COVID-19-Related Pericarditis with Pericardial Clotting as a Hallmark: Two Cases and a Review.

The prevalence of pericardial effusion and its clinical significance is not well understood in COVID-19 patients. We report two cases of COVID-19-related pericardial effusion complicated by intrapericardial clot formation. The final outcome was favorable, but intrapericardial clot remained mostly unchanged at 6-month follow-up. The treatment approach and the long-term consequences are still unclear. We propose a review of this particular cardiovascular complication in COVID-19 patients. Copyright:

INTRODUCTION

An outbreak of pneumonia caused by a new coronavirus started in China in December 2019. The infection spread to Europe starting from Italy in February 2020. On March 11, 2020, the coronavirus infection has been declared a pandemic.

Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While affecting dominantly the respiratory system, COVID-19 may also cause acute and chronic damage to the cardiovascular system. Respiratory complications have been well-documented in the novel coronavirus disease (SARS-CoV-2/COVID-19), yet an emerging body of research indicates that cardiac involvement may be implicated in poor outcomes for these patients.[1]

COVID-19-RELATED MYOPERICARDITIS

Cardiovascular comorbidities are common in patients with COVID-19 and they increase the risk of death and morbidity.[1] Even though pericardial involvement is an infrequently reported extrapulmonary manifestation of COVID-19, it should be kept in mind as intubation and positive pressure ventilation can have deleterious hemodynamic effects in these patients, especially in those with cardiac tamponade.[2] A frequent involvement of the cardiovascular system in patients with COVID-19 infection has been described in the literature. The prevalence of cardiac biomarkers elevation, electrocardiogram (ECG) or echocardiograpy abnormalities has been reported around 7,2% of patients.[3] In another study,[4] 4.8% of patients undergoing chest computed tomography (CT) had pericardial effusion and 6% of them reported chest pain in the history. These data suggest that the diagnosis of acute pericarditis in patients with COVID-19 infection may be more frequent than usually diagnosed and as a consequence, undertreated.

Gulati et al.[5] reported that, similar to MERS-CoV and SARS-CoV, COVID-19 causes acute cardiac injury in a subset of patients with corresponding elevated high-sensitivity cardiac troponin-I levels.[67] Creatine kinase-MB and high-sensitivity cardiac troponin-I were higher in intensive care unit (ICU) patients, suggesting that myocardial injury is more likely present in patients with severe disease.[89] As many as 7% of deaths in COVID-19 patients have been attributed to myocardial injury.[10] In these cases, ECG may show a regional wall motion abnormality or global hypokinesis frequently with pericardial effusion.[1] Initial ECG may show low-voltage QRS complexes in the limb leads, ST-segment elevations in leads I, II, aVL, V2–V6, and PR elevation, and ST depressions in augmented vector right, demonstrating a myopericarditis picture.[11] There should be a low threshold for SARS-CoV-2 testing in patients presenting with signs of myopericarditis, even in the absence of fever and respiratory symptoms.

Pericardial effusion has been reported in 4.55% of 2738 COVID-19 patients in a meta-analysis of chest CT imaging findings.[12]

COVID-19-RELATED PROTHROMBOTIC STATUS

COVID-19 infection is often associated with changes in the coagulation system. This coagulopathy is characterized in the early stages by the increase in D-dimer and the products of fibrin degradation.[1314] In the advanced stages, there is generally an increase in prothrombin time (PT) and activated partial thromboplastin time (aPTT), thrombocytopenia leading up to full-blown disseminated intravascular coagulation (DIC) picture.[1516] Monitoring of coagulation parameters has proven to be useful in selecting patients at greater risk of complications and with poorer prognosis. Thrombocytopenia and the increase in D-dimer are associated with an increased risk of mechanical ventilation, hospitalization in the intensive care unit, and death.[17]

Several studies have shown that D-dimer, FDP, PT elevation, and thrombocytopenia have a negative prognostic value. In a recent study by Tang et al.,[18] conducted on 183 patients, it was seen that the presence of high levels of D-dimer and fibrin degradation product (FDP) was associated with an increased mortality.

It has also been shown that the progressive worsening of these parameters during hospitalization, and not only their baseline value, was associated with a worse prognosis.[18]

The International Society of Thrombosis and Haemostasis developed and validated a sepsis-induced coagulopathy (SIC) score.[161920]

Both the definitions of DIC and SIC have been used in studies on coagulation changes in patients with COVID-19 observed in the Chinese outbreak.[1619]

Heparin treatment has been shown to be effective in improving the outcome of patients with COVID-19, especially those with elevated D-dimer values, with a prognostic benefit that was found to be directly proportional to the extent of D-dimer elevation.[21]

CASE 1

A 75-years-old man presented to the emergency room of our hospital with a 4-day history of fever and dyspnea. His medical history was unremarkable. On admission (day 1), he had a temperature of 38°C, normal blood pressure (130/80 mmHg), and heart rate (80 bpm in SR). His physical examination was unremarkable, with normal breath sounds at lung bases. Continuous positive airway pressure (CPAP) was started (days 1, 2, and 3) as he was hypoxic with SpO2 of 88% in ambient air. In consideration of the local coronavirus epidemic outbreak, nasopharyngeal and oropharyngeal swabs were immediately obtained, confirming SARS CoV-2 positivity. The patient underwent orotracheal intubation plus invasive mechanical ventilation (day 4) because of worsening respiratory status. Chest high-resolution computed tomography (HRCT) [Figure 1, Panel A] documented bilateral ground-glass opacities (GGOs) suggesting interstitial inflammatory lung disease. ECG (Figure 1, Panel B) showed sinus rhythm with heart rate of 102 bpm, a new onset left bundle branch block with QRS duration of 128 ms and QTc of 414 ms. The high-sensitivity troponin T curve was 14-27–15 pg/mL (normal value <14), N-terminal pro-BNP (NT-proBNP) was 450 pg/mL (normal value <153), and C-reactive protein was 33 mg/L (normal value <6). Markers of coagulation showed a prothrombotic status confirmed by a high D-dimer (peak of 16.6 mcg/mL-normal value range: 0–5), high fibrinogen level (peak of 791 mg/dL; normal value range: 200–400), platelet count of 269 × 109 U/L, and an aPTT of 35.3 s (normal range: 30–40 s).

Figure 1

Panel a: Case 1 – Ground-glass opacity at chest high-resolution computed tomography. Panel B: Case 1 – 12 leads electrocardiogram. Panel c, d: Case 1 – Pericardial clot at transthoracic echocardiogram. Panel e: Case 2 – Ground-glass opacity at chest high-resolution computed tomography. Panel f: Case 2 - 12 leads electrocardiogram. Panel g: Case 2 – Pericardial clot at transthoracic echocardiogram. Panel h: Case 2 – Pericardial clot at chest high-resolution computed tomography

The initial ventilation parameters were volume ventilation with tidal volume 6–8 ml/kg, according to acute respiratory distress syndrome guidelines, positive end-respiratory pressure (PEEP) 14 cmH2O, FiO2 55%, and driving pressure <15 cmH2O.

Invasive hemodynamic monitoring indicated worsening cardiac status with a reduced cardiac output index of 2.9 L/min/m2, extravascular lung water index of 7 mL/kg, and a global end-diastolic volume index of 713 mL/m2. Dobutamine support was added to therapy to maintain the cardiac index above 3 L/min/m2.

Transthoracic echocardiogram (TTE) showed a mild left ventricular systolic dysfunction (left ventricular ejection fraction [LVEF] 45%), normal right ventricular function without chamber dilation, and normal valves. There was a small pericardial effusion (max 10 mm in diastole) anteriorly with an elongated (0.5 × 2 cm) and mobile clot [Figure 1, Panel C, D]. There was near-complete resolution of the clot after therapy with 10 days of enoxaparin (1 mg/kg BID) along with lopinavir/ritonavir (400 mg BID), hydroxychloroquine, and metilprednisolone 1 mg/kg OD. The patient was extubated on the 17th day after intubation. He was on noninvasive ventilation and high-flow nasal cannula (HFNC) for 15 days and the final outcome was favorable.

At 6-month follow-up, the patient was in good conditions; HRCT demonstrated a complete resolution of lung lesions and the pericardial clot was significantly reduced in size on TTE, but it was still present.

CASE 2

A 68-year-old man presented to the the emergency system with severe dyspnea and hypoxia (SpO2: 87% in ambient air). His past medical history was significant for hypertension, obesity, diabetes, and chronic renal failure. On admission (day 1), he had a temperature of 39°C, high blood pressure (170/100 mmHg), and heart rate (110 bpm in sinus rhythm (SR)). Diffuse breath sounds (rales) were found on both lung fields and the chest HRCT [Figure 1, Panel E] revealed bilateral GGOs consistent with interstitial inflammatory lung disease. Nasopharyngeal and oropharyngeal swabs were immediately obtained, confirming SARS-CoV-2 positivity. After a CPAP attempt (days 1 and 2), the patient was intubated (day 3) with ventilatory support parameters demonstrating a high (PEEP of 15 cm H2O), FiO2 80%, and driving pressure <15 cmH2O. Serum creatinine increased to 2.3 mg/dL (glomerular filtration rate of 31 mL/min), leukocytes were 8.3 × 109 U/L, lymphocytes were 0.9 × 109 U/L, and hemoglobin was 9.3 g/dL. The high-sensitivity troponin T curve was 59-43–35 ng/L (normal value <14), NT-proBNP reached to 10.650 pg/mL (normal value <153) and C-reactive protein peak was 29 mg/L (normal value <6) with procalcitonin peak of 6.3 ng/mL (normal value range: 0–0.15). Interleuchin-6 values were 91.83 pg/mL and 37.63 pg/mL and he was treated with intravenous tocilizumab. Coagulation markers demonstrated a pro-thrombotic status with a platelet count of 160 × 109 U/L, D-dimer of 17 mcg/mL, fibrinogen of 656 mg/dL, and an aPTT of 33.8 s. ECG [Figure 1, Panel F] showed atrial fibrillation with high heart rate (111 bpm), mild ST depression, inverted T waves in V4–V6, and a QTc of 437 ms. TTE revealed a moderate left ventricular systolic dysfunction (LVEF 40%) with a mildly dilated left ventricle (end-diastolic diameter of 61 mm), normal right ventricle in size and function, and normal cardiac valves. There was a moderate pericardial effusion, anterior to the right ventricle (maximum 15 mm in diastole). A mobile and elongated (0.3 × 4 cm) clot was noted within the effusion (Panel G). The patient was treated with lopinavir/ritonavir (400 mg BID), hydroxychloroquine (200 mg BID), and enoxaparin (1 mg/kg BID). Metilprednisolone (1 mg/kg OD) was added (day 6) together with beta-blockers, diuretics, and nitrates. Due to persistent atrial fibrillation, enoxaparin was switched to edoxaban (30 mg OD) on day 9. To date (day 15), the clot continues to decrease as seen on the chest HRCT (Panel H).

The prone position was used for the first four nights in the ICU. He was extubated the 15th day after intubation; noninvasive ventilation and HFNC were used the following days to optimize oxygenation.

At 6-month follow-up, the patient was in good conditions, lung lesions appeared reduced on chest HRCT, but at TTE pericardial clot appeared unchanged [Video 1].

DISCUSSION

As the COVID-19 pandemic evolves, the medical community continues to discover novel clinical manifestations of the SARS-CoV-2 virus. Often, extrapulmonary manifestations occur simultaneously with pulmonary disease. However, there is a paucity of literature describing the cardiac manifestations of COVID-19, often in the absence of pulmonary findings.

Myopericarditis is one of the most frequent cardiac manifestations of COVID-19, but pericardial effusion remains an uncommon finding in the literature[22] and few cases of tamponade in the setting of COVID-19 have been reported.[223]

Dabbagh et al.[2] reported a 67-year-old woman who tested positive for SARS-CoV-2 1 week prior to presentation with a large hemorrhagic pericardial effusion complicated by tamponade and takotsubo cardiomyopathy. A second case, published by Inciardi et al.,[24] described a previously healthy 53-year-old Caucasian woman who tested positive for SARS-CoV-2 and presented with acute myopericarditis with circumferential pericardial effusion and left ventricular systolic dysfunction 1 week after the development of COVID-19 symptoms. Another case, published by Asif,[23] involved a 70-year-old west African woman who developed COVID-19-related pericarditis 2 weeks following treating for a non-ST-elevation myocardial infarction. There was no evidence of interstitial pulmonary disease or pneumonia in the three patients reported above.

Although the pathophysiology of effusive pericarditis in COVID-19 is unknown, it is hypothesized that it occurs secondary to the systemic inflammatory response and the subsequent cytotoxic and immune-mediated effects related to SARS-CoV-2.[222325]

In general, the causes of pericardial effusion can be broadly divided into exudates and transudates. Exudates tend to be associated with inflammatory etiologies of effusion, while transudates are typical with heart failure and hypoproteinaemic states. Hemorrhagic effusions are usually associated with acute cardiac or aortic injury, such as trauma, aortic dissection, or cardiac rupture. Hemorrhage may, however, complicate any other type of pericardial effusion and it may lead to intrapericardial clotting.[25] Chylous pericardial effusions are uncommon and are generally related to damage or obstruction to lymphatic drainage secondary to trauma (including surgery) and malignancy.[22]

Exclusion of thoracic malignancy, such as lymphoma, mesothelioma, or bronchogenic carcinoma, is mandatory when a pericardial clot is detectable.[2225]

Prothrombotic status described in COVID-19 may be an additional cause of pericarditis with thrombotic pattern in this setting of patients.

Both our patients had elevated coagulation markers (D-dimer, fibrinogen, aPTT, and platelet count), then a COVID-19-related coagulopathy was present.

This particular type of pericarditis, with pericardial clotting as hallmark, has not yet been reported in the literature among the cardiovascular complications of COVID-19. Our cases may be the first-ones reported.

The treatment approach is still unclear. Currently, there are no established guidelines for the management of pericarditis secondary to COVID-19.

In this specific type of pericarditis, anti-inflammatory and anticoagulant drugs appear to be the best option. In our patients, metylprednisolone, in association with low-molecular weight heparin (LMWH), did not lead to complete clot dissolution at 6-month follow-up.

In the same way, long-term consequences of this type of pericarditis are still unclear.

CONCLUSIONS

Acute effusive pericarditis is a rarely reported manifestation of COVID-19.

COVID-19-associated coagulopathy may lead to clot formation in several sites, including inflammatory pericardial effusion, as reported in our cases.

In these cases, LMWH, in association with anti-inflammatory medications, is recommended.

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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.