Age: 67.0
Sex: F
Vaccine: COVID19, FLU4, PPV
Symptoms: Aplastic anaemia, Reticulocyte percentage
Clinical narrative: worsening aplastic anemia; Literature Report.  This literature marketed report has been received from the authors of a published literature article, titled as stated above, and refers to a 67-year-old female patient.  The patient's medical history included Hashimoto's thyroiditis. The patient's baseline complete blood count (CBC), performed 2 years before her index presentation, was normal, with white blood cell (WBC) count of 6.3 x10^3/microl, haemoglobin 13 g/dl, and platelet count 343 x10^3/microl.   On an unknown date, the patient received the two-dose of SARS-CoV-2 vaccine (Moderna) (dose, lot #, expiry date, route of administration and anatomical location were not provided) vaccination series, which she tolerated without significant immediate side effects. Two weeks after her second vaccination, she was first noted to have mild leukopenia and anaemia on routine laboratory studies, with CBC showing WBC 3.5 x10^3/microl, haemoglobin 11.9 g/dl, platelet count 171 x10^3/microl, neutrophil count 1761 cells/microl, and a normal differential. Four weeks later (and 6 weeks total after her vaccination sequence), she developed further mild reductions in WBC and platelet count, as well as mild neutropenia, with repeat CBC showing WBC 3.3 x10^3/microl, haemoglobin 11.9 g/dl, and platelet count 146 x10^3/microl, with 1284 neutrophils/microl. These persistent cytopenias prompted additional haematology evaluation, showing a weakly positive anti-nuclear antibody (ANA;1:80), normal thyroid function, negative hepatitis A/B viral serologies and no nutritional deficiencies (vitamin B12, folate). She was given a presumed diagnosis of autoimmune leukopenia and was recommended to undergo biannual blood count monitoring. She continued to be asymptomatic during this time.  Approximately 6 months after her SARS-CoV-2 vaccine series, she received a routine pneumococcal vaccine, polyvalent (23-valent) (PNEUMOVAX23) injection (dose, lot #, expiry date, route of administration and anatomical location were not provided) for prophylaxis followed by a seasonal influenza vaccine - influenza vaccine inact split 4v (FLUZONE HIGH DOSE QUADRIVALENT) (dose, lot #, expiry date, route of administration and anatomical location were not provided).   On an unknown date (reported as two weeks after receiving her influenza vaccination), she began experiencing pulsatile tinnitus, leading to a normal otologic work-up. Soon thereafter, approximately 1 month after her influenza vaccine, she began having visual disturbances, easy bruising, progressive dyspnea on exertion, and palpitations, despite having previously followed an active lifestyle; these prompted referrals to ophthalmology and cardiology. Eventually, her planned monitoring CBC was performed, revealing severe pancytopenia with WBC 1.8 x10^3/microl, haemoglobin, 4.5 g/dl, and platelet 3 x10^3/microl, with 310 neutrophils/microl, reticulocyte was 0.8%, and immature platelet fraction 2.6%. She was admitted to the hospital for transfusions and further evaluation. An extensive investigation of causes of pancytopenia was unrevealing, including normal iron studies, vitamin B12, and folate levels; unremarkable inflammatory markers with negative ANA; and negative infectious work-up for hepatitis B/C, human immunodeficiency virus, Epstein-Barr virus, cytomegalovirus and parvovirus B-19. A bone marrow biopsy revealed a hypocellular marrow (5%) with severe trilineage hypoplasia with a relative increase in lymphocytes, composed of CD3+ T-cells and CD20+ B-cells forming occasional clusters. CD34 immunostaining highlighted rare (<1%) blasts, with no morphologic or immunophenotypic evidence of myeloid or lymphoid neoplasms. Metaphase cytogenetics were normal, and single nucleotide polymorphism array analysis showed no evidence of a clonal process. Flow cytometry for paroxysmal nocturnal haemoglobinuria was also performed, revealing minor clones in monocyte (0.08%), neutrophil (0.65%), and red blood cell populations (0.02%). The patient was given a presumptive diagnosis of severe aplastic anaemia (SAA) and was treated with frontline immunosuppressive therapy with horse antithymocyte globulin, cyclosporine, and eltrombopag. She was continuing with cyclosporine, eltrombopag, and supportive transfusions, achieving transfusion independence and a near complete response 4 months after immunosuppressive therapy. The patient developed SAA in temporal proximity to a series of vaccinations.  The reporter considered the event to be related to the suspects as the prolonged time-course with multiple vaccines containing different antigens and adjuvants suggests that worsening SAA in this case was at least in part due to vaccine and/or adjuvant-induced non-specific immune stimulation.  Upon internal review, the event worsening aplastic anemia was determined to be medically significant.  A copy of the published article is attached as further documentation of the patient's experience.