Takotsubo Syndrome Triggered by Immune Checkpoint Inhibitor-Induced Pneumonitis: A Multidisciplinary Diagnostic and Therapeutic Challenge

Introduction

The use of immune checkpoint inhibitors (ICIs) in oncology has advanced cancer care, but these drugs can cause immune-related adverse events (irAEs) that include rare cardiovascular complications. Differentiating immune-mediated myocarditis from stress-induced takotsubo cardiomyopathy (TTC) is a critical diagnostic challenge in modern cardio-oncology. Both conditions can present with acute heart failure, biomarker elevation, and EKG changes soon after ICI initiation. This report shows how advanced cardiac magnetic resonance imaging (CMRI) and endomyocardial biopsy (EMB) can resolve such ambiguity and guide safe continuation of life-prolonging immunotherapy.

Case Report

A 64-year-old woman with long-term tobacco use, emphysema, and stage IV squamous cell carcinoma of the lung with liver and brain metastases experienced acute dyspnea, cough, and pleuritic chest pain for 2 days. She started combination therapy with carboplatin, paclitaxel, and pembrolizumab 9 days before presentation.

She presented to the emergency department with hypertension (BP 156/103 mmHg), tachycardia (HR 120 bpm), tachypnea (RR 32/min), and hypoxemia (SpO2 88% on 5 L oxygen). The physical examination revealed a loud P2 heart sound, bilateral expiratory wheezing, and mild lower-extremity edema.

The initial 12-lead EKG (Figure 1) demonstrated sinus tachycardia (HR 124 beats per minute) with right bundle branch block and mild ST-segment elevation in leads V3–V5. No reciprocal ST depression was noted. The laboratory results indicated high-sensitivity troponin-T levels at 424 ng/L, troponin-I level at 31 ng/L, and proBNP levels at 865 pg/ml. Echocardiography revealed LVEF of 35% with severe hypokinesis of mid-apical LV wall segments. Based on TTE, the differential diagnosis included severe coronary artery disease (CAD), myocarditis, and stress-induced cardiomyopathy. She was immediately taken for left heart catheterization, which revealed non-obstructive coronary artery disease with a left ventricular end-diastolic (LVED) pressure of 17 mmHg (Figure 2). Serial measurements of high-sensitivity troponin (hs-T) demonstrated a downward trend (hs-T 429 → 424 → 80 → 52 → 22 ng/L; Tn-I 31 → 18 → 9 ng/L) over the course of 5 days (reference ranges are hs-T <14 ng/L and Tn-I <10 ng/L.) Her follow-up EKG on the follow-up day showed resolution of ST elevations (Figure 3).

A CMR was performed for further evaluation and concerns for ICI myocarditis. It showed LVEF at 32% with mid-to-apical anterior and anteroseptal akinesis and myocardial edema in affected segments without late gadolinium enhancement (LGE). Findings of the CMR were consistent with TTS. Quantitative parametric mapping values demonstrated T1=1100–1500 ms and T2=59 ms in the apical segments (elevated when compared with basal myocardium, T1=980 ms, T2=50 ms) with extracellular volume (ECV)=35%, which is indicative of myocardial edema (Figures 4, 5). Dynamic CMR cine imaging revealed an apical ballooning pattern with hyperkinesis of basal segments (Videos 1–3). These findings, in combination with the absence of late gadolinium enhancement (LGE) (Figure 6), established the diagnosis of takotsubo syndrome rather than myocarditis.

A chest computed tomography (CT) scan was performed, and the distribution of pulmonary infiltrates were predominantly patchy and non-dependent, without evidence of cardiomegaly, septal thickening, or pleural effusions, which are classic features of hydrostatic congestion. CT imaging favored an immune-mediated pneumonitis rather than cardiogenic pulmonary edema (Figure 7).

To verify diagnosis of TTS, an EMB was subsequently obtained from the right ventricular septum (4 samples). Histopathology showed interstitial fibrosis without myocyte necrosis. Immunohistochemistry (IHC) was negative for CD3 (T-lymphocytes), CD68 (macrophages), and PD-L1, effectively excluding ICI-induced myocarditis (Figure 8).

After multidisciplinary discussions, she received a diagnosis of ICI-related Grade 2 pneumonitis together with TTC. She received intravenous methylprednisolone (1 mg/kg/day) for 3 days, transitioned to an oral prednisone taper over 4 weeks, consistent with National Comprehensive Cancer Network (NCCN) recommendations for grade 2 pneumonitis. She improved rapidly, allowing discontinuation of supplemental oxygen by day 5. She was also started on guideline-directed medical therapy (GDMT) for TTC, which included metoprolol succinate and sacubitril/valsartan.

Re-initiation of pembrolizumab 2 weeks after discharge was approved by a multidisciplinary team (MDT) comprising oncology, cardiology, and pulmonology specialists. The decision followed comprehensive reassessment of cardiac and pulmonary function, which demonstrated full clinical recovery in 8 weeks: LVEF normalization (60%) as shown in Videos 4 and 5, resolution of pneumonitis on CT imaging, and normalization of troponin-I (<10 ng/L) and beta natriuretic peptide ([BNP] <100 pg/mL). The MDT reached the unanimous consensus that the benefits of continued immunotherapy outweighed the risks of recurrence, with a plan for serial cardiac monitoring during ongoing therapy (Table 1).

Discussion

CLINICAL IMPLICATIONS:

Clinicians should maintain a high index of suspicion for takotsubo syndrome in patients presenting with cardiopulmonary symptoms during ICI therapy [15], particularly when concurrent irAEs are identified [16]. Early multidisciplinary collaboration and sequential use of biomarkers, cardiac MRI, and histology can ensure diagnostic accuracy. This case reinforces that prompt recognition and tailored immunosuppression can allow safe continuation of immunotherapy and improve patient outcomes.

Conclusions

We report a rare case of TTS developing from ICI-induced pneumonitis, which presented with myocarditis-like symptoms. To our knowledge, this is the third reported instance of pneumonitis acting as the precipitating irAE for TTS in the context of ICI therapy [12,13]. The combination of early diagnosis through CMR imaging and a personalized steroid treatment plan enabled fast patient recovery while maintaining the essential ICI therapy for survival. Awareness of irAE-triggered TTS presentations can facilitate timely, life-saving interventions.