We report on the successful eradication of hepatitis C virus (HCV) by direct-acting antiviral therapy (DAA) with Ledipasvir/Sofosbuvir in an immunodeficient 10-year-old girl with a pathogenic and symptomatic signal transducer and activator of transcription 3 gain of function (STAT3-GOF)-mutation. The girl was born at term as the second child of nonconsanguineous parents in Albania and had recurrent episodes of autoimmune-hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) since the age of 18 months. The initial AIHA/ITP episodes were treated primarily with repeated blood transfusions in her country of origin. Documentation of further initial clinical details including results of Coombs test or auto-antibody screenings remain unknown. At the age of 3 years, she experienced a prolonged episode of AIHA, for which she received multiple transfusions, but also required transient systemic immunosuppressive therapy (IST) with oral steroids. Results of a bone marrow puncture supported the diagnosis of AIHA/ITP. At this time, infectious disease screening identified for the first time an active HCV infection, without quantitative assessment. In the absence of other risk factors, and with her family having tested negative, the infection was most likely related to the previous blood transfusions, a common medical problem in Albania before centralized PCR testing was introduced in 2016 [1]. At the age of 5 years, the familymoved to Germany, and, at the age of 7 years, the girl presented to our center with another episode of ITP that had not responded to an intravenous immunoglobulin (IVIG) application (1 g/kg), in the local primary hospital. She displayed mild facial dysmorphic features, i.e., enlarged rotated ears, thin lip vermilion, bilateral epicanthus, squinting, and discrete brachydactyly. Furthermore, mild developmental delay of motor function and speech was recognized. Size (46th percentile) and weight (61st percentile) were normal for her age. Mild splenomegaly was noted on ultrasound, but the patient showed no peripheral lymphadenopathy. Peripheral blood and bone marrow were well compatible with ITP. Molecular cytogenetic evaluation of the bone marrow was without pathological findings. The girl had a positive direct Coombs test, but no active AIHA at this time. There was no history of susceptibility to infections. Immunological studies showed normal IgA and IgM levels. IgG levels and vaccination responses were not informative due to recent IVIG treatment. Immunophenotyping showed normal total lymphocyte and CD3+ T cell count. Yet naïve CD45RA+ T-cells and naïve B-cells were reduced. Activated CD4+ and CD8+ T-cells and CD21 low B-cells were expanded and NK-cell numbers were slightly reduced. For full details, see Table S1. Quantitative PCR revealed an HCV load of 4.7 × 10 IU/ml (Abbott®). Laboratory and sonographic liver studies showed normal liver function and anatomy. After repeated, yet again ineffective, IVIG administrations (3 × 1 g/kg), oral steroid therapy (prednisone 2 mg/kg/d) induced remission of ITP (Fig. 1). An inborn error of immunity (IEI) was assumed in the context of chronic bilinear autoimmune cytopenia, splenomegaly, and dysmorphic features. She was enrolled in our center’s AL-PID study and a genetic diagnosis of germline STAT3-GOF (c.373C>G; p.Gln125Glu) was established bywhole exome sequencing and analysis on a panel of 230 known IEI genes. A 17-year-old brother is clinically healthy. After genetic counseling, the family decided against mutation analysis of further familymembers. The patient’s missense mutation leads to increased transcription of STAT3 but does not change phosphorylation (data not shown) and was observed in another patient of our cohort and functionally analyzed within our AL-PID study [2]. * Carsten Speckmann [email protected]