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Year : 2021  |  Volume : 10  |  Issue : 2  |  Page : 54-58

Challenge of coronavirus disease 2019-related myocarditis diagnosis in patients with negative real-time polymerase chain reaction test: A case series

1 Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
2 Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran; Cardiovascular Research Center, Kerman University of Medical Sciences, Kerman, Iran

Date of Submission25-Jan-2021
Date of Decision04-Apr-2021
Date of Acceptance08-Apr-2021
Date of Web Publication29-Jul-2021

Correspondence Address:
Dr. Marzieh Mirtajaddini
Cardiovascular Research Center, Kerman University of Medical Sciences, Kerman
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/rcm.rcm_5_21

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Severe acute respiratory syndrome coronavirus 2 (CoV-2), the cause of CoV disease 2019 (COVID-19), can lead to multi-organ injury including cardiac involvement. Acute myocarditis is one of the serious and fatal complications of COVID-19. In this report, we introduce two cases with acute myocarditis and negative real-time polymerase chain reaction test, presented during the COVID-19 pandemic and discuss the challenge of their diagnosis and management.

Keywords: Coronavirus, coronavirus disease 2019, myocardial injury, myocarditis, real-time polymerase chain reaction test

How to cite this article:
Naderi N, Mirtajaddini M, Houshmand G, Taghavi S, Amin A. Challenge of coronavirus disease 2019-related myocarditis diagnosis in patients with negative real-time polymerase chain reaction test: A case series. Res Cardiovasc Med 2021;10:54-8

How to cite this URL:
Naderi N, Mirtajaddini M, Houshmand G, Taghavi S, Amin A. Challenge of coronavirus disease 2019-related myocarditis diagnosis in patients with negative real-time polymerase chain reaction test: A case series. Res Cardiovasc Med [serial online] 2021 [cited 2021 Dec 4];10:54-8. Available from: https://www.rcvmonline.com/text.asp?2021/10/2/54/322585

  Introduction Top

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known as the cause of CoV disease 2019 (COVID-19), a clinical syndrome with hallmark of respiratory involvement.[1] In addition to the respiratory system, COVID-19 can lead to the other organs injury such as cardiovascular damage. Cardiac injury occurs in about 30% of COVID-19 patients and includes arrhythmia, myocardial infarction, myocarditis, acute heart failure, and sudden cardiac death.[2],[3],[4] Myocarditis is a serious complication of COVID-19 and other coronaviridae, such as SARS and middle east respiratory syndrome.[5],[6],[7] Here, we are going to report, two cases with acute myocarditis presented at the beginning of the COVID-19 pandemic and discuss about the challenges we encountered in the diagnosis and management of acute myocarditis during the pandemic.

  Case Report Top

Case 1

At the 1st month of pandemic, a 24-year-old man presented with fever, retrosternal compressive chest pain, dyspnea, gastrointestinal upset, and diarrhea without a history of cough and/or myalgia, for 2 days before admission. The patient had a history of close contact with a COVID-19-positive patient. Past drug and medical history were unremarkable. In triage unit of the hospital, he had an oxygen saturation of 96% at room air, a blood pressure of 120/75 mmHg, a heart rate of 110 beats/min, and a body temperature of 37.2°C. The only positive physical finding was bibasilar fine crackles on pulmonary auscultation. The electrocardiogram (ECG) demonstrated sinus tachycardia, normal QRS complex axis, and ST-segment elevation in leads II, III, and aVF [Figure 1], Panel A]. In laboratory tests, he had leukocytosis with a lymphocyte count <20%, a significantly elevated level of highly sensitive C-reactive protein (hs-CRP) and high cardiac troponin I (CTnI) level. Kidney and liver function and coagulation tests were within the normal range. The laboratory findings are presented in [Table 1].
Table 1: Laboratory findings of the patients

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Figure 1: Electrocardiogram, chest computed tomographic scan and cardiac magnetic resonance image of Case I. Electrocardiogram showing ST-segment elevation in inferior leads (a). Chest computed tomographic scan showing no significant findings of coronavirus disease 2019 pneumonia (b). Cardiac magnetic resonance with T2 mapping showing no inflammation (c). Cardiac magnetic resonance with T1 mapping showing a subepicardial fibrosis in the basal to the mid inferior wall (d)

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Transthoracic echocardiogram (TTE) showed a normal left ventricle (LV) size with an ejection fraction (EF) of 25%–30%, hypokinesia of anterior, anterolateral and lateral wall of the LV, mild LV diastolic dysfunction, mild right ventricular (RV) enlargement, and dysfunction. Valvular pathologies were not identified except for mild mitral and tricuspid regurgitation. Pulmonary arterial pressure (PAP) was within the normal limits, and pericardial effusion was not observed. In chest computed tomographic (CT) scanning, heart size and adjacent soft tissue were depicted normally, and there was no finding in favor of COVID-19 pneumonia [Figure 1], Panel B]. The patient underwent coronary CT angiography as well which showed normal coronary arteries.

With an impression of myocarditis, angiotensin-converting enzyme inhibitor (ACEI), beta blocker, and spironolactone were started for him. However, considering the COVID-19 pandemic, he was isolated in dedicated monitored beds, and two separate nasopharyngeal swab samples for real-time polymerase chain reaction (RT-PCR) test of SARS-CoV-2 were sent. The results of both samples were negative and after that, the patient underwent cardiac magnetic resonance (CMR) examination which demonstrated a normal LV size and mildly reduced EF [Supplementary Online Video 1]. No inflammation was detected in short-tau inversion recovery (STIR) T2-weighted images [Figure 1], Panel C]. However, in the T1-weighted late gadolinium images, there was a subepicardial fibrosis in the basal to the mid inferior wall [Figure 1], Panel D].

The clinical course was uneventful, and on the following days of admission, his symptoms were markedly relieved, the ECG changes were regressed, and the CTnI returned to the normal value.

He was managed medically and the COVID-19 recommended drugs including nonsteroidal anti-inflammatory medications and/or immunomodulators were avoided for him. He was discharged with a good clinical condition and was advised to be isolated and return if his condition was deteriorated. He had a generally good condition on his clinical follow-up about 2 weeks later with normal ECG and TTE findings.

Case 2

A 25-year-old male presented with a chief complaint of retrosternal pleuritic chest pain during the 1st day of COVID-19 pandemic. He did not report fever, sore throat, dyspnea, cough, myalgia and gastrointestinal symptoms. The physical examination was unremarkable. He had an oxygen saturation of 95%, a blood pressure of 125/70 mmHg, heart rate of 77 beats/min and a body temperature of 37.2°C at the time of presentation. The past medical and drug history was unremarkable. His ECG showed normal sinus rhythm, normal QRS complex axis, ST-segment elevation in leads II, III, aVF, V5 and V6 without any reciprocal changes or other significant findings [Figure 2], Panel A].
Figure 2: Electrocardiogram, chest computed tomographic scan and cardiac magnetic resonance image of Case I. Electrocardiogram showing ST-segment elevation in inferolateral leads (a). Chest computed tomographic scan showing near normal findings (b). Cardiac magnetic resonance with T2 mapping showing inflammation in the basal to mid-inferolateral, inferior and inferoseptal wall (c). Cardiac magnetic resonance with T1 mapping showing fibrosis in the mid inferolateral, inferior and inferoseptal wall (d)

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The laboratory tests demonstrated that the CTnI concentration was elevated more than 10 times its normal level. The patient had normal leukocyte count but a lymphocyte counts <20%, the hs-CRP level was high. D-dimer was normal. Kidney function, liver function, and coagulation tests were also within the normal range. The laboratory findings are summarized in [Table 1]. TTE revealed a normal LV size and diastolic function, LV was globally hypokinetic with an EF of 50%, the RV size and function were normal, there was no significant valvular disorder, no pericardial effusion and a normal PAP.

Our radiologist reported the chest CT within the normal limits [Figure 2], Panel B]. Coronary CT angiography showed normal coronary arteries. Considering the COVID-19 pandemic, high CTnI level and the ECG changes, he was suspected to have COVID-19 related acute cardiac injury. The patient was transferred to the COVID-19 monitoring unit and isolated. The RT-PCR test with nasopharyngeal swab sample was carried out which was negative for SARS-CoV-2 on two separate specimens.

Similar to our first case, he received ACEI and beta blocker with an impression of acute myocarditis. In CMR study, LV size and LVEF were normal [Supplementary Online Video 2]. T2-weighted STIR sequence revealed inflammation in the basal to mid-inferolateral, inferior, and inferoseptal wall [Figure 2], panel C]. T1-weighted late gadolinium enhancement sequences showed fibrosis in the same regions [Figure 2], Panel D]. The clinical and imaging features fulfilled myocarditis diagnosis.

During the hospital course, his clinical condition remained stable, no pneumonitis was developed and CTnI level returned to normal. At discharge, he had good clinical condition, and he was advised to be isolated. The patient was followed up in outpatient clinic, 2 weeks later. He had no symptoms and no ECG changes at follow-up evaluation.

  Discussion Top

In the current report, two cases with a diagnosis of acute myocarditis during COVID-19 pandemic were presented. Acute myocarditis was diagnosed in both patients considering the position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.[8] Although the clinical picture and chest CT of these patients were not typical for COVID-19, the laboratory findings were highly suggestive for the novel 2019 coronavirus infection, so despite negative results of RT-PCR, we supposed, the patients might have a cardiac presentation of COVID-19. We also decided to avoid the COVID-19 recommended medications considering the potential for their cardiac side effects and kept the patients under close observation. Fortunately, they could tolerate ACEI and beta blocker, and their clinical conditions remained stable in terms of COVID-19.

The cardiac involvement during COVID-19 has been defined as acute cardiac injury. The cardiac injury, which is known through high level of CTnI, occurs in 29% of COVID-19 patients.[9] The symptoms and signs of COVID-19-related myocarditis are similar to other viral myocarditis. The spectrum of COVID-19-related myocarditis is from a mild form with minimal signs and symptoms to cardiogenic shock.[10] Hence, recognizing COVID-19-related myocarditis just by the cardiac manifestations may be challenging[11] and the presence of its other manifestations and clinical involvements can be helpful in making a diagnosis. We encountered several challenges in the clinical approach to these patients. The most important challenges were the presence of acute myocarditis in a viral pandemic and the possibility of SARS-CoV-2 as the etiology of myocarditis after two negative RT-PCR tests despite some laboratory findings that were in favor of COVID-19. Mutation in the virus genome, time of sampling, symptoms severity, location of sampling, specimen collection, and preservation of test material methods may bring out false-negative RT-PCR tests.[12],[13] Al-Assaf et al. presented a case of intermittent complete atrioventricular block, 9 days after a close contact with a COVID-19 patient. The RT-PCR test was initially negative, while CMR showed evidence of myocarditis.[14] Serological tests are another method for COVID-19 diagnosis which identifies antibodies of IgM, IgG, and IgA against specific protein particles of SARS-CoV-2.[15] In some studies, these tests were used in suspected COVID-19 patients who had repeated negative RT-PCR tests.[16],[17] Although, similar to RT-PCR test, the sensitivity and specificity of serological tests vary and there is not a gold standard serological test for COVID-19 diagnosis.[18] Serologic tests were not performed in these patients due to its unavailability at the beginning of COVID-19 pandemic.

Spiral chest CT scan has acceptable sensitivity and specificity for the diagnosis of COVID-19[19] and is recommended in highly suspected patients who have negative RT-PCR tests.[20] There are many reports regarding the typical lung involvements in chest CT scan of the patients who have had negative RT-PCR test initially.[21],[22] The negligible pulmonary involvement in our cases was another diagnostic challenge.

We could find myocardial inflammation and scarring in CMR of our patients which have been observed in all of the COVID-19-related myocarditis cases for which CMR findings have been reported. The CMR findings may explain the pathophysiology concepts of COVID-19-related myocarditis. Binding of SARS-CoV-2 to its functional receptor, angiotensin-converting enzymeth-2, on the target cells including vascular endothelial cells and cardiomyocytes may lead to endothelial, microvascular, and myocardial dysfunction. Hence, the presence of microvascular dysfunction is accompanied with a myocardial inflammatory process which may be an explanation for the noticed subendocardial ischemic pattern in the CMRs of patients.[6],[23],[24]

Finally, although endomyocardial biopsy (EMB) would be a gold standard method for definite diagnosis of myocarditis, there are limitations in patients who are suspected to COVID-19-related myocarditis. In addition, having insufficient evidence regarding the best methods for the evaluation of the EMB samples and risk of contamination of the catheterization laboratory and the staff, particularly at the 1st day of pandemic would be further exacerbated. Furthermore, based on the guideline for EMB,[25] particularly their stable hemodynamic and clinical condition, was not indicated in our patients.

  Conclusion Top

We suggest that our patients might have a mild form of acute cardiac injury related to SARS-COV-2 despite negative RT-PCR test. The COVID-19 disease seems to be able to induce new cardiovascular pathologies and cardiovascular complications and appears to be a serious threat in addition to respiratory problems. It should also be clarified whether the nature of novel CoV 2019 in terms of being more contagious and spreading into different ethnicities and genetic backgrounds would be the cause of differences with its other ancestors.

The long-term cardiovascular effects of COVID-19, along with the effect of future specific antiviral therapies are subject for further investigations.

Further investigation is also needed to determine how patients with COVID-19-related myocarditis should be followed in the long term. Is there a possibility of recurrence in cases of myocarditis caused by the COVID-19? Will asymptomatic patients, with mild symptoms and people who have just suffered from respiratory problems without cardiovascular involvement, be at a greater risk for heart diseases in future?

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Ethical clearance

This manuscript is a case series.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1]


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