Sex: F
Vaccine: VARCEL
Symptoms: Rash vesicular, Retroperitoneal lymphadenopathy, Selective IgA immunodeficiency, Skin lesion, Splenomegaly
Clinical narrative: disseminated varicella zoster vaccine virus infection; Literature report:   This literature marketed report has been received from authors of a published article and refers to a 33-year-old female patient. Her concurrent conditions included a novel germline missense mutation in FAS death-domain, autoimmune lymphoproliferative syndrome and splenomegaly. The patient's medical history included pregnancy, child deliver, infectious mononucleosis and upper respiratory tract infection. On an unknown date, the patient was vaccinated with varicella virus vaccine live (manufacturer unknown) (formulation, dose, frequency, route of administration, lot # and expiration date were not reported) for prophylaxis. On an unknown date (reported as 2 weeks later), she developed a disseminated vesicular rash on trunk and extremities with 4050 non-synchronously evolving lesions.  The concern for varicella virus vaccine live (manufacturer unknown) strain disseminated infection and the persistent leucopenia led to an initial work-up, which revealed selective IgA deficiency and CD4 lymphopenia (111118 cells/microL). A presumed diagnosis of Idiopathic CD4 lymphopenia (ICL) was formulated, and she was referred for further evaluation. Imaging confirmed splenomegaly (17 cm cranio-caudal length) and revealed modest mesenteric and retroperitoneal adenopathy. Flow cytometric analysis of T-cell subpopulations confirmed CD4 lymphopenia (CD4 189 cells/microL), normal numbers of CD8 T cells (383 cells/microL), and an increased proportion and absolute number of CD3+TCRab+CD4-CD8-double negative T cells (DNT) (4.3%, 33 cells/microL). In addition, high proportion of cycling of CD4 T-cells and DNT (Ki67 12 and 42%, respectively) as well as increased PD-1 expression in CD4 T-cells (42%) were found. The proportion and absolute number of total B cells were within normal range (CD19+: 16.4%, 75 cells/microL). Total IgG levels were moderately elevated (1,716 mg/dL), IgM were within normal range (54 mg/dL), while IgA undetectable. Bone marrow biopsy showed scattered lymphocytic aggregates with prevalence of CD8+ cells, consistent with previously reported findings in bone marrow biopsy of patients with ALPS. Targeted NGS with custom target enrichment revealed a novel heterozygous missense variant in the death domain (NM_000043 c.719Tmore hanAp.M240K) of the FAS gene and was confirmed by direct Sanger sequencing. Functional characterization of the novel FAS genetic variant also included FAS-induced apoptosis and sensitivity to activation-induced-cell-death (AICD) assays on T cell blasts. A significant reduction of FAS-induced apoptosis was found in T cell blasts from the index patient at all concentration of crosslinking FAS antibody: at the highest concentration (1,000 mg/mL). Further immunological evaluation of the patient included measurement of plasma cytokines and showed an increased level of soluble FAS ligand (801 pg/mL, normal level  less than 200 pg/mL) and increased levels of Interleukin-18 (7,248 pg/mL). A definitive diagnosis of ALPS-FAS was formulated based in the 2010 revised diagnostic criteria as both required criteria were satisfied (chronic lymphadenopathy, splenomegaly, and increased TCRab+ DNT cells), in addition to one primary criterion (pathogenic germline mutation in FAS death domain). The outcome of the event was considered recovered/resolved as all lesions eventually crusted and resolved within 10 days from onset without any other clinical complications. The authors considered the event to be related to varicella virus vaccine live (manufacturer unknown).  Upon internal review, the event of vesicular rash on trunk and extremities was considered to be medically significant. A copy of the published article is attached as further documentation of the patient's experience.