key: cord-0704812-djaszsop authors: Suzuki, Yuichiro J.; Nikolaienko, Sofia I.; Shults, Nataliia V.; Gychka, Sergiy G. title: COVID-19 patients may become predisposed to pulmonary arterial hypertension date: 2021-01-06 journal: Med Hypotheses DOI: 10.1016/j.mehy.2021.110483 sha: eed1de533ce15690f28c477783e8419941ff8ef2 doc_id: 704812 cord_uid: djaszsop Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the current pandemic of coronavirus disease 2019 (COVID-19) that have killed over one million people worldwide so far. To date, over forty million people have officially been identified to be infected with this virus with less than 3 % death rate. Since many more people are expected to have been infected with this virus without the official diagnosis, the number of people who have recovered from the SARS-CoV-2 infection should be substantial. Given the large number of people recovered from either the mild SARS-CoV-2 infection or more severe COVID-19 conditions, it is critical to understand the long-term consequences of the infection by this virus. Our histological evaluations revealed that patients died of COVID-19 exhibited thickened pulmonary vascular walls, one important hallmark of pulmonary arterial hypertension (PAH). By contrast, such pulmonary vascular remodeling lesions were not found in patients died of SARS-CoV-1 during the 2002-2004 SARS outbreak or due to the infection by H1N1 influenza. The advancement in the treatment for the human immunodeficiency virus (HIV) infection has been remarkable that HIV-infected individuals now live for a long time, in turn revealing that these individuals become susceptible to developing PAH, a fatal condition. We herein hypothesize that SARS-CoV-2 is another virus that is capable to triggering the increased susceptibility of infected individuals to developing PAH in the future. Given the large number of people being infected with SARS-CoV-2 during this pandemic and that most people recover from severe, mild or asymptomatic conditions, it is imperative to generate scientific information on how the health of recovered individuals may be affected long-term. PAH is one lethal consequence that should be considered and needs to be monitored. This may also foster the research on developing therapeutic agents to prevent PAH, which has not so far been successful. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the current pandemic of coronavirus disease 2019 that have killed over one million people worldwide so far. To date, over forty million people have officially been identified to be infected with this virus with less than 3 % death rate. Since many more people are expected to have been remarkable that HIV-infected individuals now live for a long time, in turn revealing that these individuals become susceptible to developing PAH, a fatal condition. We herein hypothesize that SARS-CoV-2 is another virus that is capable to triggering the increased susceptibility of infected individuals to developing PAH in the future. Given the large number of people being infected with SARS-CoV-2 during this pandemic and that most people recover from severe, mild or asymptomatic conditions, it is imperative to generate scientific information on how the health of recovered individuals may be affected long-term. PAH is one lethal consequence that should be considered and needs to be monitored. This may also foster the research on developing therapeutic agents to prevent PAH, which has not so far been successful. Pulmonary arterial hypertension (PAH) affects both females and males of any age, in which the increased pulmonary vascular resistance causes right heart failure and death. 8, 9 The median survival for patients diagnosed with PAH has been reported to be 2.8 years from the time of diagnosis (3-year survival: 48%) if untreated. 10, 11 Even with currently available therapies, only 58-75% of PAH patients survive for 3 years. [12] [13] [14] [15] While the exact mechanism of how PAH is developed is unknown, this condition is associated with various conditions including viral infections such as HIV. 9 HIV-associated PAH occurs with a prevalence of approximately 1 out of 200 HIV-infected individuals [16] [17] [18] [19] that is 100 to 1000-times higher than the prevalence of PAH We hypothesize that SARS-CoV-2 possesses mechanisms that promote the pathogenesis of PAH and that some individuals infected with this virus become susceptible to developing clinically significant PAH in the future. The hypothesis is based on clinical observations that certain viral infections are associated with the development of PAH and our recent finding that patients died of COVID-19 exhibit the histological signs of thickened pulmonary vascular walls. Thus, it is logical to hypothesize that at least a subset of SARS-CoV-2 infected patients are predisposed to developing severe PAH in the future, and we herein encourage research activities to specifically evaluate this concept in order to reduce more people dying as a consequence of the current pandemic. and found that the pulmonary arterial walls of COVID-19 patients was 30% thicker than those of patients with H1N1 influenza. 8 We also noted the occurrence of pulmonary arterial wall thickening in lung histology images of patients who died of COVID-19 in China although authors did not mention this in their papers. 5, 23 These observations in deceased patients infected with SARS-CoV-2, SARS-CoV-1 and H1N1 influenza viruses indicate that pulmonary vascular wall thickening is a unique feature of the SARS-CoV-2 infection and COVID-19. As deceased COVID-19 patients consistently exhibit pulmonary vascular wall thickening, this condition may play a vital role in the development of acute respiratory failure. These results also lead us to hypothesize that some patients who recovered from COVID-19 may be predisposed to developing PAH and right-sided heart failure. While knowing whether the individuals previously infected with SARS-CoV-2 develop PAH or not need to await case reports and epidemiological studies that may not become available for years to come, we may be able to generate information that could be useful for reducing adverse health outcomes through the use of experimental animals. Experimental animals that are infected with SARS-CoV-2 virus or treated with SARS-CoV-2 viral components 20 may develop the characteristics of PAH and pulmonary vascular remodeling and/or may enhance the sensitivities of the trigger for PAH such as hypoxia and SU5416. 24, 25 Such information generated in experimental animals in conjunction with human patient case reports as well as epidemiological studies may suggest that some individuals who were previously infected with SARS-CoV-2 have tendencies to develop PAH. The increased susceptibilities to develop PAH may only occur in those patients who survived severe COVID-19 or may also occur in those who developed mild or even no symptoms in response to the SARS-CoV-2 infection. While currently there are no agents that are known to prevent the development of PAH, new research motivated by this situation may allow for obtaining effective measures to cope with this unwanted health crisis. Hopefully, our hypothesis is proven to be wrong, however, it is critical to be aware of such a possibility. Clinical features of patients infected with 2019 novel coronavirus in Wuhan Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2 Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine Pathological findings of COVID-19 associated with acute respiratory distress syndrome Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: A systematic review and meta-analysis Optimising the management of pulmonary arterial hypertension patients: emergency treatments Management of pulmonary arterial hypertension Survival in patients with primary pulmonary hypertension. Results from a national prospective registry Primary pulmonary hypertension Analysis of the lung allocation score estimation of risk of death in patients with pulmonary arterial hypertension using data from the REVEAL Registry French Pulmonary Arterial Hypertension Network. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) HIV-Related pulmonary hypertension: analytic review of 131 cases Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era High prevalence of pulmonary arterial hypertension in a cohort of asymptomatic HIV-infected patients Primary pulmonary hypertension in HIV patients: a systematic review SARS-CoV-2 spike protein-mediated cell signaling in lung vascular cells Pulmonary pathology of severe acute respiratory syndrome in Toronto The clinical pathology of severe acute respiratory syndrome (SARS): a report from China Clinical pathology of critical patient with novel coronavirus pneumonia Mechanism of the susceptibility of remodeled pulmonary vessels to drug-induced cell killing Carfilzomib reverses pulmonary arterial hypertension This work was supported in part by NIH (R21AI142649, R03AG059554, and R03AA026516) to Y.J.S. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The author has no conflict of interest.