Reverse takotsubo cardiomyopathy in fulminant COVID-19 associated with cytokine release syndrome and resolution following therapeutic plasma exchange: a case-report

Background Fulminant (life-threatening) COVID-19 can be associated with acute respiratory failure (ARF), multi-system organ failure and cytokine release syndrome (CRS). We present a rare case of fulminant COVID-19 associated with reverse-takotsubo-cardiomyopathy (RTCC) that improved with therapeutic plasma exchange (TPE). Case presentation A 40 year old previous healthy male presented in the emergency room with 4 days of dry cough, chest pain, myalgias and fatigue. He progressed to ARF requiring high-flow-nasal-cannula (flow: 60 L/minute, fraction of inspired oxygen: 40%). Real-Time-Polymerase-Chain-Reaction (RT-PCR) assay confirmed COVID-19 and chest X-ray showed interstitial infiltrates. Biochemistry suggested CRS: increased C-reactive protein, lactate dehydrogenase, ferritin and interleukin-6. Renal function was normal but lactate levels were elevated. Electrocardiogram demonstrated non-specific changes and troponin-I levels were slightly elevated. Echocardiography revealed left ventricular (LV) basal and midventricular akinesia with apex sparing (LV ejection fraction: 30%) and depressed cardiac output (2.8 L/min) consistent with a rare variant of stress-related cardiomyopathy: RTCC. His ratio of partial arterial pressure of oxygen to fractional inspired concentration of oxygen was < 120. He was admitted to the intensive care unit (ICU) for mechanical ventilation and vasopressors, plus antivirals (lopinavir/ritonavir), and prophylactic anticoagulation. Infusion of milrinone failed to improve his cardiogenic shock (day-1). Thus, rescue TPE was performed using the Spectra Optia™ Apheresis System equipped with the Depuro D2000 Adsorption Cartridge (Terumo BCT Inc., USA) without protective antibodies. Over 5 days he received daily TPE (each lasting 4 hours). His lactate levels, oxygenation, and LV function normalized and he was weaned off vasopressors. His inflammation markers improved, and he was extubated on day-7. RT-PCR was negative on day-17. He was discharged to home isolation in good condition. Conclusion Stress-cardiomyopathy may complicate the course of fulminant COVID-19 with associated CRS. If inotropic therapy fails, TPE without protective antibodies may help rescue the critically ill patient.

Because inotropic therapy was failing, we recruited the patient into our study investigating the potential role of TPE as rescue therapy in life-threatening COVID-19 associated with CRS [40]. Following informed consent from his legal representative, rescue TPE was initiated on post-ICU admission day-1, using the Spectra Optia™ Apheresis System equipped with the Depuro D2000 Adsorption Cartridge (Terumo BCT Inc., USA) [32,33]. A dose of 1.5 plasma volumes was used for the first dose then one plasma volume daily for a total of five doses (4 hours each day). Spectra Optia™ Apheresis System employs an acid-citrate dextrose anticoagulant as per Kidney Disease Improving Global Outcomes 2019 guidelines [54]. Intravenous hydrocortisone 100 mg and chlorpheniramine 10 mg were administered as adjunctive treatment during TPE to reduce any potential side-effects. Plasma was replaced with albumin 5%. Our patient did not have any coagulopathy or elevated levels of D-dimer. No side effects due to TPE were recorded (i.e., allergies, infection, and coagulopathy). Daily negative fluid balance was achieved.
After only the 2nd TPE session (day-2) LV function gradually improved (Fig. 2) although interstitial lung edema was still present (Video 2; Additional files 1 and 3). After the 3rd TPE session (day-3), he was weaned off vasopressors, and his lactate, blood pressure and LV function normalized. After completion of TPE (day-5), PaO 2 /FiO 2 ratio exceeded 300, his chest X-ray showed less infiltrates (Fig. 1), his lymphocyte count increased (from 0.55 to 1.1 × 10 9 /l) and his CRP (82.5 to 10.1 mg/ liter), LDH (840 to 140 units/liter), ferritin (3101 to 234 ng/ml) and IL-6 (398 to 11 pg/ml) decreased. He was extubated on day-7 post-ICU admission. RT-PCR test and microbiology were negative on day-17. All work-up for systemic and other viral diseases was negative. The patient was pleased with his therapy but refused any additional diagnostic testing. He was discharged to home isolation in good condition, and has been followed by our outreach team for a period of 2 months.
Importantly, we cannot conclude that TPE definitively rescued the patient. Potentially, his clinical state and biochemical aberrations could have improved without TPE; although his clinical picture was grave, and other therapies largely failed. The management of acute heart failure due to TTC, especially in patients with life-threatening COVID-19, is challenging. Patients with stress-cardiomyopathy often do not improve with fluid administration because their LV operates mainly within the flat portion of the Frank-Starling curve. This means aggressive volume resuscitation can cause pulmonary edema and hemodynamic compromise. In TCC, adrenergic stimulation is high, thus exogenous catecholamine-inotropes (i.e., dopamine, dobutamine, and norepinephrine) can further impair cardiac contractility: by exacerbating neurocardiogenic injury and calcium overload in an already stressed myocardium. The use of non-catecholamine inotropes (i.e., milrinone and levosimendan) may be beneficial providing no LV outflow obstruction [13][14][15][16][17][18][51][52][53]. Beta-blockers are important in the management of TTC complicated by LV outflow tract obstruction [55]; however, their use in RTTC without intraventricular pressure gradient remains controversial [56]. Our patient did not have LV outflow tract obstruction; however, using the beta-1 cardio-selective blocker esmolol (half-life: 9 min) has been encouraged in TTC. Fortunately this short acting agent can be discontinued if adverse effects occur (i.e., impaired LV cardiac contractility, blood pressure, and central hemodynamics) [57]. Recently, an inhospital score has been suggested to stratify TTS patient's risk by the German and Italian Stress Cardiomyopathy (GEIST) registry [58]. That study concluded that independent predictors of in-hospital complications of TTC were: male sex, history of neurologic disorder, RV involvement, and decreased LVEF (GEIST score). Hence, our patient would be at intermediate risk being a male with an LVEF of 30%, and requiring ICU admission. Notwithstanding, our patient also had lifethreatening COVID-19, which might be considered an additional risk factor complicating acute heart failure due to stress-cardiomyopathy. This is the first time, to our knowledge, that TPE has been reported as rescue therapy for cardiogenic shock due to stress-cardiomyopathy in serious COVID-19. We employed TPE with an adsorption cartridge containing activated uncoated coconut shell (carbon granules) charcoal (100 g), and the nonionic resins Amberlite XAD-7HP and Amberchrom GC300C [20,28]. These can remove interferon-gamma, interleukins − 3, − 10, −1B, − 6, − 8, and tumor necrosis factor-alpha [18][19][20][21][22][23]. Although a full cytokine panel was not available in our institution at that time, TPE resulted in pertinent biochemical improvements: decreased inflammatory mediators (CRP, LDH, and ferritin), IL-6, and increased lymphocytic count [30][31][32][33][34][35][36][37][38][39][40]. Elevated inflammation markers are associated with more severe COVID-19, and elevated IL-6 is associated with worse CRS [30][31][32][33][34][35][36][37][38][39][40]. This is why tocilizumab, a monoclonal antibody against IL-6, has been tried in severe COVID-19, albeit with conflicting results [59][60][61][62]. In our institution, tocilizumab was not available, at that time. Similarly, the antiviral remdesevir and convalescent plasma transfusion (containing a high concentration of neutralizing antibodies) have shown promise in treating serious COVID-19 but results are inconclusive [63][64][65][66]. In a recent, randomized control trial, which has been performed among patients with severe or life-threatening COVID-19, convalescent plasma therapy has been added to standard anti-COVID-19 treatment. However, when compared with standard treatment alone, convalescent plasma therapy was not associated with a significant clinical improvement within 28 days of hospitalization [67]. Moreover, the natural course of COVID-19 viremia and the developing antibodies titers remains uncertain [68][69][70], and convalescent plasma therapy is not currently widely available.
This case-report has limitations, which prevent its generalizability. First, patients with cardiogenic shock and absence of LV outflow obstruction might benefit from an intra-aortic balloon pump, but this was not available [71]. Also, cardiac magnetic resonance imaging was not performed to exclude myocarditis [14][15][16][17][18] as our follow-up period was limited to 2 months. Importantly, RTCC (as well as  can resolve with no more than supportive therapy. In other words we cannot definitively confirm that TPE rescued the patient, only that their illness severity led us to apply TPE, and the patient survived. Other limitations include that in trying to pinpoint the role played by TPE we cannot exclude other aggressive life support plus empiric therapies. The effects of all of these on biochemistry, cardiac function and survival is unclear [1,2,[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]72]. Even if TPE is beneficial, the optimal TPE regime is unclear because the course of COVID-19 viremia has yet to be elucidated [63][64][65][66][67][68]. Accordingly, we speculate that prompt TPE initiation mitigated full-blown CRS, given the associated reduction in our patient's elevated IL-6 [30][31][32][33][34][35][59][60][61][62]. Presumably, at an early stage of COVID-19 dysregulated immune system pathology may be more important than viral replication per se [73]. However, it is unknown exactly how reducing COVID-19 associated CRS works in improving stress-cardiomyopathy. It could have a direct effect (i.e., by reducing cardiac inflammation) or work indirectly (i.e., improving oxygenation, LV filling pressures and reducing the stress of critical illness).
In conclusion, stress-cardiomyopathy and related cardiogenic shock can complicate fulminant COVID-19 with associated CRS. If usual therapies fail, rescue TPE (without protective antibodies) could be considered and warrants further study.
Additional file 4. Authors' contributions FF, AA, and RA treated the patient, collected the data and drafted equally the manuscript. JP and DK provided expert echocardiographic consultation and drafted equally the manuscript. DJK, PGB reviewed the data and drafted equally the manuscript. The final version of the manuscript was approved by all authors.

Funding
The study is funded by King Saud Medical City.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate
The study was approved by the Institutional Review Board of King Saud Medical City, Riyadh, Kingdom of Saudi Arabia, protocol/serial number: H-01-R-053, IORG0010374, H1R1-29-Apr20-01. Written informed consent is obtained by all eligible patients or their legal representatives. The study is also registered at ISRCTN (ISRCTN21363594; doi.10.1186/ ISRCTN21363594).

Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.