key: cord-0863767-r1hh288x authors: Cueto-Robledo, Guillermo; Roldan-Valadez, Ernesto; Graniel-Palafox, Luis-Eugenio; Garcia-Cesar, Marisol; Torres-Rojas, Maria-Berenice; Enriquez-Garcia, Rocio; Cueto-Romero, Hector-Daniel; Rivera-Sotelo, Nathaly; Perez-Calatayud, Angel-Augusto title: Chronic thromboembolic pulmonary hypertension (CTEPH): a review of another sequel of severe post-Covid-19 pneumonia. date: 2022-03-25 journal: Curr Probl Cardiol DOI: 10.1016/j.cpcardiol.2022.101187 sha: f3020cfa3e3bea40af3b3dc58d7459b4fcc0a3e4 doc_id: 863767 cord_uid: r1hh288x The spectrum of pulmonary parenchymal and vascular pathologies related to the COVID-19 have emerged. There is evidence of a specific susceptibility related to thrombotic microangiopathy in situ and a complex immune-inflammatory cascade, especially in the pulmonary vascular bed. The potential to lead to transient or self-correcting sequelae of pulmonary vascular injury will only become apparent with longer-term follow-up. In this review, we aimed to present the findings in a group of patients with severe pneumonia due to covid-19 complicated by acute pe documented by chest angiography, who during a follow-up of more than three months with oral anticoagulant met clinical, hemodynamic, and imaging criteria of chronic thromboembolic pulmonary hypertension. We present a brief review of the epidemiology, pathophysiology, clinical findings, comorbidities, treatment, and imaging findings of chronic thromboembolic pulmonary hypertension as a sequel of severe post-covid-19 pneumonia; and compared and discussed these findings with similar reports from the medical literature. As the initial wave of the COVID-19 pandemic has subsided, a spectrum of pulmonary parenchymal and vascular pathologies related to the acute form of the disease have emerged. The combination of viral pneumonia and acute respiratory distress syndrome that characterizes the severe manifestations of acute COVID-19 disease is considered a possible precursor to pulmonary fibrosis (1) . Another potential pulmonary morbidity is the tendency to thromboembolic phenomena, both in the systemic and pulmonary circulation (2) . Apart from the risk of venous thromboembolism in hospitalized patients with acute illnesses, there is evidence of a specific susceptibility to COVID-19, related to thrombotic microangiopathy in situ and a complex immune-inflammatory cascade, especially in the pulmonary vascular bed (3, 4) . Many patients with proven COVID-19 thromboembolism have been patient reports in intensive care units, but pulmonary thromboembolism is now being reported in less critical patients in hospital and outpatient settings. Whether such pulmonary vascular injury is transient and self-correcting, or has the potential to lead to sequelae, will only become apparent with longer-term follow-up. Within the limitations of an insufficient knowledge base on the recovery of COVID-19, algorithms have been proposed for follow-up that integrate the performance of studies to identify possible vascular sequelae and pulmonary interstitial disease (5) . In this review, we aimed to present the findings in a group of patients with severe pneumonia due to COVID-19 complicated by acute pulmonary embolism (PE) documented by chest angiography, who during a follow-up of more than three months with oral anticoagulant met clinical, hemodynamic, and imaging criteria of chronic thromboembolic pulmonary hypertension (CTEPH). We compared and discussed these findings with similar reports in the medical literature. Following initial reports from China in December 2019 of atypical pneumonia caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and confirmation of person-to-person transmission, coronavirus disease 2019 rapidly progressed to a global pandemic (6, 7) . Several coronaviruses are endemic in the population: these viruses generally cause a mild respiratory tract infection in the winter months, although the disease can be severe in neonates, the elderly, and people with predisposing conditions. The highly pathogenic severe acute respiratory syndrome coronaviruses (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) caused outbreaks in humans, with a case fatality rate of 9% and 40%, respectively (8) . However, these last two viruses are not easily transmitted between humans, and therefore containment of the outbreaks was relatively simple. In contrast, SARS-CoV-2 is intermediate in virulence between endemic coronaviruses and highly pathogenic viruses, but its high human-to-human transmissibility has led to the current human pandemic. The development of diffuse interstitial lung disease has been reported in post-COVID-19 patients. An expected complication secondary to interstitial lung disease (ILD) post-COVID-19 is the development of pulmonary hypertension (PH), which has been reported in different publications (9) . CTEPH is a rare but significant complication of acute PE. There is a strong and documented causal relationship between COVID-19 and venous thromboembolism. CTEPH results from obstruction of the pulmonary artery bed by Anecdotal reports from large critical care units in the UK suggest potentially higher numbers. Autopsy findings of the first 12 consecutive deaths from COVID-19 in a single German academic medical center revealed deep vein thrombosis in 58% in whom no venous thromboembolism was suspected, with PE being a direct cause of death in four patients; however, COVID-19 has also been associated with microvascular coagulopathy, with findings similar to those seen in disseminated intravascular coagulopathy (11, 12) . During a period of 11 months (August 2020 to July 2021), 77 new cases of PE were documented by CT angiography; in 13 (16.8%), PE was established in the context of severe pneumonia due to COVID-19 with Positive RT-PCR during their hospitalization (Fig. 1) . According to the pulmonary hypertension guidelines, CTEPH is a type of precapillary PH according to the hemodynamic definition. The working group of the 6th World Symposium on PH recently proposed a new definition of precapillary PH that includes PAPm > 20 mmHg, pulmonary artery wedge pressure < 15 mmHg, and pulmonary vascular resistance (PVR) > 3 Wood units (WU) (13) . All 13 patients were receiving prophylactic anticoagulation at the time of acute PE. Three patients (23.07%) met the criteria for CTEPH, given that they received oral anticoagulation an average of 5 months before performing right heart catheterization (RHC), Table 1 . All patients had dyspnea on exertion, and the perfusion lung scan reported multiple segmental and lobar defects compatible with CTEPH. It should be noted that our three patients were free of chronic respiratory manifestations before COVID-19. Several clinical characteristics and comorbidities are associated with a poor prognosis and an increased risk of mortality from COVID-19. These include pre-existing health problems such as hypertension, diabetes, cardiovascular disease, obesity, cancer, chronic kidney, liver, lung diseases, advanced age, male sex, smoking, and race (14) . It is currently unclear if these risk factors are also predictors of longer-term COVID-19 outcomes. The comorbidity reported in the three patients was subarachnoid hemorrhage (SAH). We have learned a great deal about the broad spectrum of illnesses due to COVID-19 in the past 18 months, ranging from asymptomatic infection to severe pneumonia, respiratory failure, and death (15) . There is growing concern about whether COVID-19 survivors will have long-term lung sequelae, including fibrotic interstitial lung disease and the presence of pulmonary hypertension. Using the usual stratification guidelines, two patients correspond to high intermediate risk and one to high risk. Two patients received low-molecular-weight heparin (LMWH) at a 1.5 mg/kg (enoxaparin). The third patient initially received systemic thrombolysis with 100 mg of alteplase; however, he was hypotensive, with amine requirements and significant thrombotic load. He underwent mechanical fragmentation thrombolysis and catheter-guided thrombolysis with an additional injection dose of 10 mg of alteplase. The RHC findings in each patient meet precapillary PH criteria (Figures 2, 3, and 4 and Table 2 ). All patients are still alive. A main pulmonary artery (PA) diameter greater than 30-31 mm should raise the suspicion of PH; however, in the context of established pulmonary fibrosis, a ratio between the pulmonary artery and adjacent ascending aorta > 1.1 may be a more reliable predictor (16) . It has also been shown that a greater pulmonary artery to bronchus ratio in at least three vessels has a high specificity for PH diagnosis (17) . A ratio between the right ventricle and the left ventricle (RV: LV) > 1.0 has been shown consistently as a helpful risk stratification biomarker and predictor of poor outcome in acute PE, CTEPH, and interstitial lung disease; however, the R: LV relationship is substantially underreported, as highlighted in the 2019 National Confidential Outcome and Death Investigation (18, 19) . Together with reflux of contrast medium in the hepatic veins, these findings can be present in all forms of PH, regardless of etiology. In CTED and CTEPH, the pulmonary arteries should be checked for vascular networks and occlusions. DECT can also show multiple peripheral perfusion defects. The lung parenchyma can often show mosaic attenuation with geographic areas of low attenuation associated with peripheral scarring, the residue of previous infarction. With CT and scintigraphy, subtle pulmonary vascular abnormalities, particularly those seen in the more distal chronic thromboembolic disease, can be challenging to detect. The study of suspected PH, ventilation, and perfusion (VQ) should be considered a screening tool image. In addition to changes in the lung parenchyma, such as diffuse alveolar damage with hyaline membranes and acute pneumonia, significant vascular changes have been observed in patients with COVID-19. Vascular changes affect the entire pulmonary vascular tree, from large-caliber vessels to capillaries (20) . In patients with severe COVID-19, enlargement of the large vessels proximal to lung opacities was seen on pulmonary angiograms during the acute phase of the disease. In a UK study that also used CT pulmonary angiography, 21 of 33 COVID-19 patients and at least two evaluable lobes with no evidence of acute pulmonary emboli had dilated peripheral vessels, with 100% of patients showing defects of the perfusion on dual-energy CT, suggesting microvascular dysfunction. Every physician following post-COVID-19 patients must keep the possibility of PH in mind. CTEPH is particularly underdiagnosed; in 2015, it was estimated that, on average, only 16% of patients in the United States, Europe, and Japan who had CTEPH were diagnosed (21) . Our findings in this study represent the first series of patients described in the literature that reflects the local incidence of CTEPH in a series of patients with acute PE after COVID-19 pneumonia and who, during follow-up, meet the criteria to consider CTEPH. The problems will continue because we do not know if the current standards for acute PE that evolve to CTEPH should be used. We also do not know if the benefits of pulmonary balloon angioplasty will be superior to pulmonary endarterectomy due to the segmental or subsegmental location described in PD associated with COVID-19. Finally, what is the role of specific drug treatment in this group of patients? They will be candidates for guanylate cyclase stimulators, benefiting from phosphodiesterase 5 inhibitors or endothelin antagonists. What anticoagulant will be the ideal? Now our three patients are receiving phosphodiesterase 5 inhibitors and anticoagulation permanently. Finally, we will have to wait for new similar works where the true incidence of HPTEC can be known. Of the total number of patients with acute PE in 11 months (77 Patients), Three (3.8%) met the CTEPH criteria, which is like the original series reported by Pengo (22) . Therefore, it seems reasonable to suggest that, although patients may develop acute PE secondary to severe illness and hospitalization, the pronounced inflammatory response seen In the experience of our group, most of our patients with COVID-19 and PD have often developed PE in segmental and subsegmental vessels rather than in main or lobar pulmonary arteries. It is possible (but still unknown) that people recovering from COVID-19 may develop the chronic thromboembolic disease (CTED), CTEPH, and pulmonary hypertension (PH) secondary to lung disease, for example, diffuse interstitial lung disease. As can be seen, the emerging landscape of intense interaction between COVID-19 and chronic pulmonary hypertension globally is expected to have a significant effect on the future of both diseases. Pulmonary fibrosis secondary to COVID-19: a call to arms? 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