Ctla4 Variant of Uncertain Significance in a Patient with a History of Cytopenias

Introduction: CTLA-4 haploinsufficiency is caused by heterozygous mutations in CTLA4, a negative regulator of immune responses. Hypogammaglobulinemia, infections, and autoimmune cytopenias can be seen. Here, we describe a patient with history of ITP who presented with neutropenic fever, lymphopenia, and hypogammaglobulinemia in the setting of COVID-19 with a VUS in CTLA4. Case Description: The patient is a 24-year-old female diagnosed with ITP at 10-years-old, initially treated with IVIG/steroids, then on mycophenolate for 6-years. 5-years later, she had a relapse of ITP in the setting of viral illness, requiring steroids/IVIG/rituximab. She developed neutropenic fever, unresponsive to GCSF, but responsive to cyclosporine and was noted to have a LGL clone. At 24-years-old, she was admitted with neutropenic fever (ANC 0);adenovirus, parainfluenza-virus, and SARS-CoV-2 were positive. Immunology was consulted due to hypogammaglobulinemia (IgG 140, IgA 7, IgM <5 mg/dL). Prior genetic testing identified a missense VUS in CTLA4 c.370A>C (P.Thr124Pro), shown to affect CTLA4 function and observed in individuals with clinical features of CTLA-4 haploinsufficiency. Lymphopenia, absent lymphocyte antigen responses, and impaired vaccine immunity were noted. ANC improved with GCSF. The patient was discharged with immunology follow-up for consideration of abatacept. Discussion(s): This case highlights the importance of considering VUS in the diagnosis and treatment of primary immunodeficiency. Our patient had a history of recurrent ITP, neutropenia, and LGL clone, all likely manifestations of CTLA-4 haploinsufficiency. Subsequent recognition of hypogammaglobulinemia and lymphopenia in the setting of neutropenia supported the diagnosis. Abatacept replaces the missing CTLA4-protein and should be considered in patients with CTLA-4 haploinsufficiency presenting with cytopenias. Copyright © 2022

Rare Case of Homozygous Ifnar1 Deficiency in a Samoan Child with Disseminated Varicella after Vaccination

Introduction: Autosomal recessive interferon alpha/beta receptor 1 (IFNAR1) deficiency increases susceptibility to live-attenuated vaccines and wild-type viruses. Currently 16 cases, half with Polynesian ancestry have been reported since the discovery in 2019. Most cases present with severe MMR or yellow fever vaccine-related disease. Some cases report severe SARS-CoV-2, herpes simplex, and enterovirus. Varicella vaccine-related disease has been hypothesized but not previously reported. Case Description: A pediatric Samoan girl with congenital cardiac anomaly, otherwise healthy until receiving Varicella and MMR vaccines at 12 months. Two weeks later with presumed incomplete Kawasaki Disease with 10-day fever, red lips, and maculopapular rash, given IVIG and infliximab;also, positive SARS-CoV-2 PCR and IgG that admission. Developed diffuse vesicular rash 3 weeks after vaccination requiring re-admission for disseminated varicella. At 14 months, admitted again for acute respiratory failure with viral pericarditis, positive for rhinovirus/enterovirus on respiratory viral panel and varicella serum PCR. Samoan parents are first-degree cousins and her stillborn sister had significant homozygosity on genetic evaluation. Normal lymphocyte subsets, normal mitogen proliferation, absent antigen proliferation in vitro, and normal NK function. Intact humoral immunity. Primary immunodeficiency disease panel identified homozygous pathogenic variant in IFNAR1. Future live viral vaccines contraindicated. Managed with acyclovir with return to baseline. Discussion(s): This case demonstrates a novel finding of homozygous IFNAR1 deficiency predisposing to disseminated varicella after vaccination. TNF inhibition may have also contributed. IFNAR1 deficiency should be considered in patients with severe varicella or other severe viral illnesses, especially after live-attenuated viral vaccines in those of Polynesian ancestry. Copyright © 2022

Change from transrectal to transperineal ultrasound-guided prostate biopsy under local anaesthetic eliminates sepsis as a complication.

Transrectal ultrasound-guided (TRUS) biopsy of the prostate is associated with increased risk of post-procedural sepsis with associated morbidity, mortality, re-admission to hospital, and increased healthcare costs. In the study institution, active surveillance of post-procedural infection complications is performed by clinical nurse specialists for prostate cancer under the guidance of the infection prevention and control team. To protect hospital services for acute medical admissions related to the coronavirus disease 2019 (COVID-19) pandemic, TRUS biopsy services were reduced nationally, with exceptions only for those patients at high risk of prostate cancer. In the study institution, this change prompted a complete move to transperineal (TP) prostate biopsy performed in outpatients under local anaesthetic. TP biopsies eliminated the risk of post-procedural sepsis and, consequently, sepsis-related admission while maintaining a service for prostate cancer diagnosis during the COVID-19 pandemic.