Pulmonary embolism in patients with COVID-19: characteristics and outcomes in the Cardio-COVID Italy multicenter study

Pneumonia is the major clinical manifestation of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1, 2]. Nonetheless, the cardiovascular (CV) system is often affected in COVID-19 [3]. Abnormalities in laboratory parameters indicating activation of the coagulation cascade are frequent in patients with COVID-19, and have been related to SARS-CoV-2-initiated inflammatory response and endothelial injury [4]. At present, the main consequence of COVID-19 coagulopathy appears to be arterial and especially venous thromboembolism (VTE), with the lung being the organ most commonly involved. Autopsy studies have demonstrated the presence of thrombi in the pulmonary arteries and alveolar capillaries of individuals deceased from COVID-19 [5, 6]. Clinically, 20–30% of COVID-19 patients admitted to intensive care units (ICU) have pulmonary embolism (PE) [7‐10]. The frequency of PE in subjects with non-critical COVID-19 seems to be lower, but it has far less been studied [11‐13]. Importantly, the risk of VTE is influenced by patient- and care-related factors, such as ethnicity and intensity of treatments [4]. Moreover, the definite diagnosis of PE relies on computed tomography pulmonary angiography (CTPA), which has likely been accessible to a variable extent in different hospitals even within the same country, due to local measures adopted to limit the spreading of SARS-CoV-2. Hence, it is important to obtain data about PE in COVID-19 from heterogeneous cohorts of patients, in order to expand the knowledge and possibly inform clinical practice.

To this scope, we reviewed the dataset created by a collaborative initiative of several Cardiology Units involved in the management of COVID-19 patients in Italy.

The study included 689 COVID-19 patients, of whom 52 (7.5%) were diagnosed with PE by CTPA over 15 (9–24) days of follow-up. The corresponding incidence rate was 4.6 (95% CI 3.5–6.1) per 1000 person-months. The median time from admission to diagnosis was 10 (3–17) days. Ten (19.2%) PE were found on the day of hospital entry and the other ones throughout hospitalization (Supplemental Fig. 2). 91 (13.2%) subjects were still hospitalized at the end of follow-up, with 599 (86.9%) being therefore closed cases. The frequency and incidence rate of PE among these latter were 7.1% and 5.2 (95% CI 3.9–7.0) per 1000 person-months, respectively.

Other authors have already reported a remarkable incidence of PE in patients hospitalized for COVID-19 [15]. Most articles published so far have described subjects admitted to ICU, in whom the rate of PE was about 20% [7, 9, 10]. In 184 consecutive individuals managed in three ICU in the Netherlands, the frequency of PE was 35% [8]. In general, PE diagnosis in these series was more common than in historical cohorts of non-COVID-19 bacterial or viral acute respiratory distress syndrome, indicating that SARS-CoV-2 infection confers a specific risk of PE [7, 9]. Nonetheless, ICU patients have additional factors predisposing to VTE, such as prolonged immobilization, central venous catheters and superimposed sepsis, which may be absent in the general COVID-19 population. Indeed, according to the current evidence the frequency of PE in COVID-19 patients hospitalized in the general wards is much lower than in ICU, approximately 2–3% [11, 12].

The patients we examined were heterogeneous with respect to the severity of COVID-19 and received variable therapies. Around half had an increased respiratory rate on admission, was given antiviral drugs or corticosteroids and needed non-invasive ventilation, while 15% were intubated. However, they were managed by cardiologists and, thus, they likely represent a population with a more complex clinical profile than the one generally hospitalized for COVID-19. It is reasonable that we found a rate of PE of 7%, intermediate between those described in ICU and in general wards patients, because of these characteristics. Indeed, in a very recent analysis of a French COVID-19 cohort in which the use of invasive ventilation was around 9%, the frequency of PE was 8.3% [13].

Thus, the present work integrates the existing literature on PE in COVID-19, by providing an estimate of the rate of PE in hospitalized COVID-19 at large. It is notable, however, that features of worse COVID-19, including the rates of non-CV complications, were more common among subjects with PE.

One in five patients included in this study had PE on admission, in good agreement with the reported prevalence of PE on CTPA performed for COVID-19 at the emergency department [16]. The remaining cases of PE occurred throughout the hospitalization for COVID-19, again consistently with other investigations [7‐9, 11]. Therefore, physicians should be vigilant towards the development of PE in hospitalized COVID-19 from admission to discharge. It remains to be determined whether the risk of PE is heightened also after discharge and until when.

We found that two thirds of the subjects with PE were treated with anticoagulants, mainly LMWH at various doses, before the diagnosis of PE. We could not determine whether this thromboprophylaxis was at least partially motivated by pre-existing risk factors for VTE, such as cancer. Indeed, oral anticoagulant therapy prior to admission tended to be more frequent in patients who then suffered from PE, indicating the presence of a pro-thrombotic condition. While acknowledging that this is a speculation and that the dataset analyzed here is not proper to verify it, the question arises of whether individual predisposition cooperates with SARS-CoV-2-induced inflammation and endotheliopathy in causing VTE in COVID-19. Along these lines, it is notable that thromboelastographic hypercoagulability on admission was associated with higher thrombosis rates in critically ill COVID-19 patients, despite standard drug prophylaxis [17]. It should be also taken into account that therapies for COVID-19, such as ritonavir, tocilizumab, and hydroxychloroquine, may modulate the risk of VTE, both directly, via their effects on platelets, and indirectly, through their effects on the inflammatory system and pharmacokinetic interactions with antithrombotic medications [18].

In the absence of a clear contraindication, anticoagulant thromboprophylaxis with LMWH or, secondarily, fondaparinux is now recommended during hospitalization for COVID-19 [19, 20]. However, PE appears to complicate COVID-19 in spite of such an approach, and full-dose anticoagulation has been related to improved survival at least in some patient subsets [21]. On the other side, intermediate- or therapeutic-dose anticoagulation exposes to a higher risk of bleeding, which may be also compounded by COVID-19 coagulopathy. In this regard, it is noteworthy that, in our analysis, major bleeding episodes were also three times more frequent in subjects with PE. Interestingly, hemorrhagic complications have been reported to be more common in COVID-19 than non-COVID-19 ARDS [9]. While awaiting for a better understanding of the coagulation derangement and the impact of non-conventional strategies for VTE prevention, administration of more than standard doses of anticoagulant for thromboprophylaxis should be probably reserved to selected cases of COVID-19 [20]. The impact of PE on COVID-19 prognosis is still unclear, with some authors reporting an association with mortality and others not [22]. We observed a trend for increased in-hospital mortality in patients with PE. It can be postulate that the consequences of PE in COVID-19 vary depending on the location of the clots in the pulmonary circulation and on the extent of concomitant pneumonia. Unfortunately, this type of information was not available in the dataset we evaluated, nor was it given in most other studies.

An increase in d-dimer concentrations is the most common laboratory abnormality in COVID-19 coagulopathy and reflects the activation of the coagulation cascade [23, 24]. In this analysis, d-dimer levels were fivefold higher on admission in patients with than without PE and remained substantially higher in the former than in the latter ones until discharge, when they decreased to values similar to those of the no-PE group. The same trend has been described by other authors [25] and has been attributed to ongoing thrombosis and inflammation, which eventually fade in survivors. Therefore, we argue that d-dimer was associated with PE because it is a sensitive marker of the thrombotic activation, linked to inflammation (so-called thromboinflammation), which characterizes COVID-19. Other investigators have demonstrated that d-dimer tracks with COVID-19 severity and predicts mortality [4].

In the majority of the patients evaluated here, baseline and peak d-dimer concentrations were above both the general and the age-adjusted thresholds advised by the guidelines on PE [26]. However, these cut-offs allow excluding PE when it is clinically unlikely or with low to intermediate probability, while PE in our cohort was always suspected clinically and then documented by CTPA. The meaning of d-dimer measurement in the diagnosis of PE in COVID-19 still needs to be clarified, as well as the role of other imaging techniques. Detection of RV dilation and dysfunction by transthoracic echocardiography [27] and of lower limb vein thrombosis by Doppler ultrasonography [28] may be helpful. Moreover, echography can be performed at the bedside, avoiding patient mobilization and minimizing the exposure of the healthcare personnel to SARS-CoV-2.

The major limitations of this work are those intrinsic of a retrospective analysis. Nonetheless, prospective studies were barely feasible during the SARS-CoV-2 outbreak and retrospective data are anyway informative, being COVID-19 a completely new disease. The lack of details about PE predisposing factors and site, as well as about the treatments of comorbidities, is another shortcoming, as already mentioned. The frequency of PE is probably underestimated by this study as only clinically relevant episodes leading to further diagnostic assessment were collected and the attention towards PE in COVID-19 was low in the initial phase of the outbreak in Italy. The rate of PE could have been higher if it had been systematically searched. Lastly, we could not investigate the incidence and correlates of deep venous thrombosis, which also seems to be common in COVID-19 [26].

Finally, the results presented here concern hospitalized COVID-19 patients and may be not valid for ambulatory ones, even though PE may be relevant in them too. In fact, PE may have accounted for a large proportion of unexpected out-of-hospital deaths during the COVID-19 pandemic [29].