Age: 58.0
Sex: M
Vaccine: FLUX
Symptoms: Cytomegalovirus test negative, Elliptocytosis hereditary, Epstein-Barr virus test negative, Glucose-6-phosphate dehydrogenase normal, Haemoglobin decreased
Clinical narrative: Acute on chronic hemolytic anemia secondary to influenza vaccine; This literature received on 03-Jan-2022 and concerned a 58-year-old male patient.   The patient's concurrent conditions included end-stage renal disease secondary to hypertension, hyperlipidaemia, diabetes mellitus type 2, low degree hyperbilirubinemia and hereditary elliptocytosis. The patient's past medical history included kidney transplantation (in 1994) and elliptocytes on red cell morphologic review (in 2004 and 2007), but he did not carry a formal diagnosis of any structural erythrocyte abnormality. The patient was in his routine state of health with stable allograft function. The patient's concomitant medications were not reported, and he denied any new medications, history of allergy, or any autoimmune disease.  On an unspecified date in Oct-2018, the patient was vaccinated with the influenza virus vaccine polyvalent (brand not specified; dose: 0.5 ml, route of administration: intramuscular, anatomical location: deltoid and: not reported) as part of routine health maintenance. The batch number was not reported.  On an unspecified date in 2018, three days after receiving influenza virus vaccine polyvalent, the patient presented with malaise, chills, fever (up to 101.6 F), and yellowish discoloration of eyes. Physical examination confirmed icteric sclerae. His labs were significant for hemoglobin of 12.5 g/dl (baseline hemoglobin 14.4 g/dl), total bilirubin 5.1 mg/dl, and mildly elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and blood alkaline phosphatase (ALP). Platelet count, serum creatinine, iron and ferritin were normal. Blood lactate dehydrogenase (LDH) was elevated and haptoglobin was very low with an elevated reticulocyte percentage of 4.2. Rapid flu test was negative for influenza A and B. The clinical picture and labs were suggestive of haemolytic anaemia post routine influenza vaccine. On further work-up, blood and urine culture, acute viral hepatitis panel (HAV, HBV, HCV), direct antiglobulin test (DAT)/Coombs test, Parvovirus B19, Epstein-Barr virus, and cytomegalovirus PCR were negative. Glucose-6-phosphate dehydrogenase (G6PD) levels and pyruvate kinase levels were within normal range. A right upper quadrant ultrasound demonstrated borderline hepatomegaly along with gallstones with no acute pathology. A peripheral blood smear was ordered during his acute hemolytic event and it demonstrated normochromic and normocytic red blood cells. However, there was significant anisopoikilocytosis with a predominance of elliptocytes suggestive of hereditary elliptocytosis. The patient was managed conservatively with supportive care. As he was in a compensated haemolytic state, he did not require any blood transfusion, no steroids or intravenous immunoglobulin were used. Folic acid supplementation was started. Avoidance of hemolysis causing drugs in the future was suggested.  On an unspecified date, on follow-up, the patient had mild persistent anemia, hemoglobin 13.1-13.5 mg/dl and resolving hyperbilirubinemia (bilirubin 1.9 mg/dl). Transaminitis resolved completely.   At the time of initial reporting, the patient was recovering from the event of 'hemolytic anemia'.  The reporter assessed the event of 'hemolytic anemia' as related to influenza virus vaccine polyvalent. The patient had an underlying hereditary elliptocytosis/ovalocytosis and was prone to chronic hemolysis due to diminished mechanical stability of the red blood cell membrane. Chronic low-degree persistent hyperbilirubinemia supported this diagnosis. In addition, the patient potentially developed an acute hemolytic insult from recent influenza vaccination. He was diagnosed with acute on chronic hemolytic anemia secondary to influenza vaccine with underlying hereditary elliptocytosis. A right upper quadrant ultrasound showed gallstones, which can be seen in patients with chronic hemolytic disorders (pigment stones), further supporting this diagnosis. In addition, the previously elevated bilirubin levels as well as prior noted elliptocytosis support this entity.(e concordant acute autoimmune hemolytic anemia (AIHA) diagnosis was supported by the development of hemolysis within a short time (3 days) after administration of influenza vaccine, absence of any new drug intake, and an extensive and negative work-up).  The event of 'hemolytic anemia' was considered to be medically significant by a Physician within Seqirus' Pharmacovigilance and Risk Management Department.   Influenza vaccination may infrequently set off an episode of AIHA. Exact etiopathogenesis of such an event is not clearly understood. Molecular mimicry and role of vaccine adjuvants and other constituents have been proposed. An underlying erythrocyte membrane defect may act as a risk factor. Patients who receive an influenza vaccine should be counselled and educated about reporting any unusual signs and symptoms experienced after the vaccination.  The literature reference is Autoimmune Hemolytic Anemia in a Renal Transplant Patient following Seasonal Influenza Vaccination. Case Reports in Hematology. 2019.   Company comment: A 58-year-old male patient was administered the suspect vaccine, influenza virus vaccine polyvalent. Three days later the patient presented with malaise, chills, fever, and yellowish discoloration of eyes. The clinical picture and labs were suggestive of haemolytic anaemia post routine influenza vaccine. A peripheral blood smear was ordered during his acute hemolytic event and it demonstrated normochromic and normocytic red blood cells. However, there was significant anisopoikilocytosis with a predominance of elliptocytes suggestive of hereditary elliptocytosis. A right upper quadrant ultrasound demonstrated borderline hepatomegaly along with gallstones with no acute pathology. The patient was diagnosed with acute on chronic hemolytic anemia secondary to influenza vaccine with underlying hereditary elliptocytosis. Reportedly, the patient had an underlying hereditary elliptocytosis/ovalocytosis and was prone to chronic hemolysis due to diminished mechanical stability of the red blood cell membrane. As per authors chronic low-degree persistent hyperbilirubinemia supported this diagnosis. A right upper quadrant ultrasound showed gallstones, which can be seen in patients with chronic hemolytic disorders (pigment stones), further supporting this diagnosis. Causal role of the suspect vaccine is assessed as possibly related based on all information provided.; Reporter's Comments: The patient was diagnosed with acute on chronic hemolytic anemia secondary to influenza vaccine with underlying hereditary elliptocytosis.; Sender's Comments: A 58-year-old male patient was administered the suspect vaccine, influenza virus vaccine polyvalent. Three days later the patient presented with malaise, chills, fever, and yellowish discoloration of eyes. The clinical picture and labs were suggestive of haemolytic anaemia post routine influenza vaccine. A peripheral blood smear was ordered during his acute hemolytic event and it demonstrated normochromic and normocytic red blood cells. However, there was significant anisopoikilocytosis with a predominance of elliptocytes suggestive of hereditary elliptocytosis. A right upper quadrant ultrasound demonstrated borderline hepatomegaly along with gallstones with no acute pathology. The patient was diagnosed with acute on chronic hemolytic anemia secondary to influenza vaccine with underlying hereditary elliptocytosis. Reportedly, the patient had an underlying hereditary elliptocytosis/ovalocytosis and was prone to chronic hemolysis due to diminished mechanical stability of the red blood cell membrane. As per authors chronic low-degree persistent hyperbilirubinemia supported this diagnosis. A right upper quadrant ultrasound showed gallstones, which can be seen in patients with chronic hemolytic disorders (pigment stones), further supporting this diagnosis. Causal role of the suspect vaccine is assessed as possibly related based on all information provided.