Clinical characteristics of COVID-19 associated vasculopathic diseases

Despite a common occurrence in COVID-19, only a few data are available that investigate signs and symptoms of COVID-19 associated PE and DVT. Data of a prospective registry including patients with symptomatic and confirmed acute VTE in COVID-19 reported similar symptoms of PE as in conventional PE. 20% of patients with COVID-19 associated PE suffered from hypotension with systolic blood pressure < 100 mmHg or requirement of vasopressors and 18% had a tachycardia (heart rate > 110/min) [25]. However, symptoms of COVID-19 associated pneumonia are often similar to those of PE, including dyspnea, tachypnea, tachycardia, cough or chest pain. Thus, the clinical diagnosis of PE is potentially obscured and complicated. Of note, 88% of reported patients received thromboprophylaxis at the time of VTE diagnosis, which highlights the excessive thrombogenicity in moderate and severe COVID-19 cases [25]. Symptoms of DVT in COVID-19 were also similar to those of conventional DVT, including lower limb pain or edema as the most frequently described symptoms [26, 27]. In contrast, typical locations of COVID-19 associated PE and DVT differed from conventional PE and DVT. Most patients in a non-COVID-19 cohort presented with central PE, while segmental and subsegmental PE were predominant in COVID-19 patients [17, 28‐30]. While proximal lower limb DVT occurs predominantly in non-COVID-19 cases, data of COVID-19 patients varied with similar rates of proximal and distal DVT, although a predominance of distal DVT was observed [26, 31]. An elevation of D-dimer level is a common finding in COVID-19, but does not necessarily indicate concomitant VTE. However, concomitant VTE in COVID-19 was often accompanied by markedly increased D-dimer levels. According to one study, 72.3% of DVT cases presented with D-dimer levels > 3000 ng/mL, and levels > 5000 ng/mL were robustly related to DVT (OR 19.44) [26]. Whyte et al. [32] detected even higher D-dimer levels in PE patients with a median value of 8000 ng/mL. Furthermore, C-reactive protein (CRP) levels were also significantly elevated in both PE and DVT while prothrombin time was comparable to patients without VTE [26, 32]. However, guidelines on the diagnostic approach for VTE in COVID-19 recommend against D-dimer and biomarker-based management in general [33, 34]. Instead, the diagnostic approach for VTE in COVID-19 patients should be based on clinical features which may indicate PE or DVT, such as an acute lower limb edema, erythema or pain, abrupt and unexplained clinical deterioration, hypoxemia, or right ventricular dysfunction. If any of these features is observed, computed tomography (CT) of the pulmonary arteries or compression ultrasonography of the veins should be performed for the detection of VTE [33, 34]. Echocardiography in COVID-19 patients with PE revealed pulmonary artery pressure > 40 mmHg in 36% and right ventricular dysfunction was observed in 33% [25]. Implementation of established therapeutic guidelines for anticoagulation in PE and DVT is recommended in confirmed cases with initial administration of therapeutic low-molecular-weight heparin (LMWH) and continuation of anticoagulative therapy by switching to a direct oral anticoagulant for at least three months [34]. Outcome studies revealed that COVID-19 cohorts with DVT seem to have an increased mortality risk compared to COVID-19 cases without DVT (40.3% vs. 14.9%) [35]. However, mortality rates between patients with COVID-19 associated DVT and non-COVID-19 patients with DVT were similar (17% vs. 19%, respectively) [36]. The risk of in-hospital death in patients with PE was significantly higher in a COVID-19 cohort compared to a non-COVID-19 group (12.8% vs. 5.3%) [37].

COVID-19 symptoms typically preceded CVT-related signs in 90% of cases, and neurological signs and symptoms seemed to be analogous to conventional CVT. Headache was the most commonly described symptom (85%), followed by epileptic seizures (42%), and altered mental status (28%), while encephalopathy, focal signs, and hemiparesis also occurred as main presenting complaints [20, 38]. COVID-19 associated CVT occurred preferably in the transverse sinus (65%), while the sigmoid sinus and superior sagittal sinus were affected in approximately 45%. Moreover, COVID-19 associated CVT occurs frequently within the deep cerebral venous system and multiple cerebral venous vessel involvement is predominately observed. Additionally, hemorrhagic lesions were detected in 42% [20, 38]. Similar to COVID-19 associated PE and DVT, data of laboratory parameters revealed elevated D-dimer and CRP levels in most COVID-19 associated CVT cases. Lymphopenia was another commonly reported laboratory finding [20, 39]. Neither diagnosis nor therapy of COVID-19 associated CVT differ from conventional CVT cases, as no specific guidelines have been established so far. Therefore, CT or magnetic resonance imaging of cerebral sinuses represent the first-line imaging techniques, and administration of anticoagulative drugs represents the first-line therapy [20, 39, 40]. Outcome data of COVID-19 associated CVT revealed higher rates of in-hospital mortality (25–40%) compared to non-COVID-19 patients with CVT (6%). Especially, parenchymal hemorrhage was associated with adverse outcome [20, 38, 41].

Clinical features of COVID-19 associated acute coronary syndrome (ACS) seem to differ partially compared to non-COVID-19 ACS. Higher prevalence of atypical symptoms, such as dyspnea and syncope, than typical chest pain was observed in COVID-19 in comparison to a pre-COVID-19 cohort with ST-elevation myocardial infarction (STEMI), although chest pain was still a common symptom with up to 60% [49‐51]. Additional data revealed that COVID-19 patients with STEMI and non-STEMI (NSTEMI) had higher rates of cardiogenic shock, heart failure and malignant arrhythmia compared to non-COVID-19 patients with ACS, while cardiac arrest was comparable between both cohorts [49, 52, 53]. Of note, one study revealed significantly higher rates of very late STEMI presentation (> 12 h from symptom onset) in the COVID-19 cohort compared to a control group [54]. Considerable are the findings of different studies postulating that the fear of COVID-19 exposure on the one hand and inadequate avoidance of medical institutions to prevent overburdening the system on the other hand led to delayed consultations [55‐58]. Hence, this delay from symptom onset to seeking help likely contributed to higher rates of cardiogenic shock and heart failure. These reasons, however, also apply to ACS patients without COVID-19. In COVID-19, the additional prothrombotic and proinflammatory state might aggravate myocardial injury and oxygen mismatch and may explain the subsequent more pronounced ischemia and worse outcome [54, 59‐61]. Interestingly, the clinical characteristics of COVID-19 associated STEMI seemed to change during the pandemic, as evaluated by Garcia et al. [62]. This study revealed that patients presented significantly more often with typical ischemic symptoms and with a trend to lower cardiogenic shock rates in 2021 compared to 2020. Changes of the electrocardiogram (ECG) were comparable among ACS patients with and without COVID-19 [51, 54]. Levels of high-sensitivity troponin, creatine kinase, and N-terminal pro-B-type natriuretic peptide were significantly elevated in STEMI patients with COVID-19 compared to STEMI patients without COVID-19, while there were no significant differences for those biomarkers between NSTEMI patients with and without COVID-19 [54, 63]. Additionally, STEMI and NSTEMI patients with COVID-19 revealed higher levels of lactate dehydrogenase (LDH) and CRP compared to non-COVID-19 cases [54]. Analyses of coronary angiographies revealed a higher thrombus burden, elevated stent thrombosis rates, and greater incidence of multiple thrombotic culprit lesions in COVID-19 patients [52, 63]. Due to diagnostic similarities of COVID-19 associated ACS with only some specific differences to non-COVID-19 ACS, the European Society of Cardiology has published a guidance paper for diagnosis and management of cardiovascular disease during COVID-19 pandemic in 2022 [64, 65]. Regarding these recommendations, the ECG diagnostic criteria for all cardiac conditions also relate to COVID-19 cases and the measurement of cardiac troponin is suggested in all cases with suspected ACS, even if troponin levels are notably elevated in severe COVID-19. Additionally, according to another joint consensus statement, COVID-19 patients with signs of concomitant acute myocardial infarction, including classic symptoms and ECG findings, might benefit from additional noninvasive imaging [66]. Therefore, the use of cardiac ultrasound to assess the cardiac function and to detect wall motion abnormalities is endorsed. These results can further support a STEMI diagnosis and evaluate the need for fibrinolysis reperfusion. Both guidance papers stated that the same treatment approach is indicated in COVID-19 patients with STEMI as for non-COVID-19 patients regarding primary percutaneous coronary intervention (PCI). Urgent fibrinolysis in COVID-19 patients with STEMI at a referral hospital is recommended, as well as a subsequent transfer for rescue PCI if indicated. COVID-19 patients with NSTEMI are also managed accordingly to non-COVID-19 cases [65, 66]. Comparing STEMI treatments in cases with and without concomitant COVID-19, door-to-balloon times were markedly increased in infected subjects. The mean door-to-balloon time was more than eight minutes longer and COVID-19 patients received primary PCI less often compared to controls (71% vs. 93%) [49, 55, 67]. These aspects may also be a reason for the significantly higher mortality in patients with COVID-19 associated STEMI compared to subjects without COVID-19 [49, 54, 67]. In the study by Garcia et al. [62], a reduction of door-to-balloon times was observed together with a decline in mortality in COVID-19 patients with STEMI when comparing the year 2020 with 2021, whereas no significant differences were detected regarding PCI rates between SARS-CoV-2 positive STEMI patients in 2020 and 2021. In contrast, there were no significant differences in mortality if COVID-19 patients with NSTEMI were compared to non-COVID-19 NSTEMI patients [54]. However, it should be mentioned that the pandemic had adverse effects on all patients with ACS, regardless of their COVID-19 status, resulting in a marked reduction in PCI and longer door-to-balloon times compared to a pre-COVID-19 era [68]. Moreover, screening for SARS-CoV-2 was always indicated where available due to infection control measures before primary PCI could proceed. Therefore, dedicated Covid-catheter labs and ICU isolation beds had to be available [69]. These logistical aspects likely have contributed to longer door-to-balloon times and increased mortality in patients with COVID-19 presenting with STEMI.

COVID-19 associated ischemic stroke seems to have a predominance of large vessel involvement compared to small vessel disease, which was present in only 2-4.4% of COVID-19 cases while pre-COVID-19 stroke data attribute 20% of stroke cases to small vessel disease [70‐73]. In contrast, the rate of hemorrhagic strokes did not differ between COVID-19 and non-COVID-19 patients during the pandemic [74]. Vogrig et al. [73] detected multi-territory involvement and affection of otherwise uncommonly involved vessels as potential typical features of COVID-19 associated stroke. According to some studies, which compared COVID-19 patients with stroke patients before the pandemic, cryptogenic stroke rates were slightly increased in COVID-19 with reported rates of 35–40% [71, 73, 75]. In contrast, data from the “Global COVID-19 Stroke Registry” revealed a non-significant decrease of cryptogenic strokes in COVID-19 when compared to contemporaneous non-COVID-19 patients. Moreover, multi-territory involvement was comparable between COVID-19 and controls [72]. Studies demonstrated severe neurological deficits in patients with COVID-19 associated ischemic stroke and presenting with significantly elevated NIH stroke scale (NIHSS) scores in relation to non-COVID-19 associated stroke patients (median NIHSS 13 vs. 6 according to one study [72, 74]. Of note, ischemic stroke was associated with additional thrombotic events in about 25% of COVID-19 patients [73, 76]. The most common neurological findings in acute COVID-19 associated stroke were motor deficits, dysarthria, and sensory deficits [77, 78]. Altered level of consciousness, aphasia and facial paresis were additional frequently observed symptoms, and COVID-19 patients had more often seizures [74, 78]. Alterations of biomarkers in COVID-19 associated ischemic stroke included prolonged activated partial thromboplastin time and elevated CRP, fibrinogen and D-dimer levels, while data on LDH levels are divergent [73, 79]. Due to limited existing data on the specific diagnostic and therapeutic management in COVID-19 associated stroke, established stroke guidelines were also used in COVID-19 cases [80, 81]. CT imaging is used in suspected stroke, and systemic fibrinolysis or mechanical thrombectomy are performed in confirmed stroke cases if indicated. Studies comparing treatment strategies between stroke patients with and without COVID-19 revealed no differences in the frequency of performed systemic fibrinolysis or mechanical thrombectomy [82]. However, some data indicated a greater risk of intracranial hemorrhage after administration of recombinant tissue plasminogen activator (rtPA) in COVID-19 patients with elevated CRP and D-dimer levels, which are commonly increased in COVID-19 [83, 84]. One explanation for the increased risk of intracranial hemorrhage may be the fact that rtPA is hepatically metabolized and hepatic parameters are also commonly elevated in COVID-19 [73]. Although hemostasis and properties of clot formation can be safely measured by thromboelastography, also in acute liver injury, no decision-making is recommended for or against systemic fibrinolysis depending on laboratory markers in COVID-19 so far [84, 85]. In contrast, the performance of mechanical thrombectomy in COVID-19 associated stroke revealed lower rates of successful recanalization, while no difference was shown in treatment duration and symptom-to-treatment times [72]. In general, COVID-19 patients with stroke exhibited higher rates of symptomatic intracerebral hemorrhage, symptomatic subarachnoid hemorrhage, and 24-hour mortality following intravenous thrombolysis as well as endovascular treatment in relation to a contemporaneous non-COVID-19 cohort [72]. Another study evaluating outcome data of patients with COVID-19 associated stroke revealed a significantly elevated in-hospital mortality compared to COVID-19 patients without stroke (19.4% vs. 6.2%) with an increased risk for the development of cerebral edema, intracerebral hemorrhage, and myocardial infarction [82, 86, 87]. Additionally, COVID-19 associated stroke was associated with higher rates of ICU admission and intubation compared to stroke patients without COVID-19 [88]. Moreover, Hernández-Fernández et al. [89] revealed that COVID-19 associated stroke patients may exhibit longer hospitalization rates, slower recovery times and unfavorable functional prognosis evaluated by the modified Rankin Scale in over 64% of cases. These outcomes are supported by the “Global COVID-19 Stroke Registry” which revealed higher 3-month mortality rates, worse 3-month mortality modified Rankin scale shift as well as 3-month favorable outcomes in their COVID-19 cohort [72].

As mentioned above, COVID-19 associated ALI is a rare finding among patients with COVID-19 [2]. In the majority, ALI was diagnosed subsequently to SARS-CoV-2 infection while 27% presented to hospital with ALI symptoms alone, assuming a quite high rate of asymptomatic SARS-CoV-2 infection in ALI [90]. COVID-19 associated ALI most commonly affects femoro-popliteal arteries, followed by tibial arteries [91, 92]. Additionally, Goldman et al. [93] found higher rates of COVID-19 associated ALI in more proximal regions as well as a greater clot burden. Of the reported studies, leg pain and leg discoloration were the most frequent symptoms of COVID-19 associated ALI, which is comparable to non-COVID-19 associated ALI. Also the frequency of the Rutherford classification grading used in ALI is comparable between COVID-19 and non-COVID-19 revealing that Rutherford IIa and IIb are most commonly observed grades [91‐94]. Except of an increase of D-dimer levels during hospitalization in COVID-19, which may be an indicator of ALI, there is limited significance of other laboratory markers for the diagnosis of ALI [95, 96]. Recommendations of the European Society for Vascular Surgery on an adjusted management approach in COVID-19 associated ALI suggest a preferential use of CT angiography for the detection of ALI, but with the advice to extend the imaging from the aortic arch to the feet or hands due to the anatomically more extensive disease. Following verified ALI diagnosis, the standard management approach also applies to COVID-19 patients including adequate analgesia, rehydration and administration of heparin. Open surgery and endovascular treatment are the definite therapeutic options and thromboembolectomy is the most used technique, while hospitalized COVID-19 patients, especially those with severe disease, might benefit from endovascular techniques as a less invasive procedure [90, 96, 97]. In contrast, a systematic review by Galyfos et al. [98] revealed that medical treatment was selected as first-line therapy in more than 40% of included COVID-19 associated ALI patients. This treatment option led on the one hand to a non-significantly elevated amputation risk, but on the other hand to an increased mortality compared to COVID-19 associated ALI patients receiving any intervention. Moreover, studies reported that 14–23% of COVID-19 patients already receiving anticoagulation at the time of ALI diagnosis developed rethrombosis after revascularization despite full heparin-based anticoagulation [92, 99‐101]. Similar results were also reported by another systematic review, in which 13% of intervened COVID-19 associated ALI patients required a re-intervention due to persistent or recurring limb ischemia. Additionally, the technical success rate in these patients was low with 68%. Of note, 19% of COVID-19 associated ALI patients were ineligible for surgical or endovascular procedures due to critical status [90]. Amputation and mortality rates of COVID-19 associated ALI cohorts ranged between 8 and 25% and between 29 and 38%, respectively, which are higher compared to non-COVID-19 patients with ALI [90, 93, 96, 98, 102, 103]. Additionally, mortality and amputation rates were lower in COVID-19 associated ALI patients who had symptoms limited to the leg without other systemic or respiratory COVID-19 manifestations [93].

Other COVID-19 associated ATE include mesenteric ischemia, splenic, and renal arterial infarctions. All three conditions are, however, rarely reported in the literature and mostly only in case reports [104‐107]. While conclusive data on mesenteric ischemia are yet limited and derived at least from comprehensive or systematic reviews including case reports and small case series, conclusive data on splenic or renal arterial infarctions are to the best of our knowledge missing and cannot be reflected in this review. Another limitation of COVID-19 associated mesenteric ischemia is the fact that the derived studies differentiated only partially or not between ATE or VTE as the origin of mesenteric ischemia [108‐111]. Reported rates of detected thrombi in visceral arteries in COVID-19 associated mesenteric ischemia range from 15 to 38%, suggesting a predominant small vessel affection [109, 111]. Of those reported COVID-19 patients with arterial mesenteric ischemia, abdominal pain, vomiting and nausea were frequently observed symptoms, and abdominal distension was a common finding in physical examination. CT was the imaging method of choice for its detection [108‐111]. No differentiation was made between arterial and venous mesenteric ischemia in the reported studies regarding biomarkers, therapy or outcome. Therefore, only pooled results for arterial and venous mesenteric ischemia can be reflected in this review. D-dimer, CRP and leukocytes were commonly elevated but did not correlate with outcome [109, 111]. COVID-19 associated mesenteric ischemia was typically treated by initial administration of heparin followed mostly by laparotomy with ischemic bowel resection, while endovascular interventions were only rarely performed (< 5%) [109, 111]. Reported mortality rates of COVID-19 associated mesenteric ischemia ranged from 34 to 54% [108‐111].