Sex: F
Vaccine: COVID19
Symptoms: Computerised tomogram, Echocardiogram, Fibrin D dimer, HIV test, Heart rate
Clinical narrative: EPISODIC ATRIAL FLUTTER; PLEURAL EFFUSIONS (BILATERAL); PERICARDIAL EFFUSION; PERICARDITIS; This 59-year-old, female was participating in a Study and experienced pericardial effusion, pericarditis, pleural effusions (bilateral), and episodic atrial flutter.  The subject's medical history, as provided by the investigator, included migratory pains in joints of knees and legs, post menopause, knee replacement surgery (due to osteoarthritis), seasonal allergies, mild asthma, right knee arthritis, basal cell carcinoma nose and chest, Bell's palsy, migraine headaches, enlarged descending aorta, thoracic aorta ectasia, middle finger of left hand joint swelling, and droopy eyelids interfering with vision. Concomitant medications reported included naproxen, salbutamol, and fluticasone.  The patient was allocated to receive intramuscular mRNA-1273 or placebo for SARS-CoV-2 vaccination. The subject received the first dose of blinded study drug on 13 Aug 2020. The patient's last dose of study drug prior to event onset was on 10 Sep 2020.  On 15 Sep 2020, the patient experienced acute shortness of breath along with chest discomfort and visited the emergency room. Laboratory results included white blood cell (WBC) 10.4 K/uL (3.8-10.6), red blood cell count 4.79 M/uL (4.15-5.55), absolute monocytes 1.0 K/ul (0.00-0.80), potassium 3.4 mmol/l (3.5-5.0), blood urea nitrogen 28 mg/dl (10-25), quantitative D-dimer 1.01 ug/ml FEU (<0.59), troponin <18 ng/L (<19), prothrombin time (PT) 12.9 sec (12.1-14.5), and partial thromboplastin time (PTT) 33 seconds (22-36). Chest x-ray revealed no pneumothorax, pulmonary vasculature cardiac and mediastinal silhouettes were within normal limits, lungs were clear, osseous structures were intact, no evidence of pulmonary embolism or pericardial effusion with no acute process. The subject was discharged from the emergency room.  On 05 Oct 2020, the patient developed sinus congestion.  On 13 Oct 2020, the patient received Flublok RIV4 vaccination for influenza prophylaxis.  On 15 Nov 2020, the patient experienced chest heaviness and pain and also felt chest pressure when leaning forward.  She had a nausea spell and "passed out" after kneeling on the floor. The subject reported that her heart rate was between 84-117 beats per minute.  On 16 Nov 2020, the patient visited her primary care physician concerning the symptoms she had been experiencing (later diagnosed as medically significant events of pericardial effusion and pericarditis). Her heart rate was 114 beats per minute. She was referred to a cardiologist for additional work-up.  On 17 Nov 2020, computed tomography (CT) angiography scan showed stable minimal to mild dilatation of the ascending aorta and new small bilateral pleural effusions, left greater than right, and moderate pericardial effusion with diffuse pericardial enhancement; correlate for pericarditis.  On 18 Nov 2020, echocardiogram showed normal left ventricular ejection fraction of 60-65%, small pericardial effusion circumferentially around the entire heart with no evidence of cardiac tamponade. Etiology was suspected to be reactive (viral or inflammatory). Erythrocyte sedimentation rate (ESR) was 34 mm/hr (0-20). Treatment included high dose acetylsalicylic acid and colchicine.  On 23 Nov 2020, SARS-CoV-2 real time reverse transcription polymerase chain reaction testing was negative.  On 26 Nov 2020, the patient went the emergency room for chest pain, epigastric pain and rising fatigue. Episodic atrial flutter was noted, which was considered secondary to pericarditis. A CT showed no pulmonary embolism present, no lung consolidation, mild to moderate left and right-sided pleural effusions, underlying compressive atelectasis in the lungs and mild to moderate pericardial effusion present. Laboratory results included ESR 101 mm/hr, procalcitonin 0.38 ng/mL (<0.25), antinuclear antibodies were negative, platelets 492 k/uL (150-450), troponin <4, brain natriuretic peptide 112 pg/mL (<50), and WBC 20.0 K/uL. The subject was admitted to the hospital.  On 27 Nov 2020, echocardiogram showed improvement in the pericardial effusion. Relevant laboratory results included C-reactive protein 24.4 mg/dl (<0.5), WBC 14.3 k/uL, hemoglobin (Hgb) 10.8 g/dL (12-15), hematocrit (Hct) 32.9% (36-46), platelets 454, human immunodeficiency virus antigen and antibody testing was nonreactive, urine histoplasma antigen testing was negative, and blood cultures showed no growth. Respiratory virus panel polymerase chain reaction testing on a nasopharyngeal sample, which included adenovirus, respiratory syncytial virus, parainfluenza, coronavirus (excluding COVID-19), and influenza, was negative for all pathogens tested. Treatment with methocarbamol and paracetamol were started for pericarditis.  On 28 Nov 2020, free thyroxine was 1.05 ng/dl (0.61-1.44), thyroid stimulating hormone was 3.16 uIU/mL (0.45-5.33), PT was 16 sec, and PTT was 50 sec.  On 30 Nov 2020, laboratory results revealed WBC 9.6 k/uL, Hgb 10.7 g/dL, Hct 30.5% and platelets 474 K/uL. A left-side thoracentesis was performed, removing 450 mL of clear yellow fluid. Results of pleural fluid analyses were consistent with transudate and included cultures negative for bacteria and fungi, lactate dehydrogenase of 78 IU/L (<220) and protein of 3.3 g/dL (<8.3). Infectious disease was consulted and did not have a strong suspicion for infection. She was given ketorolac and prednisone for pericarditis.  On 01 Dec 2020, the patient was feeling better, sitting upright with no conversational dyspnea, on room air. She still had fatigue, but she was improving, overall. Vital signs included blood pressure 129/74 mmHg, pulse 67 beats per minute, temperature 36.4 degrees Celsius, respiratory rate 18 breaths per minute, and oxygen saturation 96%. The subject was discharged home in stable condition. The subject was treated with diphenhydramine. Treatment for the events continued on discharge included metoprolol tartrate for atrial flutter, colchicine and prednisone for pericarditis.  On 02 Dec 2020, she started low dose acetylsalicylic acid for pericarditis.  On 04 Dec 2020, during her post-hospitalization follow-up, atrial flutter was not observed. She was not reporting any shortness of breath or pleurodynia. Relevant laboratory results included WBC 14 K/uL, Hgb 11.7 g/dL, Hct 35.5%, platelets 555 K/uL, C-reactive protein 2.2 mg/dl, and ESR 49 mm/hr. Cardiology follow up was scheduled for 16 Dec 2020.  On 07 Dec 2020, the patient remained on a prednisone taper for pericarditis.  On 13 Jan 2021, the patient had a follow-up visit with cardiology. The patient had not experienced any symptoms related to atrial flutter since hospitalization but remained on metoprolol as a precaution. The cardiologist believed the irritation from the pericarditis caused the atrial flutter and that it had now resolved. There was no pericardial rub on exam, however she had occasional chest and upper abdominal pain that was likely related to the pericardial fluid. Prednisone tapering was continued. She was instructed to follow-up with rheumatology in Jan 2021 and cardiology again in Apr 2021.  On 18 Jan 2021, during a follow-up visit, the physician noted the subject remained with serositis (pericarditis and small bilateral pleural effusion).  On 22 Feb 2021, patient was weaned off prednisone. Subject was asymptomatic with no shortness of breath or chest pain. No pulmonology follow up appointment was scheduled.   Action taken with study drug in response to the events of pericardial effusion, pericarditis, pleural effusion (bilateral), and episodic atrial flutter, was not applicable, as the subject had already received both scheduled doses.  The events, pericardial effusion, pericarditis and pleural effusions (bilateral), were considered resolved on 22 Feb 2021. The event of episodic atrial flutter was considered resolved on 01 Dec 2020.   The investigator assessed the events, pericardial effusion, pericarditis, and pleural effusions (bilateral) as related to study drug, based on the timing of chest pain after the study dosing and diagnosis with etiology matching an inflammatory response. The event of episodic atrial flutter was assessed as not related to the study drug. The events of pericardial effusion, pericarditis, pleural effusion (bilateral), and episodic atrial flutter were assessed as not related to study procedure.  Follow-up information received on 02 Dec 2020 and 04 Dec 2020 included updated causality, seriousness criteria, severity, action taken, onset dates, hospital admission and discharge dates.  Follow-up information received on 07 Dec 2020, 08 Dec 2020, 10 Dec 2020 and 14 Dec 2020 included additional events of pleural effusions (bilateral) and episodic atrial flutter, event details and outcomes, updated action taken with study drug, investigator's rationale for causality assessment, additional lab results, and treatment medications.  Follow-up information received on 16 Dec 2020 included no new information.  Follow-up information received on 28 Dec 2020 included no new information.  Follow-up information received on 30 Dec 2020 included updated laboratory and diagnostic exam data.  Follow-up information received on 14 Jan 2021 included updated medical history, cardiologist follow-up information, and end date and outcome for event of episodic atrial flutter.  Follow-up information received on 02 Feb 2021 included updated outcomes for the events of pericardial effusion and pericarditis, updated severity for the event of pericarditis, updated treatment medications and updated event details.  Follow-up information received on 26 Feb 2021 included no new information.  Follow-up information received on 05 Mar 2021 and 09 Mar 2021 included updated event end date, event outcome, event details and additional medical history.  Follow-up information received on 06 Apr 2021 included final outcome and event end dated of the events, pericardial effusion and pericarditis.  Analysis of Similar Events: On 16-Dec-2020, the safety database was searched for events similar to Pericarditis, Pericardial effusion, and Pleural effusion using the following search criteria: PT: Pericarditis, Pericardial effusion, Pleural effusion; SMQ: Immune-mediated/autoimmune disorders (Broad/Narrow), Drug reaction with eosinophilia and systemic symptoms syndrome (Broad/Narrow), Haemodynamic oedema, effusions, and fluid overload.  As of 16-Dec-2020, under IND 019745 for mRNA-1273, the database search retrieved 44 events, including the three events in the current index case. Three of these events were previously submitted in IND Safety Reports: Angioedema (1) MOD-2020-000921, Swelling face (2) MOD-2020-000515, MOD-2020-000656. These three events were similar to one another, but differed from the index case, as all three events involved cosmetic dermal filler injections in the face and lips.  The following four events were similar in presentation but could be explained by other more likely etiologies: Pericarditis (3) MOD-2020-000302, MOD-2020-000643, MOD-2020-000811; and Pleural effusion (1) MOD-2020-000355. In MOD-2020-000811, pericarditis occurred 3 weeks after myocardial infarction; in MOD-2020-000302, the subject had a medical history significant for myocardial infarction; and in MOD-2020-000643 the subject had the relevant medical history of antiphospholipid syndrome and rheumatoid arthritis, suggesting autoimmune predisposition; In MOD-2020-000355, the subject developed pleural effusion after having undergone a recent coronary artery bypass graft procedure.  The following events were not similar in presentation, however, were reviewed per the database search strategy and were confirmed as more likely related to alternate etiologies: Angioedema (1) MOD-2020-000315: The event was determined to be due to lisinopril and resolved upon discontinuation of the medication. Swelling face (1) MOD-2020-000323: The subject had undergone a recent dental procedure on the side of swelling. Rash vesicular (1) and Rash (1) MOD-2020-000753: The events occurred 1.5 months after the second dose and recovered in a few days, which is unlikely suggestive of relationship with the study vaccination. Hepatic enzyme increased (2) MOD-2020-000753, MOD-2020-001140: The events occurred 1.5 and 3 months, respectively, after receiving the second study drug dose, which is unlikely suggestive of relationship with the study vaccination. Dermatitis bullous (1) MOD-2020-000325: This event occurred in a subject with chronic lymphocytic leukemia, exhibiting symptoms of disease progression.  The remainder of the events were not considered similar, as these could be explained by underlying etiologies related to infection or preexisting comorbidities: Acute kidney injury (5); Encephalopathy (1);  Oedema peripheral (1); Pancreatitis (1); Multiple organ dysfunction syndrome (1); Pancreatitis acute (1); Pneumonia (16);  and Thrombocytopenia (1).  Assessment of Relationship: Based on review of available data, the Sponsor cannot rule out a possible cause and effect relationship between administration of mRNA-1273 or placebo and the occurrence of pericardial effusion, pericarditis, and pleural effusion, considering acute shortness of breath, along with chest discomfort, five days following the second dose of study drug could possibly have represented the earliest manifestations of the reported events; however, no effusion was noted on CT at that time. Thus, the actual date of onset of the events remains unclear, as it is unknown whether the episode of shortness of breath with chest discomfort, five days after the second dose of IP is representing the first signs of onset of the events versus a later date. Concomitant Flubloc RIV4 vaccination and sinus congestion indicating possible viral infection, which both occurred a month before diagnosis of the events, and history of dilatation of the ascending aorta remain confounders. The event of episodic atrial flutter was considered unrelated to IP in agreement with the Investigator.  After review of the clinical details and investigator comments pertaining to this adverse event, and based upon experience to date, the Sponsor does not believe that changes to the conduct of this clinical trial are warranted. The Company will continue to monitor these, and other serious adverse events reported in association with the IMP and will communicate any relevant changes to the protocol, Informed Consent Form, Investigator's Brochure, and/or Core Safety Information.; Reporter's Comments: This case concerns a 59-year-old, White, female subject with a medical history of mild asthma, who experienced the unlisted events of pericardial effusion, pericarditis, pleural effusion, and episodic atrial flutter. The events of pericardial effusion, pericarditis, and pleural effusion were diagnosed two months and one week after the second dose of IP, and the event of episodic atrial flutter was diagnosed 2 months 17 days after the second dose of IP. The events of pericardial effusion, pericarditis, and pleural effusion were considered related to IP in agreement with the Investigator. Acute shortness of breath, along with chest discomfort, five days following the second dose of study drug might have been the earliest manifestations of the reported events; however, no effusion was noted on CT at that time. Thus, the actual date of onset of the events remains unclear, as it is unknown whether the episode of shortness of breath with chest discomfort, five days after the second dose of IP is representing the first signs of onset of the events versus a later date.  Concomitant Flublok RIV4 vaccination and sinus congestion indicating viral infection, which both occurred a month before diagnosis of the events, and history of dilatation of the ascending aorta remain confounders. The event of episodic atrial flutter was considered unrelated to IP in agreement with the Investigator.