Age: 70.0
Sex: F
Vaccine: FLU3
Symptoms: Bone density decreased, Drug-induced liver injury, Fibrosis-4 index, Gamma-glutamyltransferase increased, Haematocrit normal
Clinical narrative: elevated liver enzymes; Initial information received on 10-Sep-2024 regarding an unsolicited valid courtesy serious case received from a physician.  This case involves a 70 years old female patient (80.4 kg) who experienced elevated liver enzymes after receiving vaccine Influenza Usp Trival A-B High Dose Subvirion Vaccine [Fluzone High Dose] (Cohort A).  The patient medical history, included pure motor hemiparesis (PMH) hypertension (HTN), sleep apnea, depression, cholecystectomy, gastroesophageal reflux disease (GERD), post menopause, sleep apnea related fatigue, bilateral knee osteoarthritis, hypercholesteremia. It was also reported that the patient had a history of osteoarthritis, obesity (body mass index (BMI) 30.0-30.9), and stimulant dependence. The stimulant was armodafinil which was prescribed for chronic fatigue associated with sleep apnea. As confirmed by reporter, the patient had no history of alcohol consumption, usage of illegal drugs or genetic liver diseases. History of hepatitis A/B/C was not confirmed. The patient admitted to poor diet with daily soda intake, alcohol consumption of one beer three times per week (also reported as 4 times per week). Per patient, habit of one beer three times a week had been going on for about a year but was seasonal based on the sports teams she likes and when they were playing. Previously she was able to lose 20 lbs with dietary changes (e.g. quit ice cream). In addition, the patient reported history of prior aspartate aminotransferase (AST) elevation when she was being screened for a clinical study 10 years ago, but she did not seek follow-up for causality of that value nor had the patient had a history of abnormal liver enzymes since. The patient did not take herbal supplements or teas, and never took antibiotics while in the study. The patient denied family history of liver disease. Medical history included also: fatty liver. Concomitant medications reported included pantoprazole, olmesartan medoxomil, vortioxetine hydrobromide, tozinameran, fish oil, armodafinil, ibuprofen, venlafaxine, amlodipine besilate/hydrochlorothiazide/olmesartan medoxomil.  Prior to event onset, the patient was allocated to Cohort A (Influenza Usp Trival A-B High Dose Subvirion Vaccine) and received the first dose with 0.7 ml dosage (one time dose), Suspension for injection in pre-filled syringe, intramuscularly on 26-MAY-2023 (unknown strength, batch number, expiry date, administration site) as influenza immunization. The patients last dose of study drug was on that day, approximately 7 days prior to event onset.   On 17-MAY-2023 (at screening), the patients laboratory data was as follows: alanine aminotransferase (ALT) 25 U/L (10-33), alkaline phosphatase (ALP) 123 U/L (30-115), aspartate aminotransferase (AST) 28 U/L (10-36), creatinine 0.8 mg/dL (0.7-1.4), follicle stimulating hormone 46.7 mIU/mL (1.7-21.5), total bilirubin 0.17 mg/dL (less than or equal to 1.1), hematocrit 44.9% (33.0-47.0), hemoglobin 14.1 g/dL (11.0-15.5), platelet count 289 x1000/uL(163-375), white blood cells 5.19 x1000/uL (3.70-11.00).   On 26-MAY-2023, anti-SARS-CoV-2 was positive. Laboratory results included: normal liver enzymes: alkaline phosphatase (ALP) (123), aspartate aminotransferase (AST) (28), alanine transaminase (ALT) (25), Bilirubin (0.17).  On 01-JUN-2023, DX dexa bone density axial study showed low bone density, FRAX fracture risk was not elevated.  On 02-JUN-2023, the patient experienced elevated liver enzymes (hepatic enzyme increased) (latency: 6 days), likely pointing to drug-induced liver injury (DILI) from vaccination. On that day, her laboratory data was as follows: ALT 193 U/L, elevated (10-33), ALP 401 U/L, elevated (30-115), AST 158 U/L, elevated (10-36), creatinine 0.8 mg/dL (0.7-1.4), total bilirubin 0.43 mg/dL (less than or equal to 1.1), hematocrit 44.2% (33.0-47.0), hemoglobin 13.7 g/dL (11.0-15.5), platelet count 251 x1000/uL (163-375), white blood cells 4.79 x1000/uL (3.70-11.00), partial thromboplastin time (PTT) 11.6, international normalized ratio (INR) 1.0.   No treatment was provided.  On 13-JUN-2023, the patient was contacted and reported no symptoms (no fever, loss of appetite, headache, fatigue, weight (wt) loss, abdominal (abd) pain, gastrointestinal (GI) symptoms, muscle ache, dark urine, pale stool).  On 15-JUN-2023, the patient was seen in clinic. Her physical examination was normal with no hepatomegaly or signs of liver disease. She also reported no local and systemic reactogenicity post investigational product (IP). She denied taking any analgesics, antipyretics, alcohol, herbal tea, other medications, or other potential causes of liver enzyme elevation. There was no history of travel. Her concomitant medications have not changed. On that day, she gave a history of prior AST elevation when she was being screened for a clinical study 10 years ago, but she did not seek followup for causality of that value nor had the patient had a history of abnormal liver enzymes since. She did not follow up with primary care. Subsequently, she had participated in other studies and has not been told of elevated AST. Repeat liver function test (LFT), hemoglobin/hematocrit (Hb/Hct) and platelets (Plt) were performed (results not provided). DILI was suspected at that time. Laboratory data on that day included ALT 55 and 129, ALP 369 and 410, AST 47 and 127, creatinine 0.8, total bilirubin 0.19 and GGT 1079.  Of note, the patient was still at risk for persistent and severe liver injury given that ALP remained greater than 3x upper limit normal (ULN) upon repeat. The patient was returning for reevaluation on 20- JUN-2023, and wanted to redraw her liver panel (AST, ALT, ALP, creatinine, bilirubin) as well as her complete blood count (CBC).  On 20-JUN-2023, the hepatitis Be antibody, hepatitis A IgM, hepatitis B surface antigen, and hepatitis C antibody were negative. The patient was not tested for Epstein-Barr virus (EBV) nor Cytomegalovirus (CMV). Laboratory tests showed ALT 129 U/L (high, reference range 10 - 33), AST 127 U/L (high, reference range 10 - 36), total bilirubin 0.41 mg/dl (reference range less or equal than 1.1), gamma glutamyl transferase 1079 U/L (high, reference range 5 - 32), albumin 4.2 g/dl (reference range 3.5 - 5.5), creatinine 0.9 mg/dl (reference range 0.7 - 1.4), alkaline phosphatase 410 U/L (high, reference range 30 - 115).  On 26-JUN-2023, lab results were as follows: ALT 59 U/L (high, reference range 10 - 33), AST 46 U/L (high, reference range 10 - 36), total bilirubin 0.23 mg/dl (reference range less or equal than 1.1), creatinine 1.1 mg/dl (reference range 0.7 - 1.4), alkaline phosphatase (ALP) 336 U/L (high, reference range 30 - 115), prothrombin time 11. 6 second (reference range 9. 4 - 12. 5), prothrombin time- international normalized ratio (INR) 1. 0 (reference range 0. 9 - 1. 1) and PTT 11.6. On 01-JUL-2023, right upper quadrant (RUQ) ultrasound (U/S) abdomen limited liver showed that the liver was echogenic suggesting fatty infiltration, no focal abnormalities were identified. Intrahepatic bile ducts were not dilated. Gallbladder had been removed, common bile duct 3.0 mm diameter, normal. Impression indicated hepatic steatosis (with comparison to ultrasounds from 20- JUN-2023 and 20-SEP-2018).  On 10-JUL-2023, during unscheduled laboratory tests results showed: ALT 91, AST 72, ALP 326. On 18-JUL-2023, during unscheduled laboratory tests results were following: ALT: 86, AST: 75, ALP: 333, GGT: 877 On 01-AUG-2023, during unscheduled laboratory tests results included: ALT: 47, AST: 47, ALP: 244. At the time of the report, the patient did not report any signs or symptoms. As of 01-AUG-2023 follow-up, the patient was still asymptomatic, but laboratory values continued to be elevated. On 31-AUG-2023, during unscheduled laboratory tests results showed: ALT: 26, AST: 32, ALP: 228. On 05-OCT-2023, during unscheduled laboratory tests results showed: ALT: 32, AST: 31, ALP: 246.  On an unknown day in NOV-2023, liver enzymes continued to trend down: ALP of 161, AST of 26, and ALT of 22. Acute viral hepatitis screening was unremarkable. Viral panel was negative, autoimmune, immunoglobulin negative  On 03-NOV-2023, hepatitis A virus (HAV) Ab, IgM (external), hepatitis B virus (HBV) Surface Ag, screen (external), HBV core Ab, IgM (external), hepatitis A Ab, total w/reflex IgM (external), antinuclear antibodies (ABS), indirect fluorescent antibody test (IFA) (external) were negative, hepatitis C virus (HCV) Ab (external) was non reactive. Immunoglobulin G (external) was of 890 mg/dl (586-1602) (negative), HBV surface Ab, Qn (external) of less than 3.1 mIU/mL (low) (immunity over 9.9). Fibrosis index based on 4 factors (FIB-4) was calculated 1.58, enhanced liver fibrosis (ELF) of 10.29, mid risk of advanced fibrosis.  On 09-NOV-2023, during unscheduled laboratory tests #9 results showed: ALT: 22, AST: 29, ALP: 154. As of 11-DEC-2023, liver enzymes had been down trending since initial liver insult in June 2023. The patient would continue to monitor liver enzymes though would consider liver biopsy in the future if liver enzymes do not normalize over the next few months.  On 08-FEB-2024, laboratory tests results included: alkaline phosphatase (ALP) (44-121 IU/l) 179 (H), aspartate aminotransferase (AST) (0-40 IU/l) 50 (H), alanine aminotransferase (ALT) (0-32 IU/l) 46 (H), gamma-glutamyl transferase (GGT) (0-60 IU/l) 368 (H), 5' nucleotidase (0-11 IU/l) 19 (H), antinuclear antibodies (abs) immunofluorescence assay (IFA) negative.  On 22-FEB-2024, visit diagnoses included: abnormal liver enzymes, elevated LFTs, abnormal results of liver function studies  Action taken: not applicable.  At time of reporting, the outcome was Not Recovered / Not Resolved for the event.  Seriousness Criteria: Medically significant.; Sender's Comments: Sanofi company comment for information received on 07-Oct-2024: This case involves a 70 years old female patient (80.4 kg) who experienced elevated liver enzymes after receiving vaccine Influenza Usp Trival A-B High Dose Subvirion Vaccine [Fluzone High Dose] (Cohort A). Further information regarding tolerance, allergic history, excluding alternative etiologies for the reported event are needed to fully assess this case. Based upon the reported information, the role of the individual suspect vaccine cannot be assessed.