key: cord-0690450-kdwct0k9 authors: Baiges, A.; Cerda, E.; Amicone, C.; Téllez, L.; Alvarado-Tapias, E.; Puente, A.; Fortea, J. I.; Llop, E.; Rocha, F.; Orts, L.; Ros-Fargas, O.; Vizcarra, P.; Zekrini, K.; Ould Amara, Y.; Touati, G.; Jimenez, N.; Serrano, M. J.; Falgà, A.; Magaz, M.; Olivas, P.; Betancourt, F.; Perez-Campuzano, V.; Turon, F.; Payance, A.; Goria, O.; Rautou, P.; Hernández-Gea, V.; Villanueva, C.; Albillos, A.; Plessier, Aurélie; García-Pagán, J. C. title: Impact of SARS-CoV-2 pandemic on vascular liver diseases date: 2021-12-27 journal: Clin Gastroenterol Hepatol DOI: 10.1016/j.cgh.2021.12.032 sha: 9749226229a9fd250419edf464ceaab2dbf5cc13 doc_id: 690450 cord_uid: kdwct0k9 Background and Aims Vascular liver diseases (VLD) are represented mainly by portosinusoidal vascular disease (PSVD), non-cirrhotic splanchnic vein thrombosis (SVT) and Budd Chiari syndrome (BCS). It is unknown whether patients with VLD constitute a high-risk population for complications and greater COVID-19-related mortality from SARS-CoV-2 infection. Our objective was to assess the prevalence and severity of SARS-CoV-2 infection among patients with VLD, as well as to assess its impact on hepatic decompensation and survival. Methods This is a observational international study analyzing the prevalence and severity of SARS-CoV-2 infection in VLD between March 2020–March 2021 comparing with the general population (GP). Patients from Spain (5 centers, n = 493) and France (1 center, n = 475) were included. Results Nine hundred and sixty-eight patients were included: 274 PSVD, 539 SVT and 155 BCS. Among them, 138 (14%) were infected with SARS-CoV-2: 53 PSVD, 77 SVT and 8 BCS. The prevalence of SARS-CoV-2 infection in PSVD (19%) and SVT (14%) was significantly higher than in GP (6.5%, p < 0.05), while it was very similar in BCS (5%). In terms of infection severity, patients with VLD also presented a higher need of hospital admission (14% vs 7.3%, p<0.01), ICU admission (2% vs 0.7%, p< 0.01) and mortality (4% vs 1.5%, p < 0.05) than GP. Previous history of ascites (50% vs 8%, p < 0.05) and post-COVID-19 hepatic decompensation (50% vs 4%, p < 0.05) were associated to COVID-19 mortality. Conclusion PSVD and SVT patients could be at higher risk of infection by SARS-CoV-2 and at higher risk of severe COVID-19 disease. The hasty spread of the global pandemic by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the resultant coronavirus disease 2019 (COVID-19) has severely impacted global health with devastating effects. Certain populations have been reported as especially vulnerable to COVID-19 disease 1 . Patients with advanced age, male sex and comorbidities including arterial hypertension, obesity, heart disease, diabetes or malignancy have been consistently reported to develop severe COVID19 2 . Although there is no clear evidence on SARS-CoV-2 hepatotropism, abnormalities in liver tests are present in 15-65% of patients with COVID-19 regardless of the presence of underlying liver disease 3 . Indeed, SARS-CoV-2 is genetically related to Middle East respiratory syndrome Coronavirus (MERS-CoV), which is also known to affect liver tests. Abnormal liver tests in COVID-19 are probably multifactorial, due to a combination of immune-mediated inflammatory response, drug-induced liver injury, hepatic congestion or direct infection of hepatocytes 4 . Several studies have tried to elucidate if patients with chronic liver disease are at higher risk of SARS-CoV-2 infection. It has been shown that cirrhotic patients -specifically with decompensated cirrhosis -have a higher rate of hospitalization and mortality 5, 6 . Despite the concern raised by these studies, we currently do not know whether all chronic liver diseases are equally affected by COVID-19 or if there are specific subgroups with increased risk of mortality and morbidity. Immunosuppression does not seem to confer an increased risk for severe COVID-19 in specific subpopulations such as autoimmune hepatitis 7 or liver transplant recipients 8 . No studies have yet evaluated if patients with vascular liver diseases (VLD) also represent a vulnerable population with higher risk of complications and higher mortality than general population. VLD are a set of diseases that affect young and otherwise healthy patients that usually exhibit a preserved liver function and have a markedly different natural history from cirrhosis. Portosinusoidal vascular disease (PSVD, formerly known as idiopathic portal hypertension), chronic non-cirrhotic splanchnic vein thrombosis (SVT) and Budd Chiari syndrome (BCS) are the most common VLD. Although individually the prevalence of each of these rare diseases is less than 5 per 10,000 inhabitants 9,10 , overall they affect a significant proportion of the population. A common feature of these VLD is the presence of non-cirrhotic J o u r n a l P r e -p r o o f portal hypertension and underlying prothrombotic state 11 , either per se (high incidence of SVT in patients with PSVD regardless of associated thrombophilia) or due to associated underlying diseases (i.e. myeloproliferative disorders, inherited thrombophilia, antiphospholipid syndrome or HIV). As one of the most feared complications of COVID-19 disease is the increased systemic inflammatory response leading to a higher risk of hypercoagulability and thromboembolic disease 12, 13 , it could be argued that SARS-CoV-2 may further deteriorate the clinical condition of patients with these VLD. The aim of the present work is to assess the prevalence and severity of SARS-CoV-2 infection among patients with VLD. We provide the first international report detailing the impact of SARS-CoV-2 in VLD and we offer comparison with the corresponding data regarding general population of Spain and France. We conducted an observational multicentric international study including 5 centers in Spain belonging to the REHEVASC network (Hospital Clínic de Barcelona, Hospital Ramón y Cajal, Hospital Universitario Marqués de Valdecilla, Hospital Puerta de Hierro, Hospital de la Santa Creu i Sant Pau) and one center in France (Hôpital Beaujon). The six participating hospitals are the main tertiary referral centers in the field of VLD in Spain and France, thus providing a good description of the VLD population of the two countries. Also, all the participating hospitals prospectively register all patients diagnosed with VLD in their hospitals. The registries offer a comprehensive representation of all the stages of VLD given that both compensated patients (patients diagnosed during an outpatient study of hepatic liver disease) and patients that have required hospitalization are included in the registry. Given the nature of the study, to have a baseline registry was a necessary and limiting factor to participate in the study. The registries included baseline characteristics such as age, gender and associated comorbidities. Using the registries of each hospital as a starting point, we reviewed their clinical records to investigate if were also comparable to that of the Spanish population (1.87% in France vs 1.5% in Spain, p= 0.86). We have focused on the Spanish general population data as reference to compare it with our VLD cohort. Each vascular liver disease (PSVD, PVT and BCS) has been analyzed separately. Additionally, we have performed a subanalysis stratifying patients by age groups (< 40 years old, 40-59 years old, 60-69 years old and >69 years old) to elucidate the possible role of this confounding factor. Supplementary Table 1 lists the points of comparison between GP and our VLD cohort. Continuous variables are reported as mean + SD and categorical variables are reported as absolute and relative frequencies. Groups were compared using the T test or the Mann-Whitney test for continuous variables when appropriate, and the Fisher exact test was used for categorical variables. Logistic regression models were used to study the predictors of COVID-19 infection. Five-hundred forty-seven patients with VLD were prospectively registered in the 5 Spanish Table 1 shows that there is a high variability in baseline characteristics. However, most of these differences can be explained by the intrinsic characteristics of each disease (i.e PSVD is usually associated to HIV, IBD or history of neoplasm and chemotherapy; BCS is more frequent in women and usually decompensate as ascites and not as variceal bleeding). Supplementary Out of 274 patients with PSVD, 53 were infected with SARS-CoV-2 (19%), a prevalence significantly higher than in GP (6.5%, p < 0.05). This was observed in all age groups (Figure 2) , except in the > 70 years old group. Indeed, the prevalence reached 15%, 25% and 19% in age groups <40, 40-59 and 60-69 years, respectively. The prevalence of SARS-CoV-2 was also significantly higher in SVT than in GP. Out of 539 patients with SVT, 77 were infected with SARS-CoV-2 (14% vs 6.5% in GP, p < 0.05). Regarding age distribution (Figure 3) , it was also significantly different from GP (p < 0.05): SARS-CoV-2 infection was present in 16% of patients aged < 40 years, in 15% of patients between 40-59 years old and in 13% of patients of among age group 60-69. In patients over 70 years old the prevalence was also higher than in GP (10% vs 5.4%) but it did not reach statistical significance. Importantly, if we exclude the 13 patients that were clinically diagnosed without a confirmation test, the prevalence and severity of SARS-CoV-2 infection in patients with VLD was still higher than in GP (125 of 968, 13% p < 0.05, Supplementary Table 3) . Importantly, this was observed both in the Spanish and in the French cohort (data not shown). -Budd Chiari Syndrome (BCS) In our cohort, only 8 patients out of 155 with BCS presented with SARS-CoV-2 (5%). Thus, the global prevalence of SARS-CoV-2 in patients with BCS was very similar to that of GP even stratified by age groups. Among the 138 patients, only 21 (15%) remained completely asymptomatic throughout all the infection period. Table 2 shows the most frequent symptoms developed in this cohort and J o u r n a l P r e -p r o o f dissects them according to the VLD type. Fever and asthenia were present in 60% of patients, followed by cough in 46%. Cephalea, anosmia, dysgeusia or other symptoms were less frequent. -PSVD Median age of infected patients was 49.7 ± 17 years and 50% of them were men. There were no statistically significant differences in age and sex distribution among patients infected or not by SARS-CoV-2. We assessed if previous decompensation, variceal bleeding, ascites, hepatic encephalopathy, sex, age, comorbidities (arterial hypertension, diabetes mellitus, obesity, history of neoplasms, inflammatory bowel disease, HIV infection), use of anticoagulation, use of TIPS (transjugular intrahepatic portosystemic shunt), previous SVT in PSVD or baseline liver function were potential risk factors for COVID-19 in VLD population. Only a higher baseline bilirubin was observed in PSVD patients acquiring SARS-CoV-2 (2.5 ± 2.6 vs 1.5 ± 1.5 mg/dL, p < 0.05) without significant differences in the remaining assessed parameters (Supplementary Table 4 ). -SVT Median age of infected patients was 48.3 ± 18 and 38% of them were male. History of arterial hypertension (28% vs 16%, p < 0.05), inflammatory bowel disease (8% vs 2%, p<0.01) higher bilirubin (2.6 ± 2.8 vs 1.5 ± 1.9 mg/dL, p<0.01), higher protrombin time (38% ± 44 vs 55% ± 41, p <0.05) and use of anticoagulation (79% vs 67%, p < 0.05) were associated with SARS-CoV-2 infection, but only inflammatory bowel disease Table 5 and Supplementary Table 6 ). No further analysis was performed in patients with BCS given the low number of cases recorded and the similar prevalence to GP. Severity of COVID-19 disease in VLD J o u r n a l P r e -p r o o f Table 3 summarizes the severity of COVID-19 disease in patients with VLD using the need of hospital admission, need for ICU care and mortality as indicators. The analysis was performed either globally or categorized by age groups (Supplementary Table 7) . As shown, patients with VLD presented a higher need of hospital admission (14% vs 7.3%, p<0.01), ICU admission (2% vs 0.7%, p< 0.01) and COVID-19-related mortality (4% vs 1.5%, p < 0.05) than GP. However, COVID-19 infection increase in severity was not homogeneously distributed. Indeed, although the low sample size when subanalyzing by age groups reduces the strength of the finding, our results suggest that the increase of COVID-19 severity in VLD patients focuses in those patients below the age of 60. Regarding BCS, only one patient required hospital admission, which makes it difficult to draw any conclusions from this subpopulation. This single patient presented full recovery afterwards without further complications. thrombotic recorded events in our cohort and they were all in the splanchnic territory. The two patients with SVT had associated underlying thrombophilia that conferred them a higher risk of thrombosis and were accordingly under long term anticoagulation. Given the low number of events, to assess the risk of hepatic decompensation and risk of mortality due to COVID-19 we evaluated the VLD cohort globally. We found that history of diabetes mellitus (12% vs 42% p<0.05), previous ascites (8% vs 42%, p<0.01) or hepatic J o u r n a l P r e -p r o o f encephalopathy (3% vs 28%, p<0.05) were significantly more frequent in patients presenting further hepatic decompensation after SARS-COV-2 infection. Four patients died due to COVID-19 pneumonia and respiratory insufficiency (n=1 PSVD; n= 3 SVT). Previous history of ascites (50% vs 8%, p<0.05) and post-COVID-19 hepatic decompensation (50% vs 4%, p<0.05) were more frequent among these patients. The huge daily death toll, fast infection rates and the burden on intensive care units of COVID-19 pandemic rapidly lead to a worldwide crisis with a dramatic impact on global health care systems. This pandemic made it clear that healthcare systems need to be improved and have to be more resilient to emergencies. One of the most important items to improve the approach to the present -and, eventually, future-pandemics is the identification of vulnerable patients at higher risk of adverse outcomes. Several studies have shown that chronic health conditions can increase the risk of presenting severe COVID-19. Liver disease has also been identified as an important risk factor for severe COVID-19, being especially virulent in those patients with cirrhosis and hepatic decompensation. However, the term liver disease encompasses a broad range of pathologies that have few things in common and that require an individualized approach. Among them, VLD deserve special mention. Despite their relatively low prevalence, they represent a significant health problem in the field of liver disease. They usually affect young patients and cause portal hypertension which, in turn, leads to increased morbidity and mortality. Although fortunately in some countries the current pandemic situation is beginning to improve thanks to the development of vaccines, the emergence of multiple new SARS-CoV-2 strains make it difficult to predict the long-term protective effects of the available shots. It is therefore clear that one of the best existing strategies is the identification of vulnerable populations. Thus, the aim of the present study is to focus on vascular liver diseases and characterize the effects of SARS-CoV-2 infection in this population. The strength of our study rests in the approach and methodology used. For this study, a thorough investigation was performed and we were able to contact 80% of our patients, thus J o u r n a l P r e -p r o o f making highly unlikely a selection bias. Estimations of the real prevalence of the disease, also detecting asymptomatic patients, would have required testing of all VLD patients. However, this is not a real option and we consider that our approach is a good surrogate given that the general population underwent the same testing policy. Our results can be summarized in three important messages: 1) The prevalence of SARS-CoV-2 infection among patients with PSVD and SVT seems to be higher than in general population. On the contrary, in patients with BCS the prevalence was very similar to general population. Of note, as detailed in Table 1 , the prevalence of arterial hypertension was significantly lower in patients with BCS than in patients with PSVD and SVT, which could confer a lower risk of severe COVID-19 disease. There were no statistically significant differences in other factors such as diabetes, smoking or obesity. The higher prevalence in PSVD and SVT seems to not be influenced by patients' age. Only in age group > 70 years-old the prevalence was similar to GP, probably due to the low representation of older patients in our cohort and to a higher concern of these patients in preventing infection. A similar finding regarding absence of differences in older groups was observed in the study by Marjot et al 5 . This study showed that while patients without cirrhosis display an age-related gradient for mortality, mortality in patients with cirrhosis was higher in patients under 40 years. Higher bilirubin and IBD were the only features identified as risk factors for SARS-CoV-2 infection. However, the clinical relevance of these findings is debatable. Liver function is usually well-preserved in both PSVD and SVT and generally is not a matter of concern in these patients. Indeed, the only slightly higher levels of bilirubin found in patients with SARS-CoV-2 infection have no clinical relevance. Regarding inflammatory bowel disease, recent publications specifically focused on assessing the incidence and severity of COVID-19 in patients with Crohn's disease and ulcerative colitis suggest that IBD patients are not at higher risk of COVID-19 than GP 14 . Thus, currently we are compelled to consider these results cautiously and wait for validation in future cohorts. J o u r n a l P r e -p r o o f 2) Our data suggests that patients with SVT and PSVD could have a more severe course of COVID-19 infection than GP. This stronger severity is more evident at younger ages, which could be explained by the fact that VLD predominantly affect younger patients BCS seems to relate differently to SARS-CoV-2 than the rest of VLD. Noticeably, the severity of SARS-CoV-2 infection in patients with BCS is strictly comparable to that of GP. We hypothesize that the absence of portal hypertension in compensated BCS could explain this important difference with PSVD and SVT. Although BCS entails of course the development of portal hypertension, in chronic compensated stages patients will have either developed collateral circulation that effectively decompresses the splanchnic system or will have required the placement of a transjugular portosystemic shunt. This is also suggested by the fact that 37% of our patients with BCS were asymptomatic for COVID-19, which is a higher frequency than in SVT and PSVD. 3) We carefully assessed if well-known high risk factors such as age, diabetes, arterial hypertension, obesity or malignancy, among others, played a role in the evolution and final outcome of the SARS-CoV-2 infection. We also assessed if other concomitant diseases, especially the association to myeloproliferative diseases (very frequent in patients with SVT and BCS) could interfere in its severity. Of all the parameters evaluated, diabetes mellitus and previous hepatic decompensation were the only factors associated with post-infection liver decompensation and with mortality. Admittedly, due to the low number of deaths in our cohort the strength of these results is reduced. However, these results support and point in the direction that the higher prevalence and higher severity of COVID-19 in patients with PSVD and SVT is due to the VLD per se and is not influenced by associated comorbidities (with the exception of diabetes mellitus facilitating hepatic decompensation). Of note, although the interpretation of these results is limited by not having a comparable control group, comorbidities such as obesity, diabetes mellitus or arterial hypertension had a lower prevalence in our cohort than in both the Spanish and French GP (in our cohort prevalence of diabetes mellitus, arterial hypertension and obesity was 10%, 17% and 12% respectively vs 13.8%, 42% and 23% in the Spanish population and 8%, 30% and 26% in the French population), which can J o u r n a l P r e -p r o o f explain why metabolic factors known to increase the risk of severe COVID-19 had a low impact in the outcome of our cohort. Finally, it is remarkable that although most VLD are associated with a hypercoagulable state and COVID-19 is also considered a prothrombotic condition 16 , the rate of thromboembolic events was unexpectedly low. Although this is an important finding, in this observational study no systemic imaging tests looking for thrombotic events were performed and thus asymptomatic thrombotic events could have been underdiagnosed. Accordingly, no strong recommendations regarding venous thromboembolism prophylaxis and anticoagulation can be made based on our results. In conclusion, this international study shows that PSVD and SVT patients could be at higher risk of infection by SARS-CoV-2 and, importantly, point in the direction that they could also be at higher risk of severe COVID-19 disease. Our results have significant implications for the management and risk stratification of patients with VDL, for both the present pandemic and for future hypothetic outbreaks of new SARS-CoV-2 strains. Future research should be directed at vaccination programs, as data regarding duration of protection, tolerability and long-term safety of COVID-19 vaccines in patients with VLD has yet to be generated. In this regard, as it is known that some patients do not mount a strong immune response to the vaccines and taking into consideration the higher risk of severe COVID-19 disease in VLD, it would seem reasonable to recommend checking the anti-SARS-CoV-2 antibody levels after full vaccination in this population and administer a third dose to all patients not showing good antibody response. 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United Acute splanchnic vein thrombosis in patients with COVID-19: A systematic review What you need to know Background: It is unknown whether patients with vascular liver diseases constitute a high-risk population for complications and greater mortality from SARS-CoV-2 infection Findings: Patients with portosinusoidal vascular disorder and patients with splanchnic vein thrombosis could be at higher risk of infection by SARS-CoV-2 and at higher risk of severe COVID-19 disease. Implications for patient care: Given the higher risk of severe COVID-19 disease in this population, it would seem reasonable to recommend checking the anti-SARS-CoV-2 antibody levels after full vaccination in patients with vascular liver diseases and administer a third dose to all patients not showing good antibody response J o u r n a l P r e -p r o o f 1217 patients 539