key: cord-0989031-0ngmt7s0
authors: Kermani-Alghoraishi, Mohammad; Pouramini, Alireza; Kafi, Fatemeh; Khosravi, Alireza
title: Coronavirus disease 2019 (COVID-19) and severe pericardial effusion: from pathogenesis to management: a case report based systematic review
date: 2021-07-24
journal: Curr Probl Cardiol
DOI: 10.1016/j.cpcardiol.2021.100933
sha: dd3c3dbbfc328ef0c52044560de60d05f0507708
doc_id: 989031
cord_uid: 0ngmt7s0

The Severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) created a global pandemic that continues to this day. In addition to pulmonary symptoms, the virus can have destructive effects on other organs, especially the heart. For example, large pericardial effusion has been observed as a critical and life-threatening finding in Coronavirus disease of 2019 (COVID-19) patients. In this case report based systematic review, we review the reports of moderate to severe pericardial effusion associated with tamponade physiology. Direct cardiomyocyte and pericardium invasion, inflammation and cytokine storms and oxidative stress due to acute respiratory distress syndrome (ARDS), are the pathogenesis of this phenomenon. The results showed that the manifestations of this finding are variable. Pericardial effusion can be seen as a delayed complication, accompanied by myocarditis or pericarditis, isolated, or with ARDS. In most patients, emergency percutaneous pericardiocentesis was performed, and fluid analysis was often exudative in three pattern of hemorrhagic, serous, and serosanguinous. Medical treatment and follow-up are recommended, especially in cases of pericarditis.

Since December 2019, the first infected case of Coronavirus Disease of 2019 (COVID- 19) According to past reports, COVID-19 can lead to pericardial effusion present in different clinical settings, such as pericardial effusion in patients with pericarditis/myocarditis, isolated or accompanied by the acute respiratory syndrome. Interestingly minimal to sizeable pericardial effusion can be manifested in COVID-19 patients. In this case report-based systematic review, we aim to discuss COVID-19 cases with moderate to large pericardial effusion with tamponade physiology as a dangerous and life-threatening presentation.

We conducted a literature search using PubMed/Medline, Scopus, and Web of Sciences databases from their inception up to 16 April 2021 utilizing Boolean operators and combinations of word variants for ("coronavirus" OR "COVID-19" OR "severe acute respiratory syndrome" OR "SARS-CoV-2") AND ("Pericardial Effusion" OR "Cardiac Tamponade"). The duplicate reports were excluded from study and abstracts with English language restriction were used to identify relevant articles. The reference lists of selected articles were also reviewed for additional relevant articles. The search was conducted by an author, selecting eligible studies independently performed by two authors. A third author was consulted in the case of disagreement between the initial two reviewers.

We identified 30 suitable case reports for inclusion in this systematic review (Table 1) . Three papers have been presented as case series and brief literature review (4) (5) (6) .

There are several mechanisms of cardiovascular injury in COVID-19 patients. First is the direct involvement of SARS-COV-2, and the second is the indirect effect of this virus through the cytokine hypothesis and oxidative stress process. Similar theories have been proposed for pericardial involvement in COVID-19 patients: (1) Angiotensin-converting enzyme 2 (ACE2) receptor is expressed in different cells like cardiomyocytes and vascular endothelium, vascular smooth muscle cells, and cardiac fibroblast. SARS-COV-2 binds to cells by ACE2 receptors and activates the ACE2 signaling pathway. Ultimately the signaling pathway induces myocardial injury and cardiomyopathy, and this process may lead to pericardial effusion as a final phenomenon. However, the direct mechanism of COVID-19 in pericardial effusion is still unclear. Farina et al. report the isolation of SARS-CoV-2 in the pericardial fluid by the reverse transcription-polymerase chain reaction (RT-PCR) method (7) (8) (9) . (2) Activation of macrophage and endothelial cells cause cytokine storm and inflammation in severe cases with a massive release of TNF-α, IL-1, IL-6, and IL-8. A further level of these cytokines above the normal thresholds leads to adverse damage (9, 10) . One of the repercussions of cytokine storms in COVID-19 patients is pericarditis. Interstitial mononuclear cell infiltration in the myocardium of autopsy cases shows over activation of the immune system and inflammatory damage, too (11) . Therefore, the sustained cytokine releasing causes myocarditis and perimyocarditis (9) . Pericardial effusion may occur as a secondary reaction to myocardial and pericardial inflammation. 

With rising numbers of COVID-19 cases, various manifestations of coronavirus have appeared. As mentioned above, significant pericardial effusion can be presented in various forms, from isolated form to cases of concomitant with pericarditis, myocarditis, and even respiratory symptoms ( Figure 1 ).

Pericardial effusion can be presented as a late finding in COVID-19 positive patients. reported an acute myopericarditis and pericardial effusion case, even in the absence of respiratory symptoms (19) .

Rarely isolated myocarditis or pericarditis with pericardial effusion may be seen among 

To continue, we highlight a COVID-19 patient who developed Takotsubo cardiomyopathy following cardiac tamponade to be aware of these challenges. This case of COVID-19 reported by Torabi et al. indicates that the LV apex was dilated with systolic hypokinesis and basal segments had preserved contraction, supporting the diagnosis of the Takotsubo pattern (25) . Also, another similar case was reported by Dabbagh et al. they presented Takotsubo cardiomyopathy following large hemorrhagic pericardial effusion in a 67-year-old woman. She was hospitalized with the usual symptoms of COVID-19 and left shoulder pain.

One week later, the patient presented with progressing dyspnea and orthopnea. A sizeable pericardial effusion is shown in transthoracic echocardiography (TTE). After pericardiocentesis, this patient developed Takotsubo syndrome, as evident by TTE, ECG findings, and an increase in cardiac troponin I(26).

There are several cases of respiratory failure due to COVID-19 and cardiac tamponade. 

Pericarditis presenting with acute pericardial tamponade can be accurate in children, such as, in a case reported by Raymond et al., A seven-year-old female presented with cough, chest pain, and orthopnea for three days. A chest X-ray revealed an enlarged cardiac silhouette. An electrocardiogram showed sinus tachycardia, T-wave inversion in inferior and lateral leads, low voltage QRS with electrical alternans, and echocardiogram findings suggest large circumferential pericardial effusion with tamponade physiology (30) .

History taking, physical examination, biomarkers, ECG, and imaging findings can be used to diagnose heart disease in patients with COVID-19 ( Figure 2 ). In general, any finding to diagnose pericarditis or pericardial effusion can be substantial. The history of a patient with pleuritic chest pain radiating to the trapezius muscle is a pathognomonic sign of pericarditis which warns of the need for pericardial effusion. Shortness of breath and deterioration of symptoms, especially dyspnea and orthopnea, can be a warning sign for significant fluid in the pericardium.

On physical examination, raised JVP, tachycardia, tachypnea, hypotension, pulsus paradoxus, muffled heart sound, and pericardial friction rub can be the signs of significant pericardial effusion with or without pericarditis and myocarditis (7, 21, 31) .

Inflammatory markers, D-Dimer (31) , and brain natriuretic peptide (26) have increased in most cases, especially in cases of severe pulmonary involvement. Troponin as a non-specific biomarker can be negative (12, 20, (26) (27) (28) (29) 31) , slightly elevated (8, 13, 15, 24) , or high. In cases with high troponin levels, suspicion of concomitant myocarditis increases (18) . Chest x-rays are frequently used in COVID-19 patients. In very large effusions, the cardiac silhouette can appear Flask-liken. However, chest x-ray findings are not sensitive and specific enough. Clues to pericardial effusion in ECG are sinus tachycardia (especially without fever), low QRS voltage, and electrical alternant (12) . PR depression with concave diffuse ST elevation and non-specific ST-T changes like invert T wave are signs of pericarditis and myocarditis, respectively. Pericardial effusion may be seen as an incidental finding during a chest CT scan. According to a recent meta-analysis, 4.55% of CT scans revealed pericardial effusion. Like what happened in the case report of Rajevac et al., (32, 33 ) echocardiography helps estimate the size and detect pericardial effusion. Some echocardiography findings help diagnose cardiac tamponades, such as the collapse of the right atrium at end-diastole and the right ventricle in early diastole, reciprocal changes in left and right ventricular volumes with respiration for diagnosing of pulsus paradoxus, dilation of the inferior vena cava, and increased respiratory variation of mitral and tricuspid valve inflow. Further imaging with MRI is rarely needed; however, it can be done in patients with indeterminate echocardiography findings or suspected of myocarditis (34) .

Size can classify pericardial effusion in patients of COVID-19 as mild, moderate, and large.

Medication is limited to mild and moderate pericardial effusion cases, especially those with pericarditis pathology. In general, we do not have a specific guideline for pericardial effusion in patients with COVID-19. However, it has been suggested that using colchicine alone or in combination with anti-inflammatory medications can be helpful (4) . The WHO disagrees with the order of Non-steroidal anti-inflammatory drugs (NSAIDs) in patients with COVID-19 because NSAIDs facilitate virus invasion into cells by increasing ACE2 receptor expression (23) . However, The European Medicines Agency (EMA) said there is no scientific evidence for worsening the condition of COVID-19 patients about using NSAIDs (35) . The most commonly used NSAIDs reported was ibuprofen, which did not have any severe side effects.

The recommended duration is three months for colchicine and 7 to 14 days for NSAIDs or C-Reactive Protein (CRP) level based (20, 29, 36) . As said beforehand, colchicine has been selected as the first drug for pericarditis, and pericardial effusion in COVID-19 patients, which can directly or indirectly reduce inflammation. Steroids can be also used especially in patients with the critical condition and severe respiratory disease, like what was done in Gill et al. case report that managed with colchicine and intravenous steroids (24) . Oral steroids can be used instead of NSAIDs in patients who have not responded or are intolerant to NSAIDs. Therefore, preferably using steroids with colchicine be recommended to reduce recurrence.

Hemodynamically unstable patients with moderate/large effusion require urgent drainage (27) . There are two ways to treat large pericardial effusion: surgical drainage and percutaneous pericardiocentesis. Both techniques lead to rapid relief of cardiac effusion.

Percutaneous pericardiocentesis is more common in most hospital settings and can be performed under echocardiographic or fluoroscopy guidance (37) . Surgical drainage is done when the patient has coagulopathy, or a biopsy is desired for diagnostic purposes. For instance, Cruz et al. using the surgical technique and then sending a pericardium sample to the pathology for their patient (14) .

Three types of serosanguinous, serous, and bloody pericardial effusion have been shown in patients with COVID-19. Hemorrhagic pericardial effusion needs intensive treatment due to developed recurrence or constrictive pericarditis as a complication (38) . Also, usually, it has not associated with a viral infection, except Coxsackievirus and now COVID-19 (39) . Lactate dehydrogenase and albumin levels evaluations indicated that most of the pericardial effusions in COVID-19 are exudative 4, 15, 16, 23, 26, 42 ; however, in a few cases, a transudate pattern has been seen (27, 30) . Findings suggested the fluid was sterile and viral, fungal, and acid-fast bacteria cultures were negative. Standard viral RNA can often detect the virus in the pericardial fluid and was negative in most cases. Although, reverse transcriptase-polymerase chain reaction and electron microscopy can be used for detecting COVID-19 in the pericardial fluid (8, 14) .

Over time, we realized that the coronavirus is not limited to symptoms of the respiratory system. It can cause extra-pulmonary complications too. Severe pericardial effusion following a viral infection is generally a rare and delayed finding, but in this review, we saw its various and critical manifestations in patients with COVID-19. Pericardial effusion can be presented in COVID-19 cases from stable and outpatients to severely critical patients who needed ICU, which requires rapid invasive action in hemodynamically disruptive conditions.

As a result, it should be noted that the presence of significant pericardial effusion in COVID-19 patients indicates a poorer prognosis. However, the severity of inflammation, myocardial involvement, and pulmonary involvement is not always directly related to the severity of pericardial effusion.

None to declare. 

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The authors gratefully acknowledge Rahil Ghahramani M.D., for her help during our research.

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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