A Systematic Review of Arterial Dissections in COVID-19 Patients

Introduction

COVID-19 is often seen presenting with a myriad of signs and symptoms of multiorgan dysfunction including arterial dissection.

Method

Various theories have been proposed such as endothelial dysfunction triggered by hyper-inflammatory response that results in rupture of atherosclerotic plaque and subsequent dissection.

Result

However, the exact incidence is unknown and only case reports and case series have been published till date.

Conclusion

Here we carried out a systematic analysis of published case reports/series related to dissection of the aorta, coronary, cerebral, vertebral, cervical, renal, and splanchnic arteries.

1. INTRODUCTION

The novel virus SARS-COV-2 causing the current pandemic presents itself with a myriad of signs and symptoms involving multiorgan manifestations with a predominance of the respiratory system. There has been an exponential number of reports surfacing of multisite arterial dissections in COVID-19 patients without any antecedent causes, probably attributing to vasculopathy and/or vasculitis due to secondary causes [1]. It is proposed that SARS-COV-2-triggered inflammatory response exacerbates endothelial dysfunction, rupturing atherosclerotic plaque, thereby leading to hematoma and dissection [2].

Viral illnesses have been implicated in arterial dissection secondary to direct injury by viral replication or indirectly by autoimmune or proinflammatory cascades. Arterial dissection may be related to the intra-adventitial hematoma in a plaque dissecting the tunica by spreading longitudinally [3]. Compared to the non-influenza season, increased cases of aortic dissection and higher mortality rate in associated urgent surgeries are noted in the influenza season [4]. Viral infections with human immunodeficiency virus, hepatitis C, parvo virus B19, varicella zoster virus, and cytomegalovirus are associated with cerebral aneurysmal vasculopathy [5]. Interestingly, hepatitis B virus is responsible for around 36 to 50% of polyarteritis nodosa cases [6].

SARS-COV-2 binds to angiotensin-converting enzyme II receptors and disrupts endothelial function, resulting in endothelial inflammation (and thinning), and consequently, arterial dissection [1]. Massive cytokine storm, microthrombosis,and secondary endothelial injury are among the pathophysiological pathways implicating SARS-COV-2 in a hypercoagulable state [7]. High-dose corticosteroid therapy commonly used for the treatment of Covid-19 could also be a causative factor for spontaneous dissection in an already weakened arterial wall [8].

As the different afflictions of this virus manifest, it is pertinent that clinicians are aware of the various consequences while monitoring and providing optimal patient care. The mounting evidence of multiple cases and associated increased mortality and morbidity of Covid-19 patients with arterial dissection without any inciting factors is the basis of this review.

2. METHODOLOGY

2.1. Search Strategy and Data Extraction

We used the following search strategy: combinations of medical subject heading terms with the Boolean operators “And” or “Or”: “COVID 19”, “SARS -COV 2” “arterial dissection”/ “coronary artery dissection”/“cerebral artery dissection”/“cervical artery dissection”/ “vertebral artery dissection”. We searched the following databases: Medline, Cochrane Central, Google scholar, and Med Rx preprint server. The latest search date was 20^th October, 2021. Additionally, we carried out a manual search for eligible references from the included studies. Two reviewers (BA and SDM) independently screened and extracted the necessary details. In case of any dispute, the third author (KS) was involved in the consultation, and a decision was taken. We included only case reports/series as there were no observational studies published at the time of preparing this manuscript. We used the Joanna Briggs Institute (JBI) Critical Appraisal tools for use in JBI Systematic Review Checklists for Case Reports for evaluating the quality of included reports [9]. This checklist has eight items, of which three items (numbers 5, 6, and 7) were not applicable for the present review as they were related to interventions, and so were excluded.

2.2. Population and Outcomes Of Interest

We included case reports/series that included any patient (child or adult) diagnosed with arterial dissection with COVID-19 infection. Arterial dissection at any location confirmed with an imaging modality, such as computed tomography (CT) angiography, magnetic resonance (MR) angiography, conventional angiography, or Doppler ultrasound imaging, was considered. Only those reports that included patients with laboratory-confirmed COVID-19 infection were included. Those reports with patients receiving corticosteroids, having concomitant history of trauma, pregnancy, arterial dissection-associated connective tissue disorders, and previous arterial dissections, were excluded. The following details were captured from each of the eligible reports: site of arterial dissection, associated symptoms, risk factors, COVID-19 severity (severe cases requiring mechanical ventilation), prognosis, and other relevant epidemiological and laboratory data.

2.3. Statistical Analysis

Descriptive statistics were used to represent the variables with numbers and percentages.

3. RESULTS

3.1. Included Studies

Our search hit 287 unique citations, of which 33 were finally included (Fig. 1). The JBI checklist revealed that almost all items were reported by each of the included studies (Table 1) [10-39].

Fig. (1).

Study flowchart.

Table 1.

JBI checklist evaluation of the included studies.

JBI Checklist Item Numbers	1	2	3	4	8
Akgul et al. [10]	Y	Y	Y	Y	Y
Fesharaki et al. [11]	Y	U	Y	Y	Y
Mori et al. [12]	Y	Y	Y	Y	Y
Fukuhara et al. [13]	Y	Y	Y	Y	Y
Martens et al. [14]	Y	Y	Y	Y	Y
Tabaghi et al. [15]	Y	Y	Y	Y	Y
Farkash et al. [16]	Y	Y	Y	Y	Y
He H. et al. [17]	Y	U	Y	Y	Y
Taccherin et al. [18]	Y	Y	Y	Y	Y
Rossi et al. [19]	Y	Y	Y	Y	Y
Halasz G et al. [20]	Y	Y	Y	Y	Y
Albiero et al. [21]	Y	Y	Y	Y	Y
Gasso et al. [22]	Y	U	Y	Y	Y
Kumar et al. [23]	Y	U	Y	Y	Y
Kireev et al. [24]	Y	Y	Y	Y	Y
Cannata et al. [25]	Y	U	Y	Y	Y
Courand et al. [2]	Y	U	Y	Y	Y
Morassi et al. [26]	Y	Y	Y	Y	Y
Patel et al. [27]	Y	Y	Y	Y	Y
Papanikolaou et al. [28]	Y	Y	Y	Y	Y
Aparisi et al. [8]	Y	Y	Y	U	Y
Romiti S et al. [29]	Y	Y	Y	Y	Y
Dakay et al. [30]	Y	U	Y	Y	Y
Savic et al. [31]	Y	Y	Y	Y	Y
Hernandez-Fernandez et al. [32]	Y	U	Y	Y	Y
Jariwala et al. [33]	Y	Y	Y	Y	Y
Engin et al. [34]	Y	Y	Y	Y	Y
Dhaliwal et al. [35]	Y	U	Y	Y	Y
Voci et al. [36]	Y	Y	Y	Y	Y
Parmar et al. [37]	Y	Y	Y	Y	Y
Lopez Marco et al. [38]	U	N	U	Y	Y
Emren et al. [39]	Y	Y	Y	Y	Y

JBI checklist items: 1. Were patient’s demographic characteristics clearly described? 2. Was the patient’s history clearly described and presented as a timeline? 3. Was the current clinical condition of the patient on presentation clearly described? 4. Were diagnostic tests or assessment methods and the results clearly described? 5. Does the case report provide takeaway lessons? Y-Yes; U-Unclear.

3.2. Demography and Clinical Symptomatology

42 patients were reported in the 33 included studies, with an age range of 13 to 81 years and a male preponderance (28/42, 66.6%). Nasopharyngeal RT-PCR technique was used to confirm Covid-19 in most cases (38/42, 90.4%). Most patients with mild COVID-19 infection (26/42, 61.9%) presented with arterial dissections. The majority of the patients (21/42,50%) were between 45 to 59 years, and there was one child (1/42, 0.02%). Most cases were reported from the USA (8/42, 19%) and Italy (6/42,14.2%). Common risk factors included hypertension (12/20,60%), diabetes mellitus (3/20, 15%), dyslipidemia (3/20, 15%), and smoking (3/20, 15%). No risk factors were identified in 20 patients (47.6%). Chest pain (19/42,45.2%), fever (14/42, 33.3%), and cough (14/42, 33.3%) were the commonly reported symptoms. The period between the onset of Covid-19-like symptoms and presentation to the hospital with symptoms/signs of arterial dissection ranged from 1 day to 8 weeks (n = 34). The average range of hospitalization was 3-22 days (n = 21).

Aortic dissections (22/42,52.3%), coronary artery (10/42, 23.8%), cerebral artery (3/42, 7.1%), vertebral artery (3/42, 7.1%), cervical artery (4/42, 9.5%), renal artery (1/42, 2.3%), and splanchnic artery dissections (1/42, 2.3%) were reported. Multiple (7/42, 16.6%) and bilateral (2/42, 4.7%) dissections were also reported. Type A aortic (17/42, 40.4%) and left anterior descending artery (7/42, 16.6%) were the commonly reported dissections.

3.3. Laboratory Findings

Coronary angiography (14/42, 33.3%) and CT angiogram (13/42, 30.9%) were the commonly used imaging modalities. Elevated C-reactive protein (CRP) and D-dimer levels were reported among 7 and 4 patients, respectively (n=13 reports), and ferritin was observed in 6 (n=9 report) patients. The details of the key characteristics of the individual reports for coronary artery dissections are mentioned in Table 2, those of cerebral/vertebral artery dissections are reported in Table 3, and of aortic dissections in Table 4.

Table 2.

Key characteristics of the reports on coronary artery dissection.

Study ID	Age (Years)	Gender	Co-morbidities	Exact location of Dissection	Day of Identification	Imaging	Presenting Symptoms	CTD Workup	Elevated Inflammatory Markers	Outcomes	Covid-19 Severity	Duration of Hospital Stay (days)	Location
Albiero et al. [21]	70	M	DM, HT, CAD, smoking	Proximal LAD	Day 2	Coronary angiogram	Chest pain	NM	D-dimer = 736 ng/ml	Discharged with dual antiplatelet and anticoagulant drugs	Mild	12	Italy
Gasso et al. [22]	39	M	Nil	First obtuse marginal artery and proximal LAD	Day 1	Coronary angiogram	Fever, chest pain, dyspnea, cough	Work up was negative	D-dimer = 322 ng/ml, CRP = 26 mg/L, Serum ferritin = 967 µg/L	Discharged with dual antiplatelet drugs	Severe	NM	Spain
Kumar et al. [23]	48	F	Migraine, dyslipidemia	LAD	-	Coronary angiogram	Chest pain	NM	NM	Discharged with aspirin	Mild	NM	USA
Kireev et al. [24]	35	M	Serpiginous choroiditis	Ramus intermedia and RCA	15 days	Coronary angiogram	Chest pain, fever, cough, anosmia	NM	CRP = 12.5 mg/L, D-dimer = 234 ng/ml	Discharged following stent	Mild	13	Russia
Cannata et al. [25]	45	F	Nil	LAD	8 weeks prior	Coronary angiogram	Chest pain, anosmia	Work up was negative	NM	Discharged with dual antiplatelet drugs	Mild	NM	UK
Courand et al. [2]	55	M	PAD	Mid RCA	Day 1	Coronary angiogram+ optical coherence tomogram	Fever, dyspnea, cough, chest pain	Work up was negative	NM	Discharge with aspirin	Mild	NM	France
Morassi et al. [26]	58	M	Oligodendroglioma related epilepsy	Bilateral carotid artery	Day 1	MR angiogram	Fever, headache, neck pain, cough	Work up was negative	CRP = 45.2 mg/L	Discharged with anticoagulant	Moderate	22	Italy
Papanikolaou et al. [28]	51	F	HT	LAD	Day 1	Coronary angiogram	Fever, cough, dyspnea	Work up was negative	NM	Discharged with antiplatelet and anticoagulant	Mild	18	Saudi Arabia
Aparisi et al. [8]	40	M	NIL	Distal LAD	Day 1	Coronary angiogram	Fever, dyspnea, cough	NM	D-dimer > 10000 ng/ml, CRP > 300 mg/L, Serum ferritin > 3000 µg/L	Discharged with complete resolution along with aspirin	Severe	NM	Spain
Romiti S et al. [29]	57	F	Smoking, HT, dyslipidemia, hypothyroidism	First obtuse marginal LCX, LAD dissection	Day 1	Coronary angiogram, Intravascular USG	Fever	NM	D-dimer = 383 ng/ml, CRP < 0.1 mg/L	Discharged with anticoagulants	Mild	21	Italy
Emren et al. [39]	50	M	NIL	RCA	Day 7	Coronary angiogram	Chest pain, cough	NM	NM	Discharged with antiplatelets	Mild	2	Turkey

M - Male; F - Female; DM - Diabetes mellitus; HT - Hypertension; CAD - coronary artery disease; CTD - Connective tissue disorder; NM - Not mentioned; MR - Magnetic resonance; CTA - Computed tomography angiogram; DSA - Digital subtraction angiogram; USG - Ultrasonogram; LAD - left anterior descending artery; RCA - Right coronary artery; LCX - Left circumflex artery; PAD - Peripheral artery disease.

Table 3.

Key characteristics of the reports on cerebral/vertebral artery dissections.

	Age (in Years)	Study Type	Location	Gender	Location of Dissection	Comorbidities	Elevated Inflammatory Markers	COVID Severity	Presenting Symptoms	CTD Workup	Day of Symptom onset	Outcome	Treatment	Associated Neurological Conditions	Imaging
Dakay et al. [30]	31	Case series	USA	F	MCA and v2 segment vertebral artery dissection	Nil	Ferritin = 151 µg/L, CRP = 1.5 mg/L	Mild	NM	Negative	Day 1	Discharged	Conservative	RCVS with SAH	CTA
	57			F	Cervical ICA	Nil	Dimer 7.79 ng/ml, Ferritin = 431 µg/L, CRP = 38 mg/L	Severe	NM	Negative	Day 1	Unfavorable	Mechanical thrombectomy	Large vessel occlusion stroke	CTA
	81			M	Cervical+supraclinoid ICA	Nil	Dimer >35 ng/ml, Ferritin = 772.8 µg/L, CRP = 17 mg/L	Severe	NM	Negative	Day 1	Unfavorable	conservative		CTA
Savic et al. [31]	13	Case report	Syria	F	M2 MCA	Nil	D-dimer 2032 ng/ml, CRP = 13 mg/L	Severe	Depressed consciousness+right side weakness	NM	Day 10	Poor GCS	Frontotemporal craniectomy with hematoma evacuation	Left pseudo aneurysm +partial thrombosis	DSA, CTA
Hernandez-Fernandez et al. [32]	62	Case series	Spain	M	L vertebral artery V1+cerebellar infarction+basilar artery occlusion	HT	D-dimer 267 ng/ml, Ferritin = 918 µg/L	Mild	NM	Negative	Nil	Discharged	Mechanical thrombectomy	Vertebral-basilar infarct	CTA
	48	Case series	Spain	M	Left Bulbar carotid Artery dissection	Nil	D-dimer = 329 ng/ml, Ferritin = 361 µg/L	Mild	NM	Negative	Day 1	Discharged	Conservative	Right parietal subacute infarction	CTA
Patel et al. [27]	39	Case report	USA	M	V3-bilateral dissection	Nil	D-Dimer 224ng/ml,Ferritin 42ng/ml	Mild	Headache, neck pain	Negative	DAY 3	Discharged	Conservative-medical	V3-bilateral-stenosis	CTA

RCVS - Reversible cerebral vasoconstriction syndrome; SAH - Subarachnoid hemorrhage; DSA - Digital subtraction angiogram; CTA - Computed tomography angiogram; M - Male; F - Female; MCA - Middle cerebral artery; HT - Hypertension; ICA - Internal carotid artery

Table 4.

Key characteristics of the included reports on aortic dissections.

Study Id	Study Report	Location	Gender	Age (in Years)	Covid-19 Severity	Affected Artery	Time from Initial Presentation	Outcome	Presenting Symptoms	Management	Comorbidities	Inflammatory Mark	Cardiac Enzymes	Imaging	Ctd Work Up	Np rt pcr	Duration of Hospital Stay (Days)	Treatment
Dhaliwal et al. [35]	Case report	NM	F	76	Mild	Type II aortic dissection	NM	discharge	Dyspnea, Chest pain	surgical	HT, hyperlipidemia, COPD	NM	NM	NM	NM	+	5	Surgical
Engin M et al. [34]	Case report	NM	M	62	Mild	Type A aortic dissection	30	discharge	Chest pain	surgical	Chr atrial fibrillation, DM, lower extremity deep venous insufficiency	lactate dehydrogenase: 417 U/L, white blood cells: 11.26 103/µL; neutrophils: 10.04 103/µL; lymphocytes: 0.61 103/µ	NM	CTA	NM	+	16	Surgical
Fukuhara et al. [13]	Case series	NM	Male	66	NM	Type A aortic dissection	21	discharge	cough	Surgical repair	NM	NM	NM	NM	NM	+	18	Surgical
		NM	Female	40	moderate	Type A aortic dissection	42	discharge	Fever, cough	Surgical repair	NM	NM	NM	NM	NM	+	19	Surgical
		NM	male	53	severe	Type A aortic dissection	1	death	nil	Surgical repair	NM	NM	NM	NM	NM	+	11	surgical
Jariwala et al. [33]	Case report	India	male	45	moderate	Type B aortic dis	3	death	Fever, cough, dyspnea	Surgical repair	nil	NM	NM	CTA	NM	+	7	surgical
Akgul et al. [10]	Case report	Turkey	female	68	mild	Type A	Day 1	Discharged pod 14	Chest pain, dyspnea	Surgical repair	HT, DM	CRP, ESR high	NM	CTA	NM	NM	14	Surgical
Mori et al. [12]	Case series	USA	male	54	mild	Intra mural haematoma-aortic root + asc aorta	Day1	discharged	Chest pain	Surgical repair	nil	-	NM	CTA	NM	+	6	Surgical
Fukuhara et al. [13]	Case report	USA	male	56	severe	Type A	Day 2	death	Chest pain, abdominal pain	Surgical repair	nil	-	NM	CTA	NM	+	11	Surgical
Martens et al. [14]	Case report	Belgium	male	64	Mild	Type A	Day 3	discharged	Chest pain, cough, right leg ischaemia	Surgical repair	HT	CRP = 271 mg/dl, Ferritin = 610 ng/ml, lymphopenia	NM	CTA, TTE	NM	+	14	Surgical
Tabaghi et al. [15]	Case report	Iran	Female	47	severe	Asc aorta+aortic root	Day 1	death	Chest pain, diarrhea,cough	nil	nil	-	NM	TTE	NM	+	8
Farkash et al. [16]	Brief report	USA	Male	53	severe	Type A	Day 1	death	-	Surgical repair	NIL	Lymphocytes-18000/µl	NM	CTA	NM	+	12	Surgical
He et al. [17]	Case Series	China	Male	62	mild	Type A	Day 1	-	Chest pain	Surgical repair	NIL	NM	NM	CTA	NM	+	NM	Surgical
		China	Female	59	mild	Type A	Day 1	-	Fever, chest pain	Surgical repair	hypertension	NM	NM	CTA	NM	+	NM	Surgical
Taccherinet al. [18]	Letter to editor	Italy	Male	50	Severe	De bakey 2	7 days early	death	Fever, syncope	Surgical	NM	high	NM	CTA	NM	+	10	Surgical
Rossi et al. [19]	Case report	Italy	female	64	moderate	TypeB	Day 1	discharge	Syncope,dyspnea,chest pain	surgical	-	NM	NM	CTA	NM	+	14
Halasz G et al. [20]	Case series	Italy	male	57	mild	Type B	12	discharged	Chest pain, dyspnea	Heparin	nm	D-Dimer = 2383 ng/ml	NM	NM	NM	+	NM	NM
Lopez -Marco et al. [38]	Case series	UK	Male	55	Severe	Type A	NM	Discharged-unfavourable	Nm	Surgical	HT, IHD, smoking	NM	NM	NM	NM	+	45	Surgical
		UK	Male	54	Mild	Type A	NM	Discharged	NM	Surgical	HT	NM	NM	NM	NM	+	15	Surgical
		UK	Male	67	Mild	Type A	NM	Discharged	NM	Surgical	HT	NM	NM	NM	NM	+	9	Surgical
		UK	Male	58	Severe	Type A	NM	Died	Nm	Surgical	HT	NM	NM	NM	NM	+	4	Surgical

Note: NM - Not mentioned; HT - Hypertension; COPD - Chronic obstructive pulmonary disease; IHD - Ischemic heart disease; CRP - C-reactive protein; ESR - Erythrocyte sedimentation rate.

3.4. Treatments Provided and Outcomes

Most patients with aortic dissection underwent surgical repair (18/21, 85.7%) and patients with coronary dissections were conservatively managed with anticoagulation and/or antiplatelets. 7 deaths (16.67%) were reported, and all of them were from aortic dissection. Seven patients (9/42, 21.4%) reported an unfavorable outcome, especially among patients with aortic dissection.

4. DISCUSSION

We carried out the present review reporting the clinical characteristics, risk factors, diagnostic and therapeutic management of patients with arterial dissections in confirmed Covid-19 infection. To the best of our knowledge, this is the first attempt to discern the possibility of association of arterial dissections in COVID-19 through a systematic approach. Most of the included reports were identified to have included key elements as per the quality assessment tool. This study enhances the understanding of the vascular manifestations of SARS-CoV-2, which is primarily considered a respiratory pathogen. Arterial dissections were commonly seen in the age group of 45 -59 years.

Spontaneous coronary artery dissection is more common in women; however, in the present review, more reports have been presented in males (probably related to a higher incidence of Covid-19 infection) [8]. Arterial dissection could occur at any time during index events, adding to the difficulty in diagnosis [8]. COVID-19 virus occurs in the lungs through the binding of spike proteins with the angiotensin-converting enzyme 2 (ACE 2) receptors that are also widely present in the endothelial cells [40]. COVID-19 virus, through feedback mechanism, activates the renin-angiotensin aldosterone system, leading to an imbalance between the vasodilatory and vasoconstrictor molecules in the blood vessels, thus leading to vasculitis [41]. Systemic vasculitis and vasculitis in the cerebral blood vessels have been observed to occur in the SARS-Cov-1 virus [42]. Systemic vasculitides can be grouped as small, medium, and large-sized, wherein large size refers to the involvement of the aorta and its branches [43]. In the present review, it was observed that almost all the cases with aortic dissection hardly had dissections of the other systemic blood vessels. We hypothesize that it may be due to the differences in the section of the artery that is affected in COVID-19 disease, like the differences in the vasculitis in Takayasu arteritis (arterial thickness is greater, and all the layers are involved in hyperplasia and neovascularization observed in tunica intima) and giant cell arteritis (more severe inflammation in the innermost part of tunica media) [43, 44]. Conservative management seems to appear as a safe strategy. The thrombolysis first approach advocated in Covid-19 patients with ST-elevation myocardial infarction could be risky in case of arterial dissection [9]. The prothrombotic state of Covid-19 raises serious concerns regarding anticoagulation and antiplatelet strategies [8].

The strength of the present review is that this is the only systematic compilation of reports related to this topic. However, there is a possibility that a large fraction of patients in this Covid-19 pandemic manifesting with diseases pathogenically not related to infection are infected. Low incidence, limitation in detection, and rapid mortality rate in certain groups may cause hindrance to causality confirmation. These cases may only be a blip on the radar while keeping in mind the serious issue of under-reporting in an exhaustive pandemic situation. This study is limited by a tiny sample size with insufficient data characteristics, scarce documentation on the follow-up period, and long-term sequelae. Larger epidemiological studies with rigorous design are needed to establish any possible association of arterial dissection among COVID-19 patients and anticoagulation strategies.

CONCLUSION

With the ever-evolving clinical manifestations of the current pandemic, a high degree of suspicion in diagnosing rare complications, like arterial dissection, is pertinent for timely management. Large-scale epidemiological studies will be needed to ascertain the causality of rapidly evolving COVID-19 and arterial dissection.

LIST OF ABBREVIATIONS

JBI

Joanna Briggs Institute

CRP

C-reactive Protein

CONSENT FOR PUBLICATION

Not applicable.

STANDARDS OF REPORTING

PRISMA guidelines were followed.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

SUPPLEMENTARY MATERIAL

PRISMA checklist is available as supplementary material on the publisher’s website along with the published article.