A case of COVID‐19 masquerading as presumed Trastuzamab induced subclinical cardiotoxicity

The ongoing Coronavirus disease 2019 (COVID-19) global pandemic has resulted in over 6 million deaths worldwide.1 In addition to primary acute respiratory symptoms, COVID-19 has been demonstrated to have multisystem involvement.2 Cardiovascular system manifestations include thrombosis, acute coronary syndrome, arrhythmias, myocarditis, and evidence of subclinical myocardial dysfunction, with increased risk of mortality observed following myocardial injury.3 Cardiac magnetic resonance (CMR) imaging provides the highest diagnostic accuracy for acute myocarditis, however speckle tracking echocardiography (STE) derived strain analysis offers a more pragmatic alternative. STE examination has demonstrated reversible sub-clinical myocardial impairment of patients with only mild/moderate COVID-19 symptoms.4 This case describes a patient who suffered myocardial impairment following COVID-19 infection, whilst undergoing adjuvant chemotherapy for breast cancer. Current guidelines recommend cardioprotective therapy with potential cessation of chemotherapy if significant myocardial impairment is observed during treatment.5 A 48-year-old woman was diagnosed with right sided Grade 2 invasive breast carcinoma, no special type (NST), oestrogen receptor/progesterone receptor (ER/PR) negative and human epidermal growth factor receptor 2 (HER2) positive, in April 2021. She had received adjuvant chemotherapy with 4 cycles of anthracycline, 12 cycles of Paclitaxel, and 2 cycles of Trastuzamab chemotherapies, to be followed by bilateral mastectomy, adjuvant radiation, and on-going Trastuzumab. Prior to the initiation of chemotherapy (May, 2021), a transthoracic echocardiogram (TTE) demonstrated normal left ventricular (LV) systolic function, with left ventricular ejection fraction (LVEF) of 64% with a global longitudinal strain (GLS) of −21.8% (Figure 1A). She had routine cardiac surveillance as is clinical practice at our centre with a repeat TTE (August, 2021) after anthracycline therapy and prior to commencement of Trastuzamab (Figure 1B). This demonstrated LVEF of 59% with GLS of −19.9% (9% relative reduction and 1.9% absolute reduction in GLS compared to baseline). As is standard of care, a TTE is performed at 3 monthly intervals after commencement of Trastuzumab. Her next routine 3 monthly TTE (November 2021) demonstrated a further reduction in LVEF to 56% and GLS of −17.9% (relative reduction of 17.9% and absolute reduction of 3.9%) triggering review by a cardiologist (Figure 1C). There was no significant change in blood pressure, heart rate, LV volumes, LA volume or E/e' over this period. At cardiologist review, the patient reported no cardiovascular symptoms, in particular no dyspnoea, fatigue, or pedal oedema. She mentioned that she had COVID-19 infection (although having been vaccinated prior (×2 doses) in late September 2021) and had mild—moderate symptoms of dyspnoea and fatigue for approximately 3 weeks. She denied any chest pain or palpitations, she did not have any blood tests (for cardiac biomarkers), did not require hospitalisation, and did not receive specific antiviral therapy. On examination, she had a heart rate of 60 bpm, was normotensive with a blood pressure of 124/78 mmHg, with normal heart sounds, no murmurs or rubs. Electrocardiogram showed sinus rhythm with normal axis, and non-specific T wave inversion in leads III and aVF. The patient had an asymptomatic drop in LVEF of 9% and 17.9% relative reduction in LV GLS compared with her baseline study whilst on Trastuzumab, reaching the guideline directed threshold (GLS decrease >15%) for commencement of cardioprotective therapy (angiotensin-converting enzyme inhibitor ± Beta blocker therapy).5 However, given the history of COVID-19 infection in the interim with resolution of symptoms subsequently, a decision was made to continue with Trastuzumab therapy with TTE surveillance after further 2 cycles of Trastuzamab, without initiation of cardioprotective therapy. At follow-up, the patient reported no further symptoms, in particular no dyspnoea or fatigue. Her TTE in January 2022 demonstrated improved LVEF of 59% and GLS of −18.6% (Figure 1D). She has subsequently continued Trastuzumab with standard clinical surveillance, without commencement of cardioprotective agents. An additional assessment GLS reproducibility was performed by three accredited medical sonographers blinded to treatment regime and each other's measurements. Consistent trends were identified by all sonographers with normal GLS pre-treatment (−21.2% ± 0.62), a small GLS reduction following anthracycline therapy (−18.4% ± 0.78), further reduction following trastuzumab/ COVID-19 infection (−17.5% ± 0.59), and subsequent improvement at follow-up (−18.6% ± 0.68). In addition, intraclass correlation coefficient (ICC) for interobserver variability was 0.98 (95% CI 0.87–1.0) with mean relative GLS reduction of 17.6% (95% CI 13.5%–21.7%) during Trastuzumab therapy, compared with baseline. Myocardial dysfunction and heart failure secondary to cancer therapy (cardiotoxicity) is an important cause of patient morbidity and mortality in cancer survivors.6 Anthracycline-induced cardiotoxicity has a cumulative, dose dependant, and non-reversible presentation with cellular apoptosis. Myocardial dysfunction and/ or heart failure can be delayed for a number of years due to compensatory mechanisms.6 The highly effective treatment of monoclonal antibody Trastuzumab for HER2 positive breast cancer demonstrates partially reversible acute myocardial dysfunction with immediate improvements in left ventricular ejection fraction (LVEF) following Trastuzumab cessation, however with an ongoing subclinical reduction of LV GLS.6, 7 Prevention and management of cancer therapy induced cardiotoxicity is important for long term patient outcomes and requires screening, risk stratification, and ongoing surveillance.5 Baseline cardiac assessment should include a clinical assessment of medical history, physical examination, and vital signs, in addition to complementary tests of electrocardiography, cardiac imaging, and cardiac biomarkers.6 TTE is recommended prior to treatment with evaluation of systolic function (LVEF), diastolic function and subclinical systolic function (GLS). A staged reduction in absolute LVEF or a relative reduction in GLS >15% from baseline is indicative of cardiotoxicity and should determine treatment interruption or cessation.5 Follow-up cardiac imaging is recommended at the completion of anthracycline therapy, and then every 3 months during Trastuzumab treatment.6 Cardiotoxicity risk reduction involves anthracycline dose modification and sequential administration of anthracyclines and Trastuzumab.5 Acute myocardial dysfunction has also been described following infection with COVID-19, with reduction in GLS an independent indicator of COVID-19 related death.4, 8 Impairment has been demonstrated in both LVEF and GLS in an apical sparing pattern typical of a reverse-stress/Takotsubo cardiomyopathy.9 The prevalence of myocardial dysfunction following COVID-19 infection in the wider population remains unknown, however there is 20%–30% reported myocardial involvement in hospitalised patients.10 Conflicting reports have been presented regarding improvement of LVEF and GLS following COVID-19 recovery, which may indicate a need for ongoing monitoring and/or administration of cardioprotective agents.8, 9 GLS assessment is a highly sensitive marker of subclinical LV systolic function and demonstrates reduced intra- and inter-observer variation when compared with LVEF.11 Absolute GLS variation of ±2 to ±5 is observed however, with reproducibility dependent on consistency of ultrasound vendor, sonographer, and reporting doctor.12 While absolute changes of GLS presented in this case are small, complete consistency of measurement factors was employed, and reproducibility was demonstrated through post-hoc assessment. Myocardial dysfunction is a recognised sequela of both cancer therapy related cardiac dysfunction and COVID-19 infection. Crucially, cancer therapy related cardiotoxicity is a devastating consequence for cancer patients with the highest cause of morbidity and mortality second to malignancy.13 In this case our patient demonstrated myocardial dysfunction during Trastuzamab therapy, albeit following a COVID-19 infection. Recovery was observed in the course of ongoing Trastuzamab treatment without administration of cardioprotective agents, indicating a probable subclinical myocarditis following COVID-19 infection. This study demonstrates the importance of taking a history of prior COVID-19 infection, or other significant viral infections that may alter LV function, in addition to vigilant TTE surveillance of patients undergoing chemotherapy. The author would like to confirm that the case and images are presented with signed patient informed consent. Open access publishing facilitated by The University of Sydney, as part of the Wiley - The University of Sydney agreement via the Council of Australian University Librarians. The authors declare no conflicts of interest.