key: cord-1053172-pitp5wkb
authors: Chitturi, Kalyan R; Thacker, Sameer; Al-Saadi, Mukhtar A; Kassi, Mahwash
title: Successful treatment of acute heart failure in COVID-19-induced cytokine storm with tocilizumab: a case report
date: 2020-07-17
journal: Eur Heart J Case Rep
DOI: 10.1093/ehjcr/ytaa188
sha: 851257fbbae1980f36ac644828219cbcd2903133
doc_id: 1053172
cord_uid: pitp5wkb

BACKGROUND: SARS-CoV-2 is known to induce a cytokine storm, a hyperinflammatory state driven by up-regulation of interleukin 6 (IL-6) and immunomodulatory chemokines that may result in acute heart failure. CASE SUMMARY: A 65-year-old woman with confirmed SARS-CoV-2 developed shock with multiorgan system failure, including acute biventricular heart failure, 2 weeks after the initial onset of fever, cough, and shortness of breath. The patient experienced myocardial recovery within 48 h after administration of tocilizumab, a humanized monoclonal anti-IL-6 receptor antibody, and multiple supportive vasoactive medications. DISCUSSION: The differential diagnosis of acute heart failure in critically ill patients with COVID-19 infection is broad, including sepsis-induced cardiomyopathy, Takotsubo syndrome, viral lymphocytic myocarditis, and acute coronary syndrome. Immunomodulatory treatment with tocilizumab may benefit patients who develop cardiogenic shock associated with SARS-CoV-2-induced cytokine storm.

Cytokine storm, the abrupt onset of systemic hyperinflammation in the most critically ill patients infected by SARS-CoV-2, is associated with high mortality. 1 The pathophysiology of SARS-CoV-2-induced cytokine storm involves high expression of interleukin-6 (IL-6), which activates hepatocyte synthesis of acute-phase reactants. 2 A cardioprotective proinflammatory cytokine in the acute setting, IL-6 stimulates immune cells to prevent myocardial injury from oxidative stress and apoptosis, though marked increases result in dysregulation. 3 IL-6 blockade with tocilizumab may be beneficial for the treatment of acute heart failure associated with SARS-CoV-2-induced cytokine storm.

• SARS-CoV-2-induced cytokine storm may result in acute heart failure due to Takotsubo syndrome, sepsis-induced cardiomyopathy, viral lymphocytic myocarditis, or acute coronary syndrome • Dysregulation of interleukin-6 (IL-6) and related immunomodulatory chemokines, as seen in SARS-CoV-2-induced cytokine storm, is associated with myocardial injury and impaired contractility • Tocilizumab, a humanized monoclonal antibody against IL-6, may be an effective treatment of acute heart failure in patients with SARS-CoV-2-induced cytokine storm 

A 65-year-old woman presented to the emergency room for evaluation of progressively worsening fever, cough, and shortness of breath over 1 week. Her past medical history was notable for obesity, type 2 diabetes mellitus, hypertension, hyperlipidaemia, transient ischaemic attack, and left-sided breast cancer in remission after mastectomy and adjuvant docetaxel and cyclophosphamide. She was seen by her general practitioner earlier the same day and recommended to go to the hospital after being found to be hypoxemic with an oxygen saturation of 87% on room air. A chest computed tomography (CT) 1 day previously demonstrated bilateral ground-glass opacities. Medications on admission included: aspirin 81 mg daily, losartan-hydrochlorothiazide 50-12.5 mg daily, simvastatin 80 mg nightly, levothyroxine 100 lg daily, omeprazole 40 mg daily, metformin 500 mg twice daily, and liraglutide 1.8 mg daily injection.

On admission, she had a temperature of 36.1 C, blood pressure 107/62 mmHg, and heart rate 83 b.p.m. Physical exam revealed diminished breath sounds at lung bases. Chest X-ray demonstrated bilateral infiltrates suggestive of pneumonitis. Nasopharyngeal swab confirmed SARS-CoV-2 positivity. The patient was admitted to a specialized COVID-19 unit and initiated on treatment with remdesivir per clinical trial and empiric antibiotics for community-acquired pneumonia.

On the seventh day of hospitalization (2 weeks after initial symptom onset), the patient rapidly deteriorated into multisystem organ failure, comprising acute biventricular heart failure, acute respiratory distress syndrome, acute kidney injury [estimated glomerular filtration rate (eGFR) 26 mL/min/1.73 m 2 ], and ischaemic hepatitis with markedly elevated inflammatory markers, concerning for cytokine storm ( Table 1 ). The patient underwent emergent rapidsequence intubation and was transferred to the medical intensive care unit (ICU).

A non-contrast chest CT confirmed ground-glass opacities ( Figure 1 ). Electrocardiogram (ECG) showed new-onset T-wave inversions in leads V1-V2, and QTc 457 ms ( Figure 2 ). High-sensitivity troponin I (TnI) trended 1.058-1.966-0.519 ng/mL (normal value <0.04). Brain natriuretic peptide (BNP) was 401 pg/mL (normal value <100). Transthoracic echocardiogram (TTE) showed severe globally depressed left ventricular systolic function [left ventricular ejection fraction (LVEF) 25%] and right ventricular (RV) systolic function with paradoxical septal motion ( Figure 3 ; Supplementary material online, Videos 1 and 2).

The differential diagnosis of new-onset acute biventricular heart failure included sepsis-induced cardiomyopathy, Takotsubo syndrome, viral lymphocytic myocarditis, and acute coronary syndrome. Though beneficial for further differentiation of shock, a Swan-Ganz catheter was not placed for invasive haemodynamic assessment due to clinical instability, and the risk of exposing healthcare personnel to infection. 4 Due to haemodynamic instability and an acute kidney injury, cardiac catheterization or ECG-gated CT angiography for evaluation of coronary artery disease or pulmonary embolism was not feasible. Cardiac magnetic resonance (CMR) or endomyocardial biopsy (EMB) for further tissue characterization was also not possible for similar reasons.

The patient was treated with norepinephrine, vasopressin, dobutamine, sodium bicarbonate, inhaled epoprostenol, hydrocortisone, and a 400 mg dose of tocilizumab. Tocilizumab, a humanized monoclonal antibody against soluble and transmembrane IL-6 receptor, was provided for SARS-CoV-2-associated cytokine storm. 5 Norepinephrine, vasopressin, and hydrocortisone were used for distributive shock refractory to fluid resuscitation. Dobutamine was used for inotropy, and inhaled epoprostenol facilitated RV unloading, as a component of the severe RV dysfunction appeared to be related to acute respiratory distress syndrome (ARDS). Sodium bicarbonate was provided for severe acidosis. Propofol, fentanyl, and Figure 4) , titration off norepinephrine, vasopressin, dobutamine, and sodium bicarbonate infusions, and cessation of neuromuscular blockade. Continuous cardiac monitoring did not reveal any significant dysrhythmia. Repeat TTE 48 h after ICU admission demonstrated significant myocardial recovery, showing an LVEF of 64%, mild RV dysfunction, Grade 2 diastolic dysfunction, and a small circumferential pericardial effusion (Figure 3 ; Supplementary material online, Videos 3 and 4). Eventually undergoing tracheostomy before subsequent discharge from the ICU and hospital, the patient is currently undergoing a prolonged ventilatory wean at a long-term acute care facility. 

We report the first case of a patient with cardiogenic shock associated with SARS-CoV-2-induced cytokine storm, most probably sepsis-induced cardiomyopathy or Takotsubo syndrome, who survived without ECMO or mechanical circulatory support (MCS) after treatment with tocilizumab and supportive vasoactive medications. [6] [7] [8] [9] Sepsis-induced cardiomyopathy and Takotsubo syndrome share similar pathophysiology with the up-regulation of IL-6. In vitro models of IL-6 demonstrated direct negative inotropic effects on papillary muscle function and down-regulation of sarcoplasmic reticulum Ca 2þ ATPase (SERCA2) in cardiomyocytes, and increased IL-6 has been shown to reduce myocardial contractility in vivo. 10, 11 The systemic up-regulation of proinflammatory cytokines such as IL-6 in SARS-CoV-2-induced cytokine storm may lead to cardiac infiltration by leucocytes and macrophages, resulting in a 'myocardial stunning', manifested as a transient depression of global systolic function. The potential confounding of other medications and the most effective dose of tocilizumab are questions that remain in this case. However, the phase III randomized clinical trial COVACTA for the evaluation of the safety and efficacy of tocilizumab in patients with severe COVID-19 pneumonia aims to answer the latter question. 12 Additionally, the patient met many of the Heart Failure Association diagnostic criteria for Takotsubo syndrome, with an identifiable physical stressful trigger in SARS-CoV-2, wall motion abnormalities extending beyond a single epicardial vascular distribution, new and reversible ECG abnormalities, and a relatively small elevation in TnI. 13 Though the degree of acute biventricular heart failure and shock exceeded the level of BNP elevation in our patient, BNP levels do not necessarily correlate with cardiac haemodynamic indices in patients with Takotsubo syndrome and may be <400 pg/mL. 14 . . . . . . .

Though no evaluation of coronary anatomy is a limitation, acute coronary syndrome (ACS) was excluded on clinical grounds as the underlying aetiology of acute biventricular heart failure due to the rapid recovery of LVEF in the absence of revascularization. Likewise, viral lymphocytic myocarditis was deemed less plausible given the discrepancy in cardiac biomarker elevation to the extent of myocardial dysfunction and rapid myocardial recovery within 48 h. A case of acute lymphocytic myocarditis associated with SARS-CoV-2 mimicking reverse Takotsubo syndrome has been reported recently, with myocardial recovery achieved at 7 days, though notably SARS-CoV-2 genomic testing of biopsied cardiomyocytes was negative and the patient improved in cardiac function before receiving any therapy directed against SARS-CoV-2. 15 Though CMR and EMB could aid diagnosis, our patient was too haemodynamically unstable to undergo either test during the time at which either study would be of the most benefit.

In conclusion, we report the first case of acute biventricular heart failure complicated by cardiogenic shock associated with SARS-CoV-2-induced cytokine storm that resolved with tocilizumab and supportive medications alone, and without the assistance of ECMO or MCS. Tocilizumab may be considered as a therapeutic option for patients with cardiogenic shock in the setting of SARS-CoV-2induced cytokine storm, as IL-6 blockade may revive myocardium stunned from sepsis-induced cardiomyopathy or Takotsubo syndrome.

Kalyan Raghavendra Chitturi is finishing residency training at Houston Methodist Hospital and will be joining the University of Missouri for cardiology fellowship. He completed medical school at the University of North Texas Health Science Center and undergraduate studies at the University of Michigan -Ann Arbor. His research interests include cardiovascular outcomes in cardio-oncology, heart failure, and structural heart disease. Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.

The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.

Conflict of interest: none declared.

COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal

The cytokine release syndrome (CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonist tocilizumab may be the key to reduce the mortality

Inflammatory cytokines in heart failure: roles in aetiology and utility as biomarkers

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First case of COVID-19 complicated with fulminant myocarditis: a case report and insights

The variety of cardiovascular presentations of COVID-19

Coronavirus disease 2019 (COVID-19) and cardiovascular disease

Myocardial localization of coronavirus in COVID-19 cardiogenic shock

Negative inotropic effects of cytokines on the heart mediated by nitric oxide

Leukemia inhibitory factor and interleukin-6 downregulate sarcoplasmic reticulum Ca 2þ ATPase (SERCA2) in cardiac myocytes

Bethesda (MD): National Library of Medicine (US)

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Brain natriuretic peptide in apical ballooning syndrome (Takotsubo/stress cardiomyopathy): comparison with acute myocardial infarction

Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection

We thank all the nurses, physicians, and intensive care staff at Houston Methodist for their tireless efforts caring for critically ill patients during the global pandemic. Tocilizumab for cardiogenic shock in COVID-19

Supplementary material is available at European Heart Journal -Case Reports online