Can exertional dyspnea be a symptom of myocarditis in a patient receiving immune‑checkpoint inhibitor therapy?

Can Dyspnea on Exertion Be a Symptom of Myocarditis in Patients on Immune Checkpoint Inhibitors?

Yes, exertional dyspnea is a recognized symptom of immune checkpoint inhibitor (ICI)-associated myocarditis and should prompt immediate cardiac evaluation, as this complication carries a 46% risk of major adverse cardiac events and can be fatal even when ejection fraction appears normal. 1, 2

Clinical Presentation of ICI-Associated Myocarditis

ICI-related myocarditis presents with nonspecific symptoms that make diagnosis challenging:

• Shortness of breath is one of the cardinal symptoms, occurring alongside chest pain, myalgia, and fatigue 1
• Symptoms can manifest as reduced exercise tolerance and fatigue with activities of daily living 1
• The presentation overlaps significantly with other conditions including pneumonitis, making accurate diagnosis difficult 1
• Dyspnea may be the predominant feature in patients who also have concurrent myositis or myasthenia gravis, which co-occur in 42% of severe myocarditis cases 1

Recent registry data demonstrates that dyspnea at presentation is actually a predictor of reduced left ventricular ejection fraction (<50%) in patients with ICI-myocarditis, underscoring its clinical significance 3

Critical Timing and Risk Factors

The temporal pattern is crucial for recognition:

• Median onset occurs at 34 days (approximately 5 weeks) after starting ICI therapy 2
• However, 64% of severe cases occurred after only 1-2 doses of ICI 1
• Myocarditis presents earlier (median 12 weeks) compared to non-inflammatory left ventricular dysfunction (median 26 weeks) 4

High-risk populations requiring heightened vigilance include:

• Patients receiving combination anti-CTLA-4/anti-PD-1 therapy (34% vs 2% in controls) 2
• Those with diabetes mellitus (34% vs 13% in controls) 2
• Patients with concurrent immune-related adverse events in other organ systems 1

Why This Matters: The Malignant Course

The Society for Immunotherapy of Cancer and NCCN guidelines emphasize that cardiac irAEs are among the most common causes of ICI-related death 1:

• 46% of patients develop major adverse cardiac events (cardiovascular death, cardiogenic shock, cardiac arrest, complete heart block) 2
• Mortality reaches 23% even with rapid assessment and immunosuppression 1
• Critically, 38% of major adverse cardiac events occur with normal ejection fraction, meaning preserved systolic function does not exclude severe disease 2

Immediate Diagnostic Approach

When a patient on ICI therapy presents with exertional dyspnea, the following workup is mandatory 1:

Baseline cardiac evaluation (should be obtained immediately):

• ECG to assess for conduction abnormalities, arrhythmias, or ST-segment changes 1
• Cardiac biomarkers: Troponin I or T, BNP or NT-pro-BNP, total creatine kinase 1
• Two-dimensional echocardiography to evaluate ventricular function and wall motion abnormalities 1

Critical threshold for high-risk disease: Troponin T ≥1.5 ng/mL confers a 4-fold increased risk of major adverse cardiac events (HR 4.0,95% CI 1.5-10.9) 2

Chest imaging (X-ray and/or CT) is essential to exclude:

• Pulmonary embolism (especially if accompanied by oxygen desaturation or tachycardia) 1
• Pneumonitis (which can present identically with dyspnea and reduced exercise tolerance) 1
• Pleural effusions or pericarditis 1

Distinguishing Myocarditis from Other Causes

The differential diagnosis in ICI patients with dyspnea is broad 1:

Pulmonary causes that mimic myocarditis:

• ICI-related pneumonitis (3.6% incidence with PD-1 inhibitors) presents with dyspnea, cough, reduced exercise tolerance 1
• Pneumonitis typically shows infiltrates on imaging, whereas myocarditis may have clear lung fields 1

Cardiac causes beyond myocarditis:

• Pericarditis (fever, chest pain with inspiration, diffuse ST elevation) 1
• Arrhythmias and conduction abnormalities 1
• Non-inflammatory left ventricular dysfunction (NILVD), a newly recognized entity that presents later (26 weeks vs 12 weeks), lacks inflammatory markers, and does not require steroids 4

Key distinguishing features of myocarditis 5, 6, 2:

• Elevated troponin disproportionate to degree of symptoms
• ECG changes resembling STEMI (ST-segment elevations)
• Segmental wall motion abnormalities on echocardiography
• Concurrent myositis symptoms (myalgias, elevated CK) in up to 42% of cases 1

Common Pitfalls to Avoid

Do not dismiss symptoms as "atypical" or attribute them solely to cancer progression or deconditioning 1:

• The non-specific nature of symptoms (fatigue, dyspnea) leads to under-recognition 1
• Myocarditis is likely under-reported due to varying definitions and absence of systematic monitoring in trials 1

Do not wait for reduced ejection fraction to diagnose myocarditis 2:

• 38% of major adverse cardiac events occur with preserved LVEF 2
• Symptom intensity does not correlate well with LVEF or biomarker levels 1

Maintain a low threshold for cardiology referral 1:

• Immediate consultation is warranted for any patient with dyspnea plus abnormal ECG, elevated troponin, or reduced ejection fraction 1
• The potential for rapid clinical deterioration and high mortality demands urgent specialist evaluation 1

Treatment Implications

Recognition of myocarditis fundamentally changes management:

• Immediate ICI discontinuation is required for grade 2 or higher cardiac toxicity 1
• High-dose corticosteroids (not low-dose) are associated with better outcomes; lower steroid doses correlate with higher residual troponin and increased major adverse cardiac events 2
• A minimum 4-6 week steroid taper is recommended to prevent recrudescence 1
• Additional immunosuppression with infliximab or cyclophosphamide may be needed for refractory disease 1

In contrast, if the diagnosis is non-inflammatory left ventricular dysfunction rather than myocarditis, steroids are not required and ICI can potentially be restarted safely 4