Successful Steroid Pulse Therapy in Suspected Immune Checkpoint Inhibitor–Associated Myocarditis With Isolated Troponin Elevation

Abstract

Background

The optimal timing and indications for corticosteroid therapy in patients with suspected immune checkpoint inhibitor (ICI)–associated myocarditis and isolated cardiac troponin (cTn) elevation remain unclear.

Case Summary

A 67-year-old man with recurrent esophageal cancer developed marked cTnI elevation (6,714 pg/mL) 3 weeks after the first nivolumab-ipilimumab cycle. The patient was asymptomatic but was suspected to have ICI-associated myocarditis. Steroid pulse therapy was promptly initiated, and after 5 days, cardiac magnetic resonance imaging confirmed myocarditis. His cTnI levels normalized within 2 weeks, and cardiac function was preserved.

Discussion

This case highlights the potential benefits of immediate steroid pulse therapy in asymptomatic patients with suspected ICI myocarditis. Treatment before diagnostic confirmation may prevent disease progression.

Take-Home Messages

Even in asymptomatic patients, early corticosteroid therapy should be considered for isolated cTn elevation suggesting ICI-associated myocarditis. Institutional awareness and preparedness for early intervention are crucial for effective allocation of short-term intensive medical resources.

Visual Summary

Visual Summary.

Summary of the Clinical Course

Numbers (1) through (8) indicate the chronological clinical course of a patient with suspected ICI-related myocarditis. CMR = cardiac magnetic resonance imaging; EMB = endomyocardial biopsy; ICI = immune checkpoint inhibitor; IPI = ipilimumab; irAEs = immune-related adverse events; LVEF = left ventricular ejection fraction; NIVO = nivolumab; NT-proBNP = N-terminal pro–B-type natriuretic peptide; PCR = polymerase chain reaction.

History of Presentation

A 67-year-old man with locally recurrent esophageal cancer and upper paraesophageal lymph node metastasis presented for a second administration of nivolumab, 3 weeks after initial combination therapy with nivolumab (360 mg/body) plus ipilimumab (1 mg/kg). Laboratory tests revealed a marked elevation in the cardiac troponin I (cTnI) levels to 6,714 pg/mL (Figure 1). On a standardized interview, he reported only mild fatigue without other symptoms. His body weight decreased by 1.0 kg after treatment initiation, reaching 56.3 kg at presentation. Vital signs were as follows: blood pressure 123/64 mm Hg, heart rate 92 beats/min, body temperature 36.5 °C, and oxygen saturation 96% on room air.

Take-Home Messages

• •Prompt high-dose corticosteroid pulse therapy was effective in a patient with suspected ICI-associated myocarditis who presented with isolated cardiac troponin elevation. However, the indications, optimal timing, and dosages of corticosteroids remain unclear.
• •Early detection and treatment necessitate short-term, intensive allocation of medical resources, along with institutional understanding and agreement regarding ICI-associated myocarditis.

Figure 1.

Trends in Cardiac Troponin I and Creatine Kinase

Day 1 indicates the first day of hospitalization. The upper horizontal dotted line represents the upper reference limit of CK and the lower horizontal dotted line represents the upper reference limit of cTnI. CK = creatine kinase; CMR = cardiac magnetic resonance imaging; cTnI = cardiac troponin I; EMB = endomyocardial biopsy; IPI = ipilimumab; NIVO = nivolumab.

Past Medical History

The patient had no comorbidities and was in good general health before the onset of symptoms. Four months earlier, he had completed chemoradiotherapy (4 cycles of 5-fluorouracil and cisplatin, with a total radiation dose of 60 Gy) but developed disease recurrence, for which nivolumab and ipilimumab combination therapy was initiated. Baseline cTnI and N-terminal pro–B-type natriuretic peptide levels immediately before therapy were <10 and 120 pg/mL, respectively.

Differential Diagnosis

Considerations included acute coronary syndrome, pulmonary embolism, and myocarditis, including COVID-19–related or immune checkpoint inhibitor (ICI)–associated myocarditis.

Investigations

On presentation, there were no clinical signs of heart failure, S3 gallops, pulmonary rales, peripheral edema, cold extremities, or diaphoresis. No ptosis, diplopia, dysarthria, or dysphagia was observed. Laboratory tests revealed a marked elevation in cTnI levels, whereas creatine kinase (CK) levels were within the normal range at 159 U/L (reference range: 59-248 U/L). Liver function tests revealed mildly elevated lactate dehydrogenase (252 U/L; reference range, 124-222 U/L) and alkaline phosphatase (130 U/L; reference range, 38-113 U/L) concentrations, with all other parameters within normal limits. The renal and thyroid function test results were normal. The C-reactive protein level was mildly elevated at 1.89 mg/dL (reference range: <0.14 mg/dL). COVID-19 infection was ruled out by polymerase chain reaction testing.

Electrocardiography revealed notching within the QRS complex in leads III and aVF, with no other abnormalities (Figure 2). Transthoracic echocardiography (TTE) revealed normal left ventricular wall motion and a left ventricular ejection fraction of 70% without pericardial effusion (Video 1, Video 2, Video 3, Video 4). Coronary computed tomography (CT) angiography revealed no significant stenosis or occlusion of the coronary arteries, excluding acute coronary syndrome. Chest CT excluded pulmonary embolism and pneumonia.

Figure 2.

Serial Electrocardiograms

Electrocardiograms obtained before immunotherapy (pre-IT, day –28), at onset (day 1), and after steroid pulse therapy (post-SPT, day 17). Heart rates were 91, 92, and 82 beats/min, respectively. Notchings within the QRS complexes (yellow arrows) were observed in leads III and aVF on days 1 and 17. IT = immunotherapy; SPT = steroid pulse therapy.

Treatment

The patient was informed that ICI-associated myocarditis was suspected, and therefore ICI therapy should be discontinued and high-dose corticosteroid therapy should be initiated immediately to suppress excessive immune activation. The possible adverse effects of corticosteroid pulse therapy were explained to the patient. Informed consent was obtained before admission to the general ward. High-dose intravenous methylprednisolone (1,000 mg/d) was administered on the day of admission. Serum cTnI levels decreased by approximately half the following day (Figure 1). During hospitalization, telemetry monitoring revealed occasional premature atrial and ventricular contractions without nonsustained ventricular tachycardia. The patient's heart rate was slightly elevated initially, but gradually normalized. Cardiac magnetic resonance imaging (CMR) performed on day 5 confirmed acute myocarditis (Figure 3). TTE performed on day 7 revealed preserved cardiac function with a left ventricular ejection fraction of 70%. As the hemodynamics remained stable, other cardioprotective medications were not administered. Endomyocardial biopsy (EMB) of the right ventricular septum was performed on day 11. Histopathological examination revealed subendocardial and interstitial fibrosis, without myocyte necrosis or degeneration. Mild lymphocytic infiltration was observed (Figure 4). The patient's N-terminal pro–B-type natriuretic peptide level on day 14 was 171 pg/mL. The corticosteroids were gradually tapered, and at discharge on day 20, the oral prednisolone dose was reduced to 40 mg/d.

Figure 3.

Cardiac Magnetic Resonance Imaging

(A) Fat-suppressed T2-weighted short-axis image shows high signal intensity in the inferior and septal walls, consistent with myocardial edema. (B and C) Late gadolinium enhancement short-axis image obtained 10 minutes after contrast administration shows enhancement in the inferior, septal, anteroseptal, and anterior subepicardial walls, consistent with myocarditis.

Figure 4.

Results of Endomyocardial Biopsy

(A to C) Subendocardial and interstitial fibrosis with thickening were observed on (A and B) hematoxylin and eosin staining and (C) Azan-Mallory staining. (D) CD3-positive, (E) CD4-positive, and (F) CD8-positive T cells were sparse, and no myocardial necrosis was observed. Programmed death–1 immunostaining showed no positive results. Original magnifications: (A) ×100, (B to F) ×200.

Outcome and Follow-Up

After 56 days of follow-up, oral prednisolone was tapered to 30 mg/d without re-elevation of cTnI levels. ICI therapy was not resumed, and no recurrence of myocarditis occurred during follow-up.

Discussion

Nivolumab and ipilimumab are monoclonal antibodies targeting the programmed cell death–1 receptor and cytotoxic T-lymphocyte–associated antigen 4 on T cells, respectively. They synergistically enhance T-cell activation and antitumor-immune responses by blocking inhibitory signals. Compared with chemotherapy, the combination of these 2 agents has been shown to prolong overall survival in patients with esophageal squamous cell carcinoma that is previously untreated and either unresectable, recurrent, or metastatic.¹ However, excessive immune activation can result in immune-related adverse events affecting various organs.² Among these, ICI-associated myocarditis is a rare condition, with an incidence of 1% to 2%, yet it carries a high mortality rate. Its clinical presentation is often nonspecific, ranging from asymptomatic troponin elevation to fulminant heart failure or cardiogenic shock, and it may occasionally overlap with other immune-related adverse events such as myositis, myasthenia gravis, or hepatitis.2, 3, 4

On the first day of presentation (Figure 1), our patient exhibited a substantial elevation in cTnI levels but reported no symptoms or other abnormal findings. Although the diagnosis of ICI-associated myocarditis had not yet been confirmed, we advised the patient to discontinue immunotherapy, to be admitted immediately, and to initiate high-dose corticosteroid pulse therapy despite the potential adverse effects. Coronary CT performed on day 1 ruled out acute coronary syndrome, further supporting the suspicion of ICI-associated myocarditis. The halving of cTnI levels on day 2 strengthened this suspicion (Figure 1). CMR results on day 6 confirmed the diagnosis of ICI-associated myocarditis, consistent with the proposed cardio-oncology case definitions.⁵ Such short-term, intensive medical interventions require an institutional understanding and consensus regarding the importance of early detection and prompt treatment of ICI-associated myocarditis, which our institution has been striving to establish.

At the “possible” stage of ICI-associated myocarditis, immunotherapy should first be withheld after multidisciplinary discussion between the cardiology and oncology teams. However, corticosteroid therapy should not be routinely initiated in suspected cases. The current consensus suggests continuing the diagnostic evaluation and starting corticosteroids early only when symptoms worsen, cTn levels continue to increase, new electrocardiogram or TTE abnormalities emerge, or CMR shows evidence of myocarditis.⁶ In patients with suspected ICI-related myocarditis, early initiation of steroid pulse therapy should be considered when there are no clear contraindications, such as uncontrolled infection, gastrointestinal perforation, or poorly controlled diabetes. Furthermore, the initiation of corticosteroid therapy may preclude continuation of ICI treatment or eligibility for clinical trial enrollment; therefore, close consultation with oncologists is warranted.

To assess whether our patient's markedly elevated cTnI level (6,714 pg/mL) justified initiating corticosteroid therapy, we referred to the Franco-German prospective study of 42 patients with ICI-associated myocarditis.⁷ In that study, the ratio of peak cTnI within 72 hours to the upper reference limit had a median of 14 (IQR: 6-61) overall and 38 (IQR: 11-522) among 15 patients who experienced major adverse cardiotoxic events (MACE) such as heart failure hospitalization or cardiac death. The ratio in our case was 196 (6,714/34), corresponding to the MACE group. Therefore, we decided to prioritize prompt corticosteroid therapy while awaiting diagnostic confirmation.

Furthermore, a registry study by Nowatzke et al⁸ demonstrated that when coexisting coronary artery disease necessitates coronary intervention, delays in myocarditis treatment can worsen prognosis, supporting our decision for early steroid initiation. Regarding dosage, we referred to the registry data by Zhang et al³ showing that a “higher initial corticosteroid dose and earlier initiation were associated with improved cardiac outcomes,” as well as to the current guideline recommendations.⁷

We performed an EMB after the diagnosis of myocarditis had been confirmed by CMR and the patient had already responded well to corticosteroid therapy. This was because although the clinical course indicated ICI-related myocarditis with isolated elevation of cTnI, the subsequent trajectory of this case was unpredictable. We considered that obtaining histological information at this point would be valuable for future reference, should myocarditis recur or dilated cardiomyopathy develop, as it could provide a baseline for understanding the pathological progression in this patient. In addition, we were interested in understanding the pathophysiological features of the myocardium at this stage. An EMB performed on day 12 revealed interstitial and subendocardial fibrosis with minimal lymphocytic infiltration and no myocyte necrosis, corresponding to grade 1A (myocardial inflammation) according to the pathological classification by Palaskas et al.⁹ Since the biopsy was obtained after normalization of cTnI, these findings likely represent a recovery phase. Although focal necrosis at the unsampled sites cannot be ruled out, the mild elevation in CK levels suggests that no significant myocyte necrosis occurred. Taken together with the imaging findings, these results may reflect an ultra-early stage of ICI-associated myocarditis. The marked dissociation between cTn and CK levels in this case suggests that mechanisms other than overt necrosis, such as apoptosis, increased membrane permeability, or intracellular release of degradation products may have contributed to cTn elevation.¹⁰ Ongoing observation is warranted, as delayed apoptotic processes could still progress in seemingly intact myocardium.

Conclusions

We promptly administered high-dose corticosteroid pulse therapy to a patient with suspected ICI-associated myocarditis who presented with isolated cTn elevation. This favorable outcome supports the strategy of early detection and rapid intervention. However, the appropriateness, optimal timing, and dosing of corticosteroid therapy in such cases remain subjects for ongoing discussion.

Funding Support and Author Disclosures

Dr Takenouchi has received lecture fees from Bristol-Myers Squibb, MSD, and Ono Pharmaceuticals. Dr Tanaka has received lecture fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, and Ono Pharmaceutical and research funding from Amgen, AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Janssen Pharmaceutical, MSD, and Ono Pharmaceutical. Dr Inomata has received lecture fees from AstraZeneca and Ono Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Appendix

Video 1

Transthoracic Echocardiographic Findings: Parasternal Long-Axis View

Views in all 4 supplemental videos demonstrate normal cardiac structure and function, without wall motion abnormalities or pericardial effusion.

Video 2

Transthoracic Echocardiographic Findings: Parasternal Short-Axis View

Views in all 4 supplemental videos demonstrate normal cardiac structure and function, without wall motion abnormalities or pericardial effusion.

Video 3

Transthoracic Echocardiographic Findings: Apical 4-Chamber View

Views in all 4 supplemental videos demonstrate normal cardiac structure and function, without wall motion abnormalities or pericardial effusion.

Video 4

Transthoracic Echocardiographic Findings: Apical Long-Axis View

Views in all 4 supplemental videos demonstrate normal cardiac structure and function, without wall motion abnormalities or pericardial effusion.