Life-threatening cardiogenic shock in a pediatric patient with SARS-CoV-2-associated myocarditis treated with remdesivir: a case description and report of similar cases from the Literature

Background Children are relatively spared from Coronavirus disease 2019 (COVID-19), but some severe cases have been reported. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children may affect the cardiovascular system. We hereby report about a case of myocarditis evolving to cardiogenic shock in a SARS-CoV-2 positive child.

treated with catecholamine support, mechanical ventilation and empiric anti-infectious therapy, including broad spectrum antibiotics and the antiviral agent remdesivir. All additional microbiological investigations yielded negative results.
We observed a gradual improvement of LVEF within 5 days. A cardiac magnetic resonance con rmed the suspicion of myocarditis. After 21 days of hospitalisation, the child was discharged without sequelae.

Conclusions
Our hypothesis is that the child suffered from SARS-CoV-2-induced fulminant myocarditis, probably in the setting of cytokine release syndrome (CRS). The peculiarity of this SARS-CoV-2 infection is the presence of cardiac failure in a previously healthy child without a respiratory illness. The positive outcome is in line with published Literature about the overall better prognosis of COVID-19 children compared to adults. Remdesivir, an investigational antiviral therapy, may have played a role on the clinical improvement of the child.

Background
The World has recently witnessed the epidemic outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, spreading globally and rapidly evolving into a pandemic phenomenon.
In spite of its utmost and potentially life-threatening involvement of the respiratory system, the novel coronavirus disease 2019 (COVID -19) has been recently reported as a causative factor for severe cardiac injury in adult patients. (1,2) Whether the impairment of cardiac function results from direct detrimental effect of the virus on the myocardium or should be regarded as a secondary outcome of the systemic in ammatory response elicited by COVID-19 is still debated.
Indeed, an increasing number of Authors have been highlighting the onset of severe cytokine storms in COVID-19 patients. When cytokine release syndrome (CRS) targets the cardiovascular system,(3) the clinical picture includes tachycardia, hypotension, troponin elevation, arrhythmias, QT prolongation, cardiomyopathy and acute heart failure.(3) In COVID-19 patients, all the previous clinical pictures have been described.(4) Interleukin-6 (IL-6) seems to play a pivotal role in CRS, activating complement and the coagulation pathway and inducing endothelial damage. Moreover, IL-6 has been reported to depress the myocardial function. (3,5,6) In COVID-19 patients high levels of IL-6 and C-reactive protein (CRP) appear to be negative prognostic markers. (7,8) Most children experience no or just mild signs and symptoms of SARS-CoV-2 infection, even though severe cases, mainly occurring in patients with an underlying disease, have been described. (9)(10)(11) Pediatric COVID-19 patients may experience respiratory, gastrointestinal, neurological symptoms, but few is known about cardiovascular involvement. (9,10) We hereby report the rst pediatric case of myocarditis in a child affected by COVID-19 and presenting with cardiogenic shock.

Case Presentation
An otherwise healthy 12-year-old boy was admitted to a peripheral hospital (Lombardy -northern Italy), with complaints of fever, vomiting, diarrhoea and drowsiness for the previous three days. Though no respiratory symptoms were reported, both his parents have been presenting with cough and low-grade fever for several weeks. Patient's past medical history was unremarkable.
On admission, blood tests showed normal full blood count but raised CRP (23.4 mg/dL, reference range < 0.5) and procalcitonin (PCT -3.3 ng/ml, reference range < 0.5). Despite negative ndings at chest x-ray, based on the clinical and family history, COVID-19 was suspected and a nasopharyngeal swab was Upon arrival, the patient was ill-appearing, highly febrile (body temperature: 39.0°C) and tachycardic (140 beats per minute), though he presented with normal blood pressure (110/70 mmHg) and room-air pulseoximetry (98%).
Given the overall worsening of both clinical and biochemical picture despite ongoing antibiotic treatment, Ceftriaxone was empirically switched to a combination of intravenous meropenem and vancomycin. In addition, antithrombotic therapy with intravenous unfractioned heparin was introduced.
In a few hours the child developed severe hypotension (blood pressure: 70/40 mmHg) and clinical signs consistent with progressive peripheral hypoperfusion, refractory to intravenous uid resuscitation (saline solution: 20 mL/Kg in 15 minutes) and vasoactive amines infusion (norepinephrine). Urgent bedside echocardiography showed a severe decrease in ventricular systolic function, with a left ventricle ejection fraction (LVEF) of 25%, increased left ventricular dimensions with diffuse hypokinesis but retained right ventricular function. Both troponin T (TnT, 602 ng/L with reference range < 14) and N-terminal brain natriuretic peptide (NT-proBNP, 27075 pg/mL with reference range < 300) were found to be remarkably raised.
Due to a progressive deterioration of the clinical picture and the need for mechanical ventilation, invasive hemodynamic monitoring and combined norepinephrine and dobutamine infusion, the patient was transferred to our Intensive Care Unit (ICU).
As showed in gure 1, after an initial improvement, the patients experienced a steep exacerbation of both clinical and biochemical data within 48 hours. Interleukin-6 was tested at this stage and showed a peak value of 8209 pg/ml (reference range: < 7). A chest and abdomen CT scan showed radiological signs consistent with uncomplicated colitis, while pulmonary ndings were unremarkable.
The patient was therefore started on antiviral treatment with remdesivir, an investigational nucleoside analogue prodrug with supposed e cacy on SARS-CoV-2, at the loading dosage of 200 mg, followed by 100 mg every 24 hours. Vancomycin was discontinued and replaced with tigecycline and clindamycin, while treatment with meropenem was continued unchanged. Support therapy including vasoactive and inotropic amines, short course hydrocortisone (due to its mineralocorticoid effect), furosemide and captopril was undertaken. With the exception of SARS-CoV-2, all the remaining microbiological investigations performed yielded negative results, including peripheral blood cultures for fungi and bacteria and serologies for cardiotropic infectious agents (echoviruses, coxsackieviruses, cytomegalovirus, adenovirus and mycoplasma) and PCR essays on blood and stool for enterovirus genus nucleic acids.
During the following days, patient's clinical condition progressively improved. Figure 1 shows how the gradual drop of in ammation and myocardial damage markers corresponded to a concomitant increase of LVEF, leading to restoration of cardiac function by the fth day of intensive care. In two additional days' time, the patient was progressively weaned from vasoactive support and de nitely extubated. The SARS-CoV-2-targeted nasopharyngeal swab and bronchoalveolar lavage performed seven days after the start of antiviral treatment showed negative results, and remdesivir was therefore discontinued.
Gadolinium-enhanced cardiac Magnetic Resonance Imaging (MRI), performed on day 13, detected an area of subepicardial delayed enhancement within the left ventricle, consistent with recent myocarditis (See gure 2 for detailed description of radiological ndings).
After 21 days of hospitalization, the child was discharged with no sequelae.

Discussion And Conclusions
We hereby report about a 12-year-old SARS-CoV-2-positive patient who presented with biochemical and clinical signs of acute cardiac injury (raised necrosis markers, severely depressed left ventricle function) in the presence of radiological signs consistent with myocarditis and no signs of respiratory involvement.
In our opinion, several points are worthy of discussion.
Firstly, we presented a rare case of SARS-CoV-2-related cardiac involvement in childhood. Viral infections are the commonest cause of myocarditis in children (12) and myocardial involvement has already been reported in a few SARS-CoV-2-positive patients. Table 1 compares the clinical, laboratory and diagnostic features of all the cases published hereinbefore. (13)(14)(15)(16)(17)(18)(19)(20)(21) Secondly, in our patient, acute onset with progressive clinical deterioration and refractory cardiogenic shock met the diagnostic criteria for fulminant myocarditis (FM). (22,23) This is not unexpected in adulthood, as 4 out of the 9 published cases involving adult patients diagnosed with myocarditis met the criteria of COVID-19-related FM (Table 1). Our case highlights that in case of rapid otherwise unexplained deterioration of clinical conditions in SARS-CoV-2-positive patients, also pediatricians should keep a high index of suspicion and deem FM as a potential diagnosis.
Other than myocarditis, myocardial infarction, disseminated intravascular coagulation (DIC)-associated damage, stress induced cardiomyopathy and CRS-associated damage have been described as possible clinical presentations of cardiac involvement in COVID-19.(4) Indeed, cardiac injury in COVID-19 probably has a multi-factorial genesis. Many Authors agree that different mechanisms may interplay leading to cardiac injury: direct viral damage on myocardial cells, overwhelming in ammation process due to cytokine storm and hypoxia due to the imbalance between increased myocardial oxygen demand and decreased pulmonary oxygen supply during acute respiratory syndrome. (1,24) As showed in Figure 1, in our case increased TnT and NT-pro-BNP levels, as well as decreased ejection fraction at echocardiography were signi cantly correlated with IL-6 and CRP levels over time. Similar data have already been described in published Literature. (24) A recent meta-analysis demonstrated that elevated IL-6 values are associated with increased severity and mortality of SARS-Cov-2 disease (8) and patients treated with IL-6 inhibitors, such as Tocilizumab, have reported a clinical improvement. (25) We decided not to administer tocilizumab to our patient because clear demonstrations of the safety and clinical effectiveness of this anti IL-6 drug is currently lacking. (8,26) As showed in table 1, both in our pediatric case and in several adult patients, cardiac failure due to myocarditis in otherwise healthy patients may occur without any associated respiratory symptoms. On the other hand, the complete lack of electrocardiographic signs found in our patients is infrequent amongst adults.
Third, there are few reports of remdesivir use in children, and none of them in patients with acute myocarditis. Remdesivir has recently been associated with some clinical bene t in adult patients with COVID-19 (27), leading the US Food and Drug Administration to issue an emergency use authorization for the treatment of COVID-19 in adults and children hospitalized with severe disease. Similarly, remdesivir has been proposed as the preferred agent in children, when antiviral treatment is regarded as potentially bene cial.(28) Nonetheless, most COVID-19 pediatric patients with either mild or severe disease described so far, recovered with supportive care only. Accordingly, ascertaining whether antiviral therapy played a central role on the clinical improvement experienced by our patient is challenging and potentially misleading.
Finally, we are aware that the present case report has some limitations. Firstly, in a highly febrile patient who presented with remarkably raised CRP and PCT, it may be argued that the cardiac impairment could be secondary to concomitant septic shock. Cardiac biopsy could have demonstrated the primary myocardial involvement, but it was contraindicated due to the procedure-related risk in a hemodynamically instable patient. However, cardiac MRI, increasingly used to diagnose myocarditis (29) on the back of the non-invasiveness of the technique, con rmed the diagnosis throughout pathognomonic ndings. In addition, the lack of etiological agents other than SARS-CoV-2 identi ed at repeated cultures decreases the likelihood of a cryptogenic bacterial systemic infection. Furthermore, our patient was treated with supportive therapy, empirical antibiotics and remdesivir. Assessing the relative contribution of each of these treatments and discerning between therapeutic effectiveness and natural history of the disease in an otherwise healthy child may be misleading. However, the timing of remdesivir administration suggests that it may have played a role in the positive evolution of the overall clinical picture.

Availability of data and materials
Not applicable

Competing interests
The authors declare that they have no competing interests.

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download. CARECHECKLIST.pdf