A Case of Recurrent Myocarditis after COVID-19 Vaccination due to Acute Myeloid Leukemia.

A 25-year old male presented with chest pain and elevated troponin following COVID-19 vaccination. Despite initial response to nonsteroidal anti-inflammatory drugs, he developed a recurrent and relapsing course requiring multiple readmissions. Cardiac magnetic resonance imaging confirmed myocarditis. Due to progressing macrocytic anemia, he was eventually diagnosed with acute myeloid leukemia, thought to be the underlying cause of driver of his recurrent and persistent myocarditis.

Case Report

A 25-year old male presented with chest pain and elevated troponin following COVID-19 vaccination. Despite initial response to nonsteroidal anti-inflammatory drugs, he developed a recurrent and relapsing course requiring multiple readmissions. Cardiac magnetic resonance imaging confirmed myocarditis. Due to progressing macrocytic anemia, he was eventually diagnosed with acute myeloid leukemia, thought to be the underlying cause of driver of his recurrent and persistent myocarditis.

Initial Presentation with Myopericarditis (May 2021)

The patient was otherwise healthy with no allergies, history of vaccine complications, nor any personal or family history of any cardiac disease or malignancy. Seven days after his first dose of the COVID-19 vaccine (Pfizer-BioNTech) he developed chest tightness radiating to his arm and was diagnosed at a separate hospital with suspected vaccine-associated myopericarditis based on symptoms, timing, and elevated troponin (Table 1 ). COVID-19 nasopharyngeal PCR was negative. Echocardiogram was normal, and no further imaging was done. The case was reported to Health Canada. He was prescribed three months of colchicine and one month of aspirin, and the symptoms completely resolved after approximately three weeks of therapy.

Table 1

Biomarker trends.

	Troponin ng/L	ESR mm/hr	CRP mg/L	Hemoglobin g/L	MCV fL	Ferritin ug/L	Leukocytes x10E9/L
First presentation (May 19, 2021)	395	-	-	148	93	-	2.9
Myocarditis recurrence (July 20, 2021)	630	21	11	146	91.2	277	3.1
Readmission (September 26, 2021)	852	41	41	121	103.2	827	3.2
Chronic myocarditis (December 6, 2021)	232	45	19	102	114.5	714	3
Day 1 Induction chemotherapy (December 22, 2021)	11	-	-	88	115.7	-	4.1
Post-Induction chemotherapy (January 28, 2021)	15	-	-	124	96.9	-	7

Myopericarditis Recurrence (July 2021)

Eight weeks following the initiation of colchicine and approximately five weeks since last symptoms, he experienced recurrent chest pains, biochemical evidence of myopericarditis, and mild leukopenia (Table 1). Hemoglobin, platelets, and blood film were normal, and COVID-19 nasopharyngeal PCR was negative. Transthoracic echocardiogram (TTE) was normal. CMR showed reduced left ventricular ejection fraction (LVEF) of 47%, hyper-intense T2 signal, and multifocal subepicardial late gadolinium enhancement (LGE), mainly in the anterolateral wall (Figure 1 ). The native T1 mapping confirmed elevated T1 values in the mid and apical slices, confirming acute myocarditis (Supplemental Figure S1). Despite another 7-day course of high dose NSAIDs, chest pain persisted and biomarkers increased (Table 1). Although there are no treatment guidelines for COVID-19 vaccine-associated myopericarditis, case reviews have indicated that NSAIDs, with or without colchicine, are reasonable first-line options, with corticosteroids reserved for refractory cases.1 Guidelines recommend tapering corticosteroids slowly, especially as the dose approaches 15 mg, and only if asymptomatic with negative biomarkers.2 He was started on prednisone, with taper guided by outpatient Cardiology.

Figure 1

A (left) shows T2 weighted imaging showing increased signal intensity in patchy distribution in anterolateral wall. B (right) shows late gadolinium enhancement in anterolateral wall.

Diagnostic workup included computed tomography coronary angiogram, autoimmune serology with an extended antibody panel for myositis, testing for infectious causes, and urine toxicology screening. These tests revealed no alternative cause for myocarditis, and the patient was advised to avoid future COVID-19 mRNA vaccines based on the presumption that his myocarditis was vaccine-associated. At discharge he was asymptomatic with decreasing biomarkers.

Myocarditis Fails to Resolve and Anemia Develops (September 2021)

When prednisone was decreased to 5 mg chest pain recurred, biomarkers increased, and he was readmitted (Table 1). COVID-19 nasopharyngeal PCR was negative. Repeat CMR showed LVEF 42% with sub-epicardial and mid-myocardial LGE in the inferior, inferolateral, and, less prominently, anterolateral walls, again confirming myocarditis (Supplemental Figure S2). At this point endomyocardial biopsy (EMB) was discussed, but not performed since the relapse was felt to be related to the pace of prednisone taper and the presumed etiology was still the COVID-19 vaccine. Prednisone was increased to 30 mg with a more gradual taper guided by symptoms and biomarkers, which both improved at time of discharge (Table 1). A macrocytic anemia and elevated ferritin were new findings (Table 1). Thyroid stimulating hormone, reticulocytes, platelets, hemolytic panel, blood film, liver profile, hemochromatosis gene (HFE) testing were normal, and abdominal ultrasound showed no hepatosplenomegaly nor lymphadenopathy. The anemia and abnormal ferritin were therefore attributed to inflammation and/or myelosuppression from prolonged colchicine use. He was referred to outpatient Hematology for further investigation, including possible bone marrow biopsy should the abnormalities persist.

Chronic Myocarditis Leads to a New Diagnosis (December 2021)

With prednisone reduction to 15 mg, he was admitted with another recurrence of symptoms and elevated biomarkers (Table 1). COVID-19 nasopharyngeal PCR remained negative (December 6th and 9th). Hemoglobin had declined by approximately 20 points since the last admission and by >45 points since the initial diagnosis of myocarditis (Table 1). The combination of clinical and biochemical progression despite treatment raised concern for a primary hematologic disorder. A bone marrow biopsy was diagnostic for AML with 25% blasts. Cytogenetics, next generation sequencing, and genetic testing, including FLT3, JAK2, NPM1, TPMT, and KMT2A, showed wildtype, with a normal male karyotype . He was started on induction chemotherapy with 3+7 (daunorubicin and cytarabine) with gemtuzumab ozogamicin. The potential for cardiotoxicity with daunorubicin raised concerns that chemotherapy could worsen myocardial dysfunction, particularly if the etiology was solely vaccine-associated, so regular TTE follow up was recommended. Prior to induction chemotherapy he tested positive for COVID-19 on routine screening (December 21st, strain not typified), but was only mildly symptomatic. He received sotrovimab to prevent severe disease given his immunosuppression with only one dose of the COVID-19 vaccine. Following AML treatment the chest pain resolved, troponin normalized (Table 1), and repeat TTE was normal.

Discussion:

The key question in this case is the underlying etiology of myocarditis. Vaccine-associated myocarditis was the lead candidate in the differential diagnosis due to similarities to concurrent reports of adverse effects from mRNA COVID-19 vaccines in the medical literature and general media. We tried to remain wary of the risk for confirmation bias and availability heuristic in this context. Cases of COVID-19 vaccine-associated myopericarditis in Canada are consistently reported to have occurred more often in males, in those 12-29 years old, within a week of vaccination, and following the second dose.3 Symptoms generally begin within a week of vaccination, and disease has tended to be mild.1

The ongoing complexity of our patient’s course seemed unusual, and there are still no reports of recurrent vaccine-associated myopericarditis without a subsequent dose of COVID-19 vaccine. This prompted consideration of alternative causes. The working hypothesis of solely vaccine-associated myocarditis seemed unlikely when, in September 2021, clinical worsening was accompanied by new hematological changes. Our patient had hematologic lab abnormalities earlier in the course of his illness (Table 1), but these were mild, nonspecific, and originally attributed to systemic inflammation or colchicine-related myelosuppression. While AML is an established cause for myocarditis, it is rare. Only three cases in the literature describe initial myocarditis leading to the diagnosis of AML in adults.4,5,6 Those patients also presented with chest pain, elevated troponin, and imaging findings of myocarditis, but their initial bloodwork immediately raised suspicion for an acute myeloprofilerative disorder. In our described case, the hematologic abnormalities up until the time of the failed steroid taper (September 2021), were not deemed significant enough to perform a bone marrow biopsy (Table 1).

EMB was considered at this point, but not pursued for several reasons including improvement in symptoms after prednisone was increased and clinical suspicion of recurrence being treatment-driven, mildness of cardiac dysfunction without clinical heart failure, negative serologic autoimmune panels, and the plan for further hematologic investigations. Luk et al (2021) suggest performing EMB in suspected vaccine-associated myocarditis when another specific cause of myocarditis is being considered for which there is a disease-specific therapy, or if the patient is unstable or has unexpected deterioration despite usual care.1 There have been few biopsy-confirmed myocarditis cases in the pandemic, but reviews to date suggest EMB may be normal or nonspecific.1

The pathophysiology of COVID-19 vaccine-associated myocarditis is not well established. Thurner et al have suggested mRNA COVID-19 vaccines, like the COVID-19 virus itself, induce myocarditis through upregulation of cytokines, and in particular interleukin-1 (IL-1).7 IL-1 release is normally curbed by endogenous interleukin-1 receptor antagonist (IL-1Ra). A higher prevalence of autoantibodies targeting IL-1Ra were identified in 12 of 40 EMB-confirmed cases of myocarditis following mRNA COVID-19 vaccination.7 These antibodies against IL-1Ra suppressed IL-1Ra activity in vitro and appeared to lower IL-1RA levels in vivo, leading to the hypothesis that the COVID-19 mRNA vaccine causes myocardial damage by impairing the body’s innate moderation of IL-1, thus leading to unchecked inflammation.7 Similarly, abnormal clonal myeloid cells in AML release pro-inflammatory cytokines, typically IL-1.8 In addition, AML has been shown to specifically cause direct myocardial damage through leukemic infiltration, localized hemorrhage, or both, and is frequently subclinical.4,6 Our hypothesis remains that the COVID-19 mRNA vaccine acted as a trigger for myocarditis in the setting of immunologic dysfunction from occult leukemia, and subsequent progression to fulminant AML precipitated his recurrence and steroid resistance. The vaccine may have heightened an already dysregulated cytokine system, particularly with subclinical cardiac infiltration from yet-undetected abnormal myeloid cells. If so, this is the first reported case of vaccine-associated myocarditis recurring due to underlying AML. Similar to other case reports of myocarditis in AML, the patient’s symptoms and biomarkers resolved with chemotherapy, further supporting the theory that the malignancy was driving active cardiac inflammation at that time.4,5,6 This case highlights that recurrent and persistent disease in suspected COVID-19 vaccine-associated myopericarditis should prompt investigation for an alternative or concurrent inflammatory trigger.

This case also demonstrates the potential risk of restricting subsequent mRNA vaccine doses in patients with myopericarditis following COVID-19 vaccination. Our patient contracted COVID-19 and, while he managed to avoid complication, was high risk for severe infection due to immunosuppression and single vaccine dose. At present, Public Health Canada recommends that additional doses of a COVID-19 mRNA vaccine be deferred in individuals 12 years and older with a history of confirmed myocarditis after vaccination, but that they “may choose to receive another dose of vaccine after discussing the risk and benefit with their healthcare provider”.3 More data is needed to provide guidance to patients with a history of confirmed myopericarditis following vaccination.